an atlas of investigation and management hiv/aids hiv-aids chp1.pdf · a catalogue record of this...

HIV/AIDSAlison J Rodger • Tabitha W Mahungu • Margaret A Johnson

CLINICAL PUBLISHING

An Atlas of Investigation and Management

CL

INIC

AL

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HIV/AIDSAuthors based at a leading centre for the study andtreatment of HIV present a comprehensive andaccessible introduction to HIV and AIDS. Thisillustrated guide begins with epidemiology andpathogenesis, followed by coverage of newinterventional therapies for HIV infection and theirside effects. Also discussed are treatments for thenumerous systemic and metabolic diseases thataccompany, or result from, HIV infection such ascardiovascular disease, liver disease, neurologicdisorders, opportunistic infections and malignancies.The authors also address the sensitive issuessurrounding conception and pregnancy in couplesaffected by HIV.

A useful visual reference for clinicians specializing inthe treatment of HIV and AIDS, as well as a valuabletool for hospital physicians and trainees.

Related titles:

Problem Solving in Infection, S Dancer, A SeatonISBN 978 1 904392 83 5

Emerging Infections: Atlas of Investigation andManagement, R Salata, D BobakISBN 978 1 904392 75 0

Website: www.clinicalpublishing.co.uk

ISBN: 978 1 904392 90 3

HIV

/AID

SR

odger • Mahungu • Johnson

HIV cover 13 mm spine_hl.qxd:288x230mm 9/6/11 08:12

CLINICAL PUBLISHINGOXFORD


HIV/AIDS

Alison J RodgerMBChB, MRCP, FFPH, MSc, DipHIV, MD

Senior Lecturer and Honorary Consultant in HIV and Infectious DiseasesRoyal Free NHS Trust, London, UK

Tabitha W MahunguBMedSci, BM BS, DTM&H, MRCP

Speciality Trainee in Infectious Diseases and Medical MicrobiologyRoyal Free NHS Trust, London, UK

Margaret A JohnsonMBBS, MD, FRCP

Consultant Physician in Thoracic Medicine, Professor of HIV MedicineRoyal Free NHS Trust, London, UK

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Clinical Publishingan imprint of Atlas Medical Publishing LtdOxford Centre for InnovationMill Street, Oxford OX2 0JX, UK

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© Atlas Medical Publishing Ltd 2011

First published 2011

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted,in any form or by any means, without the prior permission in writing of Clinical Publishing or Atlas MedicalPublishing Ltd.

Although every effort has been made to ensure that all owners of copyright material have been acknowledgedin this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions broughtto our attention.

A catalogue record of this book is available from the British Library

ISBN print 978 1 904392 90 3ISBN e-book 978 1 84692 629 7

The publisher makes no representation, express or implied, that the dosages in this book are correct.Readers must therefore always check the product information and clinical procedures with the mostup-to-date published product information and data sheets provided by the manufacturers and themost recent codes of conduct and safety regulations. The authors and the publisher do not acceptany liability for any errors in the text or for the misuse or misapplication of material in this work.

Clinical Publishing and Atlas Medical Publishing Ltd bear no responsibility for the persistence oraccuracy of URLs for external or third-party internet websites referred to in this publication, and donot guarantee that any content on such websites is, or will remain, accurate or appropriate.

Back cover, top image: reproduced with permission from Cornelia Büchen-Osmond, Columbia University

Colour reproduction by Henry Ling, Dorchester Press, Dorset, UKPrinted by Marston Book Services Ltd, Abingdon, Oxon, UK

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Preface viiAcknowledgements viiContributors viiiAbbreviations ix

1 Introduction 1TW MAHUNGU

History of the HIV epidemic 1Transmission of HIV infection 3Natural history of HIV infection 4Classification of HIV infection 5HIV testing 7References 12Further reading 12

2 Pathogenesis of HIV infection 13HIV virology 13AM GERETTI, C BOOTH

Virus classification 13Virus structure 16Viral genome 16HIV replication 18HIV tropism 18HIV replication dynamics, genetic

variability, and fitness 20Virological assays used to diagnose and

monitor HIV infection 21References 23

HIV and the immune system 25S KINLOCH-DE LOES, C CELLERAI

HIV transmission and immunopathogenesis 25

Immune responses 26CD4 T-cell depletion 28Chronic immune activation 28

HIV-1 prophylactic vaccine 29Conclusion 29References 29

3 Treatment of HIV infection 31AJ RODGER, N MARSHALL, AM GERETTI, C BOOTH

Assessment of the new HIV patient 31When to start treatment 32HIV treatment and guidelines 37Monitoring treatment response 38Toxicities and side-effects 41The future 44

Antiretroviral drug resistance 46References 50Further reading 52

Appendices to Chapter 3: antiretroviral drug dosing guidelines 53

4 Clinical management issues in HIV patients 61Common clinical scenarios 61AJ RODGER, TW MAHUNGU, M HELLER, K CWYNARSKI, S BHAGANI, J GREEN, N MARSHALL

Pyrexia of unknown origin 61Dyspnoea 63Diarrhoea 65

Haematological abnormalities 69M HELLER, K CWYNARSKI

Cytopenias 69Clotting disorders 73

Contents

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vi Contents

Liver disease and viral hepatitis co-infections 74AJ RODGER, S BHAGANI

Viral hepatitis co-infection 74HIV/HBV co-infection 74Cryptogenic cirrhosis and noncirrhotic

portal hypertension 77Noninvasive investigation of liver

fibrosis 78References 80Further reading 81

HIV and the central nervous system 82J GREEN, AJ RODGER, N MARSHALL

Introduction 82Presentation of disease and general

management 83Meningitis 83Space-occupying lesions 87Encephalitis 92HIV encephalopathy 92HIV associated neurocognitive

impairment 92Progressive multifocal

leukoencephalopathy 94Immune reconstitution disease of

the CNS 94Spinal cord disease 95Peripheral neuropathy 97References 97

Metabolic complications 98D NAIR, AJ RODGER

Epidemiology 98Cardiovascular risk factors in patients

with HIV infection 98Screening for metabolic disease 101Management of dyslipidaemia 102Management of hypertension 103Conclusion 103References 104Further reading 104

5 HIV and opportunistic infections 105AJ RODGER, TW MAHUNGU, M LIPMAN, N MARSHALL

Introduction 105Pneumocystis jirovecii

pneumonia (PCP) 105Candidiasis 109Mycobacterium tuberculosis 110Atypical mycobacteria 122Varicella-zoster virus 125Cytomegalovirus 126Herpes simplex 129

6 HIV and malignancies 131Kaposi’s sarcoma 131M KRONFLI, C COLLIS

Introduction 131Aetiology 132Diagnosis 134Management 138References 140

Haematological malignancies and HIV 142M HELLER, K CWYNARSKI

AIDS-related lymphoma (ARL) 142Multicentric Castleman’s disease 146Further reading 148

7 Reproduction and prevention 149HIV and pregnancy 149R SHAH, TW MAHUNGU

Introduction 149Mother-to-child transmission of HIV 150

Conception in HIV serodiscordant couples 158TW MAHUNGU, R SHAH

Horizontal transmission 158

Post-exposure prophylaxis of HIV infection following sexual andoccupational exposure 160TW MAHUNGU, R SHAH

Post-exposure prophylaxis 160

Index 165

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vii

AcknowledgementsWe would like to extend our heartfelt thanks to the HIV-infected individuals without whom publication of this atlaswould have been impossible. We are grateful to AndrewGardner, Head of Medical Illustration at the UniversityCollege of London Medical School and his colleagues fortheir expert help with the preparation and processing of theimages. We thank all our colleagues in the Department ofHIV Medicine at the Royal Free NHS Trust for supportingthis project and giving their time to contribute to thispublication.

We are also grateful to the following individuals forproviding images from their personal collections forinclusion in this publication:

Ian Cropley, Consultant in Infectious Diseases, Royal FreeNHS Trust, London; Amar Dhillon, Consultant

Histopathologist, Royal Free NHS Trust, London; MalcolmGalloway, Consultant Neurohistopathologist, Royal FreeNHS Trust, London; Lucy Melly, ConsultantHistopathologist, Royal Free NHS Trust, London; ColmO’Mahony, Consultant in HIV, Countess of ChesterFoundation Trust Hospital, Chester; John Williams, SeniorPrincipal Clinical Scientist, London School of TropicalMedicine and Hygiene, London; Pauline Wilson,Consultant Ophthalmologist, Royal Free NHS Trust,London; James Kalmakoff, Associate Professor, Departmentof Microbiology and Immunology, University of Otago,New Zealand; Victor Hoffbrand, Professor, Department ofHaematology, Royal Free NHS Trust, London; RobShorten, Clinical Scientist, Royal Free NHS Trust,London.

PrefaceThe advent of effective antiretroviral therapy 15 years agohas led to a dramatic improvement in the life expectancy ofpatients with HIV infection. Consequently, our wards nowhave many fewer admissions of patients with opportunisticinfections and AIDS-related malignancies. As we now seevery few of these complications on a regular basis togetherwith new clinical problems that our patients face, there is areal need for an atlas of this kind. Increasingly, we arelooking after patients with the complications of living long-term with HIV infection and the complications ofantiretroviral therapy, and these are covered in this atlas.

Many admissions are now due to late diagnosis and so

there is a very pressing need for our clinical colleagues inboth primary and secondary care to advocate testing of theirpatients whenever HIV could be considered as part of adifferential diagnosis.

This atlas will be a valuable resource across the spectrumof medicine and, as with any publication with manycontributors, this is a posy of other man’s flowers and I wishto thank all the contributors for their huge effort inproducing this book.

Margaret A Johnson

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ContributorsSanjay BhaganiDepartment of Infectious DiseasesRoyal Free NHS TrustLondon, UK

Claire BoothDepartment of VirologyRoyal Free NHS TrustLondon, UK

Cristina CelleraiDepartment of ImmunologyRoyal Free NHS TrustLondon, UK

Christopher CollisDepartment of OncologyRoyal Free NHS TrustLondon, UK

Ian CropleyDepartment of Infectious DiseasesRoyal Free NHS TrustLondon, UK

Kate CwynarksiDepartment of HaematologyRoyal Free NHS TrustLondon, UK

Anna Maria GerettiDepartment of VirologyRoyal Free NHS TrustLondon, UK

Justin GreenDepartment of Infectious DiseasesRoyal Free NHS TrustLondon, UK

Marc HellerDepartment of HaematologyRoyal Free NHS TrustLondon, UK

Margaret A JohnsonDepartment of HIV MedicineRoyal Free NHS TrustLondon, UK

Sabine Kinloch-de LoesDepartment of HIV MedicineRoyal Free NHS TrustLondon, UK

Miranda KronfliDepartment of OncologyRoyal Free NHS TrustLondon, UK

Marc LipmanDepartment of Respiratory MedicineRoyal Free NHS TrustLondon, UK

Tabitha W MahunguDepartment of HIV MedicineRoyal Free NHS TrustLondon, UK

Neal MarshallDepartment of HIV MedicineRoyal Free NHS TrustLondon, UK

Devaki NairDepartment of Clinical BiochemistryRoyal Free NHS TrustLondon, UK

Alison J RodgerDepartments of Infectious Diseases and HIV MedicineRoyal Free NHS TrustLondon, UK

Rimi ShahDepartment of HIV MedicineRoyal Free NHS TrustLondon, UK

viii

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ix

AbbreviationsABC abacavirADAMTS-13 ADAM metallopeptidase

with thrombospondin type 1 motifADC AIDS dementia complexADCC antibody-dependent cellular

cytotoxicityADI AIDS-defining illnessAFB acid-fast bacilliAFP alpha-fetoproteinAIDS acquired immunodeficiency

syndromeAITP autoimmune thrombocytopeniaALT alanine aminotransferaseAMI acute myocardial infarctionARL AIDS-related lymphomaART antiretroviral treatmentAST aspartate aminotransferaseARV antiretroviralATV atazanavirAUC area under curveAUROC area under the receiver

operating characteristic curveAXR abdominal X-rayAZT azidothymidine (zidovudine)BAL bronchoalveolar lavageBBB blood–brain barrierBCG bacillus Calmette-GuérinBHIVA British HIV AssociationBMI body mass indexCAP community acquired pneumoniaCCR5 chemokine receptor type 5CDC Centers for Disease Control and

PreventionCHOP cyclophosphamide, doxorubicin,

vincristine, prednisoloneCM cryptococcal meningitisCML chronic myeloid leukaemiaCMV cytomegalovirusCNS central nervous systemCPAP continuous positive airway

pressureCRAG cryptococcal antigenCRF circulating recombinant formCRP C-reactive proteinCSF cerebrospinal fluidCT computed tomographyCTL cytotoxic T lymphocyte

CVD cardiovascular diseaseD4T stavudineDAT direct antiglobulin (Coombs) testDBP diastolic blood pressureDC dendritic cellDDI didanosineDLBCL diffuse large B-cell lymphomaDM diabetes mellitusDNA deoxyribonucleic acidDRV darunavirEACS European AIDS Clinical SocietyEBV Epstein–Barr virusECS elective caesarean sectionEFV efavirenzeGFR estimated glomerular filtration

rateELISA enzyme-linked immunosorbent

assayEMU early morning urineFBC full blood countFDA Food and Drug AdministrationFDG fluorodeoxyglucoseFNA fine-needle aspirateFPV fosamprenavirFTC emtricitabineG6PD glucose-6-phosphate GIST gastrointestinal stromal

carcinomaGUM genitourinary medicineH&E haematoxylin and eosin (stain)HAART highly active antiretroviral

therapyHbA1c glycosylated haemoglobinHBeAg hepatitis B e antigenHBsAb hepatitis B surface antibodyHBsAg hepatitis B surface antigenHBV hepatitis B virusHCC hepatocellular carcinomaHCV hepatitis C virusHDL-c high-density lipoprotein

cholesterolHHV human herpesvirusHIV human immunodeficiency virusHIVAN HIV-associated nephropathyHPA Health Protection AgencyHPLC high-performance liquid

chromatography

HSCT haematopoietic stem celltransplantation

HSR hypersensitivity reactionHSV herpes simplex virusHT hypertensionHTN hypertensionHUS haemolytic uraemic syndromeICP intracranial pressureIFAT immunofluorescent antibody testIFN interferonIGRA interferon gamma release assayIGT impaired glucose toleranceIHD ischaemic heart diseaseIL interleukinIRIS immune reconstitution

inflammatory syndromeITU intensive care unitIVDU intravenous drug userKS Kaposi’s sarcomaKSHV Kaposi’s sarcoma-associated

herpesvirusLDH lactic dehydrogenaseLDL-c low-density lipoprotein

cholesterolLFT liver function testLGV lymphogranuloma venereumLP lumbar punctureLPV lopinavirLTBI latent TB infectionLTR long terminal repeatMAC Mycobacterium avium

intracellulare complexMAI Mycobacterium avium

intracellulareMC&S microscopy, culture, and

sensitivityMCD multicentric Castleman’s diseaseMCV mean cell volumeMDR multidrug-resistantMDT multidisciplinary team meetingMRI magnetic resonance imagingMSM men who have sex with menMTB Mycobacterium tuberculosisMTCT mother-to-child transmissionNAb neutralizing antibodyNASBA nucleic acid sequence based

amplification

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Abbreviationsx

NHL non-Hodgkin’s lymphomaNK natural killer (cell)NNRTI non-nucleoside reverse

transcriptase inhibitorNPA nasopharyngeal aspirateNPV negative predictive valueNRTI nucleoside reverse transcriptase

inhibitorNtRTI nucleotide reverse transcriptase

inhibitorNVP nevirapineOD opportunistic diseaseOGD oesophagogastroduodenoscopyOHL oral hairy leukoplakiaOI opportunistic infectionPACTG Pediatric AIDS Clinical Trials

GroupPAP Papanicolaou (stain)PCP Pneumocystis jiroveci pneumoniaPCR polymerase chain reactionpegIFN pegylated interferonPEP post-exposure prophylaxisPEPSE PEP after sexual exposurePET positron emission tomographyPGL persistent generalized

lymphadenopathyPI protease inhibitorPK pharmacokinetic

PML progressive multifocalleukoencephalopathy

POEMS polyneuropathy,organomegaly, endocrinopathy,monoclonal gammopathy, and skinchanges

PORN progressive outer retinalnecrosis

PPD purified protein derivativePPV positive predictive valuePrEP pre-exposure prophylaxisPUO pyrexia of unknown originRAL raltegravirRCC red cell count/renal cell

carcinomaRNA ribonucleic acidRT reverse transcriptaseRVR rapid virological responseSBP systolic blood pressureSIV simian immunodeficiency virusSJS Stevens–Johnson syndromeSOL space-occupying lesionSPECT single photon emission

computed tomographySQV saquinavirSTI sexually transmitted infectionSVD spontaneous vaginal deliverySVR sustained virological response

TB tuberculosisTBM tuberculous meningitisTC total cholesterolTDF tenofovirTDM therapeutic drug monitoringTEN toxic epidermal necrolysisTG triglycerideTh helper T lymphocyteTLR Toll-like receptorTNF tumour necrosis factorTreg T regulatory cellTST tuberculin skin testTTP thrombotic thrombocytopenic

purpuraULN upper limit of normalURF unique recombinant formVDRL Venereal Disease Research

LaboratoryVEGF vascular endothelial growth

factorVL viral loadvWF von Willebrand factorVZV varicella zoster virusWHO World Health OrganizationXDR extensively drug-resistantZDV zidovudineZN Ziehl–Neelsen (stain)

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Chapter 1

1.1 Key events leading up to the era of HAART. AZT: azidothymidine; HIV: human immunodeficiency virus; MSM: menwho have sex with men; PCP: Pneumocystis jirovecii pneumonia.

1

bounds (1.1). The greatest has been the advent of highlyactive antiretroviral therapy (HAART) in the mid-1990sresulting in the transformation of HIV infection from aterminal illness into a manageable chronic disease.Unfortunately, despite the fact that many resource-poorcountries have made considerable progress in improvingaccess to HIV prevention and treatment, universal access isyet to be achieved. According to the Joint United NationsProgramme on HIV/AIDS (UNAIDS) there wereapproximately 33 million people living with HIV infectionat the end of 2009 (1.2). Sub-Saharan Africa continues toaccount for over two-thirds of the epidemic (1.3). Despitethese alarming figures, the prevalence of HIV infection inadults appears to have levelled off over the last 7 years. Weremain hopeful that by 2015 universal access will become areality to all affected populations in line with theMillennium Development Goals.

History of the HIV epidemic

The first cases of acquired immunodeficiency syndrome(AIDS) were reported in 1981 by the Centers for DiseaseControl and Prevention (CDC) after the emergence ofbiopsy-confirmed pneumocystis pneumonia in five young,previously healthy male homosexuals1. Incidentally all fivepatients had a history of cytomegalovirus infection andcandidiasis. These initial reports were subsequentlyfollowed by a cluster of cases of pneumocystis pneumoniawith Kaposi’s sarcoma also in male homosexuals. InUganda, physicians were confronted by an equally bafflingfatal, wasting, diarrhoeal illness which they referred to as‘slim disease’2. The aetiology of this devastating illnessremained unknown until 1983 when the retrovirus wasisolated by Luc Montagnier’s3 and Robert Gallo’s4 group,linking human immunodeficiency virus (HIV) to AIDS.

The HIV epidemic is just under three decades old.During this period, there have been several leaps and

IntroductionTW Mahungu

1981 1982 1983 –4 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 –6

PCP in MSM Los Angeles

Isolation ofretrovirus

Era of HAARTbeins

HIV viral loadtesting becomes

availableAZT

approvedFirst antibodytest approved

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Introduction2

1.2 Number of people living with HIV and percentage adult HIV prevalence.Solid lines, estimates; dotted lines ranges. (Adapted from UNAIDS data2010.)

1.3 Adult (age 15–49 years) prevalence of HIV by geographical regions. (Adapted from UNAIDS data 2010.)

Number of people living with HIV4035302520151050

’90 ’91 ’92 ’93 ’94 ’95 ’96 ’97 ’98 ’99 ’00 ’01 ’02 ’03 ’04 ’05 ’06 ’07 ’08 ’09

Adult and child deaths due to AIDS2.52.01.51.00.50.0

’90 ’91 ’92 ’93 ’94 ’95 ’96 ’97 ’98 ’99 ’00 ’01 ’02 ’03 ’04 ’05 ’06 ’07 ’08 ’09

Mill

ions

Mill

ions

No data <0.1% 0.1–0.5% 0.5–<1% 1–<5% 5–<15% >15–28%


Transmission of HIV infection

HIV infection can be transmitted viaSexual intercourseUnprotected sexual intercourse is the most common routeof HIV transmission, accounting for up to 85% of allinfections5. There is no doubt that an individual is at theirmost infectious during primary HIV infection when thevirus undergoes extensive, uncontrolled replication withHIV viral loads frequently exceeding a million copies permillilitre. The risk of transmission is amplified in receptiveanal intercourse and by the presence of concurrent sexuallytransmitted infections. Studies in serodiscordantheterosexual couples have shown that in established HIVinfection, the risk of transmission is highly dependent onthe plasma HIV viral load6.

Contaminated blood and blood productsAfter the development of the first HIV antibody test in1985, most industrialized countries adopted universalscreening of all blood donations for HIV infection.Unfortunately, due to financial constraints the risk ofacquiring HIV infection from contaminated blood and

Introduction 3

blood products remains a reality in many resource-poorcountries. Outside sub-Saharan Africa sharing unsterilizedneedles and syringes remains an important route oftransmission in intravenous drug users.

Mother to child transmissionThe prevention of mother to child transmission (MTCT)remains one of the most successful HIV preventionstrategies. In an antiretroviral-naïve pregnant mother, thereis a 30% risk of transmitting HIV infection in utero or atdelivery. Most of the transmission occurs in the thirdtrimester and at delivery but there remains a residual risk ofinfection through breastfeeding. Where the appropriatemeasures are taken to prevent MTCT, the risk of verticaltransmission falls to less than 1%7. As the rate oftransmission is governed by the availability of effectiveantiretroviral therapy, the rates of MTCT in other parts ofthe world reflect local practice.

The factors determining HIV infectivity and the risk ofHIV transmission by route of exposure are summarized inTables 1.1 and 1.2. FACTOR

Host

Genetics• Host genetic factors determine susceptibility, e.g.

CCR5-Δ32 deletion confers high level of protection

EnvironmentBarriers• Direct inoculation into blood stream more efficient than

via mucous membranes• Transmission determined by the integrity of the

mucous membrane, e.g. STIs increase transmission,circumcision reduces transmission

High-risk practices• Risk increases with number of high-risk sexual

partners, contaminated needles

Agent

HIV virus• HIV-2 less easily transmitted than HIV-1• In-vitro studies have shown that some subtypes are

more infectious

HIV viral load• HIV viral load is one of the strongest predictors of

transmission

Table 1.1 Factors determining HIV infectivity


Exposure Estimated risk of transmission per exposure (%)

Blood transfusion 90–100

Mother to child 30

Anal intercourseReceptive 0.1–3.0Insertive 0.06

Vaginal intercourseReceptive 0.1–0.2Insertive 0.03–0.09

Receptive oral sex (fellatio) 0–0.04

Needle stick injury 0.3

Sharing injecting equipment 0.67

(Adapted from Fisher M, et al. Int J STD & AIDS2006;17:81–92)

Table 1.2 Risk of HIV transmission by route ofexposure

1.4 Natural history ofuntreated HIV infection.RNA: ribonucleic acid.

4 Introduction

Natural history of HIV infection

There are three distinct phases in the natural history ofuntreated HIV infection (see 1.4).

Primary HIV infection is often missed or misdiagnosed aspatients may be asymptomatic or the clinical presentationresembles a nonspecific viral illness. This period lasts fromthe time of HIV transmission to the moment an individualmounts a detectable antibody response. During this phase,there is extensive viral replication resulting in a markeddrop in CD4 cells. The CD4 count normally bounces backup but to levels lower than the pre-infection count.

Following acute HIV infection, a viral set point, which isgoverned by the unique immune response of the host to thevirus, is reached. Patients now enter the next phase ofchronic HIV infection. During this phase there is a steadydecline of CD4 cells. Towards the end of this phase patientsmay begin to experience constitutional symptoms anddevelop illness referred to as indicator diseases. The rate ofCD4 cell decline is variable with a small minority neverprogressing to AIDS, i.e. ‘long term nonprogressors’. Withinthis group lies a subset of individuals who control HIVreplication to undetectable levels, i.e. ‘elite controllers’.

Once an individual’s CD4 count drops below 200cells/mm3, they have advanced HIV infection and are at riskof developing a number of opportunistic diseases. Althoughrare, there are well documented reports of opportunisticinfections occurring in patients with CD4 cell counts above200 cells/mm3.

0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11Weeks Years

1,200

1,100

1,000

900

800

700

600

500

400

300

200

100

0

107

106

105

104

103

102

CD

4 T

lym

phoc

yte

coun

t (c

ell/m

m3 )

HIV

RN

A c

opie

s/m

l pla

sma

Primaryinfection

Acute HIV syndrome wide dissemination of virus seeding of lymphoid organs

Clinical latency

Viral set point

Constitutionalsymptoms

Opportunisticdisease

Death


Primary • Asymptomatic• Acute retroviral syndrome

Clinical stage I• Asymptomatic• Persistent generalized lymphadenopathy (PGL)

Clinical stage II• Weight loss (<10% of body weight)• Mucocutaneous disease, e.g. seborrhoeic dermatitis,

recurrent oral ulceration• Herpes zoster (within last 5 years)• Recurrent upper respiratory tract infections

Clinical stage III• Weight loss (>10% of body weight)• Chronic diarrhoea (>1 month)• Unexplained fever (>1 month)• Oral candida• Oral hairy leukoplakia• Pulmonary tuberculosis (within past year)• Severe bacterial infection

Clinical Stage IV• HIV wasting syndrome• Pneumocystis jirovecii pneumonia• Cerebral toxoplasmosis• Diarrhoea secondary to cryptosporidiosis (exceeding

1 month)• Extrapulmonary cryptococcosis• CMV disease (of any organ other than liver, spleen,

and lymph nodes)• Herpes simplex• Progressive multifocal leukoencephalopathy• Disseminated endemic mycosis• Oesphageal, tracheo-bronchial candidiasis • Disseminated atypical mycobacteria• Nontyphoid salmonella septicaemia• Extrapulmonary tuberculosis• Lymphoma• Kaposi’s sarcoma• HIV encephalopathy

Table 1.3 WHO clinical staging of HIV infection

A B CCD4 Asymptomatic Symptomatic AIDS-defining(cells/mm3) PGL conditions conditions

Acute HIV (excluding A or C)

≥500 A1 B1 C1

200–499 A2 B2 C2

<200 A3 B3 C3

(Adapted from CDC data: http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm)

Table 1.4 CDC classification system of HIV infection

Introduction 5

Classification of HIV infection

The Centers for Disease Control and Prevention (CDC)and the World Health Organization (WHO) have developedstaging systems that classify patients on the basis of certainclinical conditions and infections. The WHO system isreliant on clinical symptoms as laboratory evaluations are

not always available in resource-poor settings. The CDCsystem on the other hand consists of a composite ofassociated clinical conditions and infections and the CD4count. These are summarized in Tables 1.3–1.5.

(Adapted from WHO data: http://www.who.int/hiv/pub/guidelines/HIVstaging150307.pdf)


Table 1.5 CDC symptomatic and AIDS-defining conditions

PresentationAcute HIV-I infection is symptomatic in 40–90% of allcases. The most common symptoms include:• A triad of fever, maculopapular rash (upper trunk), and

lymphadenopathy.• Oropharyngeal ulceration.• Other manifestations are summarized in Table 1.6.

Important differential diagnoses include: Epstein–Barrvirus (EBV) infectious mononucleosis, toxoplasmosis,

6 Introduction

Primary HIV infectionPrimary HIV infection is classically described as an ‘acutemononucleosis-like illness’ occurring between 2 and 6weeks after HIV infection8. It normally lasts for between 1and 2 weeks but can last considerably longer in a minorityof cases. Unfortunately, the seroconversion illness is oftenmissed. The diagnosis of HIV infection is often late with asignificant number of patients presenting with anopportunistic infection several years after seroconversion.

Symptomatic conditions

• Bacillary angiomatosis

• Oropharyngeal candidiasis

• Vulvovaginal candidiasis, persistent or resistant

• Pelvic inflammatory disease

• Cervical dysplasia/cervical carcinoma in situ

• Oral hairy leukoplakia

• Idiopathic thrombocytopenic purpura

• Constitutional symptoms, such as fever or diarrhoealasting >1 month

• Peripheral neuropathy

• Herpes zoster (≥2 episodes or ≥1 dermatome)

AIDS-defining conditions

• Recurrent bacterial pneumonia

• Candidiasis of the bronchi, trachea, or lungs

• Oesophageal candidiasis

• Cervical carcinoma, invasive, confirmed by biopsy

• Coccidioidomycosis (disseminated or extrapulmonary)

• Extrapulmonary cryptococcosis

• Chronic intestinal cryptosporidiosis

• CMV disease (other than liver, spleen, or nodes)

• HIV encephalopathy

• Herpes simplex: chronic ulcers or bronchitis, pneumonitis, or oesophagitis

• Histoplasmosis (disseminated or extrapulmonary)

• Chronic intestinal isosporiasis

• Kaposi’s sarcoma

• Lymphoma

• Atypical mycobacteria (disseminated orextrapulmonary)

• Mycobacterium tuberculosis, pulmonary orextrapulmonary

• Pneumocystis jirovecii pneumonia (PCP)

• Progressive multifocal leukoencephalopathy (PML)

• Salmonella septicaemia, recurrent (nontyphoid)

• Cerebral toxoplasmosis

• HIV wasting syndrome due to HIV (involuntary weightloss >10% of baseline body weight) associated witheither chronic diarrhoea (≥2 loose stools per day ≥1 month) or chronic weakness and documented fever ≥1 month

(Adapted from CDC data: http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm)


Generalized/constitutional

• Fever

• Lymphadenopathy

• Arthralgia

• Myalgia

• Loss of appetite

• Weight loss

• Malaise

Gastrointestinal

• Abdominal pain

• Nausea and vomiting

• Diarrhoea

• Transaminitis

AIDS-defining illnesses

• Rare

Neurological

• Headache

• Aseptic meningitis

• Transverse myelitis

• Encephalitis

• Peripheral neuropathy

• Guillain–Barré-like syndrome

Dermatological/mucosal

• Rash

• Oral ulceration

• Pharyngitis

Table 1.6 Signs and symptoms of acute HIV infection

7Introduction

benefits of early antiretroviral treatment (ART) are eagerlyawaited. In the meantime, any patients being considered forART during this period should be treated within a clinicaltrial. Recognition of acute HIV infection allows the earlydiagnosis of HIV infection before patients present withopportunistic disease. It also provides an opportunity todecrease onward transmission, as patients tend to be attheir most infectious at this time point.

HIV testing

Throughout the world, HIV infection continues to bediagnosed late. In industrialized nations most of these latediagnoses are in ethnic minorities and marginalized groupswhere heterosexual transmission remains the primary routeof HIV infection. In the United Kingdom (UK) the HealthProtection Agency (HPA) reported that of the estimated86,500 people living with HIV in the UK at the end of2009, 26% were unaware of their infection. Unlinked,anonymous prevalence surveillance reveals that men whohave sex with men (MSM) and sub-Saharan-born

rubella, measles, secondary syphilis, influenza, primaryherpes simplex virus (HSV)/cytomegalovirus (CMV), andviral hepatitis.

DiagnosisThe diagnosis is dependent on the demonstration of HIV-1replication in the absence of HIV-1 antibodies. Followingclinical suspicion, individuals should have both an HIV-1antibody test and HIV-1 ribonucleic acid (RNA)quantification. A new diagnosis must be confirmed with afollow up HIV-1 antibody test during the next 12 weeks.There is often a marked increase in CD8-positive T-cellsduring primary HIV infection, indicating increased immuneactivation.

TreatmentTreatment is often supportive. However, there isconsiderable interest in the use of antiretroviral therapy toshorten the duration of the acute syndrome, therebyreducing the number of infected cells and preserving HIV-1 specific immune responses9. The results of the firstrandomized trial (SPARTAC) powered to investigate the

(Adapted from BHIVA, UK National Guidelines for HIV Testing 2008, BHIVA 2008)


1.5 Estimated number of adults living with HIV (bothdiagnosed and undiagnosed). (Adapted from HPA data,2010.)

1.6 Estimated late diagnosis of HIV infection byprevention group, 2007. (Adapted from HPA data, 2010.)

as well as the very poor prognosis of an AIDS diagnosisresulted in a test that was only performed if an individualhad received pre-test counselling and provided informedconsent. It may be argued that in the long term, in an erawhere HIV is now considered to be a chronic disease, thesemeasures may have contributed to the slow uptake of HIVtesting outside HIV specialist settings. The benefits of earlyHIV testing include:• Identification of HIV-infected individuals as early into

their infection as possible.• Reduction of the onward transmission of HIV infection

to others.

In most healthcare systems, HIV testing occurs in anumber of settings. In one setting, individuals may self-present to genitourinary medicine (GUM) or same-daytesting centres. In another setting, individuals seekingmedical care in specific settings are informed that an HIVtest is routinely performed on everyone unless they explicitlydecline (opt out). This is common practice in UK GUM

8 Introduction

heterosexuals account for the highest proportions ofundiagnosed HIV infection (1.5). Furthermore, 30% of theindividuals newly diagnosed with HIV were diagnosed late,i.e. with a CD4 count below 200 cells/mm3. Theproportion of late diagnoses was highest in heterosexualwomen and men (1.6).

Unfortunately, individuals presenting with advanceddisease are more likely to present with opportunisticinfections and have suboptimal clinical outcomes. Asignificant proportion of these ‘late presenters’ have hadcontact with medical services prior to their diagnosis wherethe opportunity to offer an HIV test has often been missed.There is therefore a need to increase the uptake of HIVtesting in non-HIV clinical settings.

Since the United States of America (USA) Food andDrug Administration (FDA) approved the first HIVantibody test in 1985, HIV testing has evolved from a toolthat was designed to screen blood supplies to a voluntarytest that is offered in healthcare settings. At the beginningof the AIDS epidemic, the fear of stigma and discrimination

MS

M

Het

eros

exua

l men

bor

nin

Afr

ica

Het

eros

exua

l wom

enbo

rn in

Afr

ica

Het

eros

exua

l men

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nin

UK

/els

ewhe

re

Het

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UK

/els

ewhe

re

Inje

ctin

g dr

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ser

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Inje

ctin

g dr

ug u

ser

wom

en

Diagnosed

Undiagnosed

30

25

20

15

10

5

0

Num

ber

(000

s)

80

70

60

50

40

30

20

10

0

Total (15– 59 years = 80,800 (76,500–85,800)Total (all ages) = estimated 86,500

Pro

port

ion

of n

ewdi

agno

ses

(%)

≥50

year

s15

–49

year

s

≥50

year

s15

–49

year

s

≥50

year

s15

–49

year

s

≥50

year

s15

–49

year

s

All MSM Hetero-sexualmen

Hetero-sexualwomen

<200 between 200 and 350

67

50

59 5865

37

73

68

3443

61

47

5342

52

23


Universal testing • Genitourinary medicine clinics• Antenatal care• Termination of pregnancy services• Drug dependency programmes• Patients with TB, hepatitis B/C, lymphoma

Routinely perform (Department of Health Guidance) • Blood donors• Dialysis patients• Organ transplant donors and recipients

Routinely offer• All sexual partners of individuals known to be HIV

positive• All patients diagnosed with a sexually transmitted

disease• All patients with indicator diseases• All injecting drug users• All female and male sexual contacts of men who

have sex with men• All men and women from countries with an HIV

prevalence of >1%• All men and women reporting sexual contact (locally

or abroad) with individuals from countries with an HIV prevalence of >1%

If local HIV prevalence >2/1,000, consider testing • All patients registered in general practice • All general medical admissions

(Adapted from BHIVA, UK National Guidelines for HIVTesting 2008, BHIVA 2008)

Table 1.7 British HIV Association (BHIVA)guidelines for HIV testing

• Explain indication for test• Obtain a thorough and chronological history of sexual

and other high-risk practices• Ascertain whether individual is within ‘window period’• Explain practicalities of test, i.e. how it will be

performed, how and when results will be given• Explain implications of positive test• Give an opportunity to ask questions• Obtain informed consent


Table 1.8 Components of the pre-test discussion

Provide results (should be confidential)

If positive:• Reinforce implications of positive test• General education regarding the natural history of

HIV infection and the current treatment options• Establish whether there is a need for psychological

support• Discuss the need for testing partners or children if

appropriate• Discuss risk-reduction behaviour• Obtain blood test for confirmation of diagnosis• Book patient into new patient clinic within a week

If negative:• Establish whether there is a need for retesting if

individual ‘within window period’• Establish whether post-exposure prophylaxis is

indicated• Discuss risk-reduction behaviour


Table 1.9 Components of the post-test discussion

9Introduction

(BHIVA) guidelines are summarized in Table 1.7. Thisinformation must be disseminated to healthcare workersoutside HIV specialist centres, as this is where patients arelikely to present.

In all settings it is important that the offer of an HIV testremains voluntary and the results confidential. As with anyother medical test it is important that individuals under -stand the implications and results of the test. It is thereforeimportant that patients are counselled before and after thetest. See Tables 1.8, 1.9 for BHIVA recommendations.

and antenatal services, where the uptake of HIV testing is upto 77% and 95% respectively. More frequently, individualspresenting with suggestive symptoms or high-risk behaviourare offered a diagnostic HIV test (opt in).

Since 2006, the CDC recommends universal testing ofALL individuals presenting to a medical facility. In the UKand Europe, there is a move towards more targeted testingwhere local HIV prevalence data as well as the presence ofindicator diseases determine whether HIV testing isroutinely performed10. The British HIV Association



ADULT HIV INFECTIONRespiratory • Tuberculosis• Pneumocystis

Neurology • Cerebral toxoplasmosis• Primary cerebral lymphoma• Cryptococcal meningitis• Progressive multifocal

leukoencephalopathy

Dermatology• Kaposi’s sarcoma

Gastroenterology • Persistent cryptosporidiosis

Oncology• Non-Hodgkin’s lymphoma

Gynaecology• Cervical cancer

Haematology

Ophthalmology• Cytomegalovirus retinitis

ENT

Other conditions where HIVtesting should be considered

• Bacterial pneumonia • Aspergillosis

• Aseptic meningitis/encephalitis• Cerebral abscess• Space-occupying lesion of

unknown cause• Guillain–Barré syndrome• Transverse myelitis• Peripheral neuropathy• Dementia• Leukoencephalopathy

• Severe or recalcitrantseborrhoeic dermatitis

• Severe or recalcitrant psoriasis• Multidermatomal or recurrent

herpes zoster

• Oral hairy leukoplakia • Oral candidiasis • Chronic diarrhoea of unknown

cause• Weight loss of unknown cause• Hepatitis B infection• Hepatitis C infection• Shigella, salmonella, or

campylobacter

• Anal cancer or anal intra-epithelial dysplasia

• Lung cancer• Seminoma• Head and neck cancer• Hodgkin’s lymphoma• Castleman’s disease

• Cervical intraepithelial neoplasia(Grade 2 or above)

• Vaginal intraepithelial neoplasia

• Any unexplained blooddyscrasia including: – lymphopenia– neutropenia– thrombocytopenia

• Any unexplained retinopathy• Infective retinal diseases,

including herpes viruses andtoxoplasma

• Lymphadenopathy of unknowncause

• Lymphoepithelial parotid cysts• Chronic parotitis


ADULT HIV INFECTION (cont.)Other

PAEDIATRIC HIV INFECTIONENT

Oral

Respiratory• Pneumocystis• CMV pneumocystis• Tuberculosis

Neurology • HIV encephalopathy

meningitis/encephalitis

Dermatology• Kaposi’s sarcoma

Gastroenterology • Wasting syndrome• Persistent cryptosporidiosis

Oncology• Lymphoma• Kaposi’s sarcoma

Haematology

Ophthalmology• Cytomegalovirus retinitis

Other• Recurrent bacterial infections,

e.g. meningitis, sepsis,osteomyelitis, pneumonia

• Pyrexia of unknown origin

Other conditions where HIVtesting should be considered

• Mononucleosis-like syndrome(primary HIV infection)

• Pyrexia of unknown origin • Any lymphadenopathy of

unknown cause• Any sexually transmitted

infection

• Chronic parotitis • Recurrent and/or troublesome

ear infections

• Recurrent oral candidiasis• Poor dental hygiene

• Recurrent bacterial pneumonia • Lymphoid interstitial pneumonitis• Bronchiectasis

• Developmental delay• Childhood stroke

• Severe or recalcitrant dermatitis• Multidermatomal or recurrent

herpes zoster• Recurrent funagal infections• Extensive warts or molluscum

contagiosum

• Unexplained persistenthepatosplenomegaly

• Hepatitis B infection• Hepatitis C infection

• Any unexplained blooddyscrasia including: – lymphopenia– neutropenia– thrombocytopenia

• Any unexplained retinopathy

Table 1.10 Clinical indicator diseases for adult and paediatric HIV infection

10 Introduction

(Adapted from BHIVA, UK National Guidelines for HIV Testing 2008, BHIVA 2008)


1.7 Oral hairy leukoplakia. This is one of the mostcommon oral diseases in HIV. It is caused by EBV and ischaracterized by asymptomatic white plaques on thelateral borders of the tongue as well as on the buccalmucosa and the gingiva.

1.8 AIDS retinopathy. Characteristic indented(‘hourglass’) cotton wool spots with an otherwise normalfundus caused by immune complex microthrombi in theretinal vasculature.

1.9 Bacterial pneumonia. Community acquiredpneumonia is 10 times more common in HIV-infectedpatients in comparison to the general population.

1.10 Acute retroviral syndrome. Maculo-papular rashpredominantly affecting the upper trunk. Oftenassociated with fever and lymphadenopathy.

and HIV, and the British Infection Society have compiled alist that contains a number of clinical conditions that ifpresent should alert the clinician to consider HIV infection inthe differential diagnosis (Table 1.10).

Indicator diseases (1.7–1.11)In the HIV context, indicator diseases are defined as diseasesassociated with a co-morbid HIV incidence of significance.All AIDS-defining illnesses are included in this list. BHIVAin conjunction with the British Association of Sexual Health

11Introduction


References

1 Pneumocystis pneumonia – Los Angeles. MMWR MorbMortal Wkly Rep 1981 Jun 5;30(21):250–2.

2 Serwadda D, Mugerwa RD, Sewankambo NK, LwegabaA, Carswell JW, Kirya GB, et al. Slim disease: a newdisease in Uganda and its association with HTLV-IIIinfection. Lancet 1985 Oct 19;2(8460):849–52.

3 Chermann JC, Barre-Sinoussi F, Dauguet C, Brun-Vezinet F, Rouzioux C, Rozenbaum W, et al. Isolationof a new retrovirus in a patient at risk for acquiredimmunodeficiency syndrome. Antibiot Chemother1983;32:48–53.

4 Gelmann EP, Popovic M, Blayney D, Masur H, SidhuG, Stahl RE, et al. Proviral DNA of a retrovirus,human T-cell leukemia virus, in two patients withAIDS. Science 1983 May 20;220(4599):862–5.

5 Royce RA, Sena A, Cates W, Jr., Cohen MS. Sexualtransmission of HIV. N Engl J Med 1997 Apr10;336(15):1072–8.

6 Gray RH, Wawer MJ, Brookmeyer R, Sewankambo NK,Serwadda D, Wabwire-Mangen F, et al. Probability ofHIV-1 transmission per coital act in monogamous,heterosexual, HIV-1-discordant couples in Rakai,Uganda. Lancet 2001 Apr 14;357(9263):1149–53.

Introduction12

7 Mother-to-child transmission of HIV infection in the eraof highly active antiretroviral therapy. Clin Infect Dis2005 Feb 1;40(3):458–65.

8 Jolles S, Kinloch de LS, Johnson MA, Janossy G.Primary HIV-1 infection: a new medical emergency?BMJ 1996 May 18;312(7041):1243–4.

9 Fidler S, Fox J, Porter K, Weber J. Primary HIVinfection: to treat or not to treat? Curr Opin Infect Dis2008 Feb;21(1):4–10.

10 Gazzard B, Clumeck N, d’Arminio MA, Lundgren JD.Indicator disease-guided testing for HIV – the next stepfor Europe? HIV Med 2008 Jul;9(Suppl 2):34–40.

Further reading

HIV in the United Kingdom: 2010 report. HealthProtection Agency. Available at: http://www.hpa.org.uk/

Joint United Nations Programme on HIV/AIDS(UNAIDS). 2010 report on the global AIDS epidemic.Available at: http://www.unaids.org/

WHO case definitions of HIV for surveillance and revisedclinical staging and immunological classification of HIV-related disease. World Health Organization 2007.Available at:http://www.who.int/hiv/pub/guidelines/HIVstaging150307.pdf

Centers for Disease Control and Prevention (CDC). 1993Revised classification system for HIV infection andexpanded surveillance case definition for AIDS amongadolescents and adults. MMWR Recomm Rep 1992 Dec18;41(RR-17):1–19. Available at:http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm).Centers for Disease Control and Prevention (CDC ).Revised Recommendations for HIV testing of adults,adolescents, and pregnant women in health-care settings.MMWR Morb Mortal Wkly Rep 2006;55(RR14):1–17.Available at:http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5514a1.htmBritish HIV Association, British Association of SexualHealth and HIV, British Infection Society. UK NationalGuidelines for HIV Testing 2008.Available at: www.bhiva.org

1.11 Molluscum contagiosum. Characteristic waxy, dome-shaped, umbilicated, flesh coloured papules caused bythe DNA pox virus. They are commonly located on face,neck, axillae, and ano-genital region. Although not listedas an indicator disease in the BHIVA guidelines, inadvanced HIV infection lesions tend to be multiple, larger,and persistent.


Pathogenesis of HIV infection

Chapter 2

HIV virologyAM Geretti and C Booth

Virus classification

Like all members of the Retroviridae family, HIV-1 andHIV-2 share a common step in their replication cycle, i.e.transcription of single-stranded genomic RNA into double-stranded complementary DNA by the viral reversetranscriptase (RT) enzyme.

HIV-1and HIV-2 represent cross-species, zoonoticinfections1–3. All known strains of HIV-1 are closely relatedto SIVcpz (simian immunodeficiency virus of chimpanzees),while the origin of HIV-2 has been traced to SIVsm foundin sooty mangabeys (2.1).

The molecular epidemiology of HIV-1 infection iscomplex and in continuous evolution4. Phylogeneticanalyses identify nine genetically equidistant subtypes

13

within group M of HIV-1, which diverge by 20–30% in theenv gene and 15–22% in the gag gene. Multiple inter-subtype circulating and unique recombinant forms (CRFsand URFs) have also been identified (2.2). In WesternEurope several HIV-1 strains co-circulate, whereas subtypeB accounts for most infections in North America (2.3).

HIV-1 subtypes show important differences in theirgenetic sequences and responses to gene expressionregulatory factors, which influence cellular tropism, kineticsof viral replication, rate of disease progression,susceptibility to antiretroviral drugs, and drug resistancepathways. The classification of HIV-1 and HIV-2 issummarized in Table 2.1.

HIV-1 HIV-2

Family Retroviridae Retroviridae

Genus Lentivirus Lentivirus

Prevalence Global West Africa

Group M (major) >90% of infections worldwide –O (outlier) West AfricaN (non-M/O) West Africa

Subtypes A–D, F–H, J, K (all within Group M) A–HCirculating recombinant forms (CRFs)Unique recombinant forms (URFs)

Related to: SIVcpz SIVsmFound in chimpanzees native to West Africa Found in sooty mangabey(Pan troglodytes troglodytes) (Cercocebus atys)

Table 2.1 Classification of HIV-1 and HIV-2


2.1 Phylogenetic tree; genetic relationship between HIV-1, HIV-2, and SIVcpz. (Reprinted by permission from MacmillanPublishers Ltd: Nature Reviews Microbiology 5(2):141–151, copyright 2007.)

14 Pathogenesis of HIV infection


2.2 Global prevalence of HIV-1 group M subtypes andCRFs. (Adapted from Osmanov S, et al., 20025.)

15Pathogenesis of HIV infection

2.3 Global distribution of HIV-1 group M subtypes and CRFs.

North and CentralAmerica

B

South AmericaB, F1,

CRF12_BF

Western EuropeB

A, C, G

Western AfricaCRF02_AG

East AfricaA, D, C

Central AfricaMost CRFs

A, C, D, G, H, J, K, D, N

South AfricaC

Australia B

Eastern EuropeA,

CRF03_AB

Southeast AsiaCRF01_AE, B

ChinaB

CRF07_BC, CRF08_BC

South AsiaC

C48%

B12%

D5%

CRF_AE3%

Othersubtypesand CRFs

5%

A/CRF_AG27%


2.4 Electron micrograph of HIV particles. (Reproducedwith permission from James Kalmakoff, University ofOtago, New Zealand.)

2.5 Structure of the HIV particle. (Reproduced with permission from Cornelia Büchen-Osmond, Columbia University (A),and the National Institutes of Health, Bethesda (B), NY, USA.)


Virus structure

The HIV particle has a diameter of 120 nm (2.4). Itconsists of:• The core, which contains two single strands of positive-

sense RNA surrounded by a conical capsid, composed ofthe viral p24 protein. The matrix, which is composed ofthe viral protein p17, surrounding the capsid.

• The enve lope, which surrounds the core and iscomposed of two lipid layers derived from the host cellmembrane and containing the viral glycoproteins (gp)120 and 41 (2.5).

Viral genome

The RNA genome is 9.8 kb in size and contains (2.6):• Three structural genes: gag, pol, and env.• Six accessory and regulatory genes: tat, rev, nef, vif, vpr,

and vpu (vpx in HIV-2).• Long terminal repeat (LTR) sequences that flank each

RNA strand.

A B

gp120 dockingglycoprotein

gp41transmembrane

glycoprotein

Capsid

Reversetranscriptase

Lipidmembrane

Matrix

RNA

p24 core protein

gp 120

Single strandedHIV-1 RNA

gp41 transmembrane protein

Lipidbilayer

p17matrix

protein


2.6 Organization of the HIV-1 genome.

Structure Function

Protease Homodimer Cleavage of gag (p55) and gag-pol (p160) Each half composed of 99 amino acids precursor proteins into core proteins and viral

enzymes

Reverse Heterodimer with two subunits: Reverse transcription (RNA-dependent DNA transcriptase • p66: polymerase domain (440 amino acids) + polymerase), ribonuclease (RNaseH), DNA-

C-terminal RNAse H domain (120 amino acids) dependent DNA polymerase• p51: corresponds to polymerase domain of p66

Integrase 288 amino acids Integration of proviral DNA into host genome, 3 domains: N-terminal, catalytic core, and through exonuclease, endonuclease, and C-terminal strand transfer/ligase functions

Table 2.2 HIV enzymes


The gag gene encodes a precursor protein, p55, which iscleaved into the smaller core proteins MA (matrix, p17),CA (capsid, p24), NC (nucleocapsid, p9), and p6.

The pol gene encodes the viral enzymes protease, RT,ribonuclease (RNAseH), and integrase, which areexpressed within the context of a gag-pol precursor

polyprotein (p160). The env gene encodes gp120 andgp41.

The LTR regions control virus production in response toviral or cellular proteins.

The structure and function of major HIV enzymes aresummarized in Table 2.2.

gag pol env

vif vpr rev vpu

tat rev

Core proteins Viral enzymes gp120 and gp41

LTR

LTR


2.7 The life cycle of HIV. (Adapted from a figure supplied by the Gladstone Institute, University of California SanFrancisco, USA.) Drug action points (see Chapter 3): 1: Entry inhibitors (Appendix 3.7); 2: NRTIs (Appendix 3.2), NtRTI(Appendix 3.3), NNRTIs (Appendix 3.5), 3: integrase inhibitors (Appendix 3.6); 5: protease inhibitors (Appendix 3.1).


HIV tropism

Tropism is defined by the virus’s preferential use and thecellular distribution of co-receptors. Although several co-receptors can mediate HIV entry, most strains bind toeither CCR5 or CXCR46,7. Three main phenotypes arerecognized:1 CCR5-using (R5) strains: R5 viruses play a key role in

infection (Table 2.3, 2.8).2 CXCR4-using (X4) strains: X4 viruses tend to become

dominant in advanced infection, but it is still debatedwhether their emergence is the cause or consequence ofdisease progression8–11.

3 Dual tropic (R5/X4) strains: which can use both co-receptors.

HIV replication

The life-cycle of HIV comprises six main steps (2.7).1 Virus entry begins with binding of the viral gp120 to

both the CD4 receptor and one of two main co-receptors(CCR5 or CXCR4) on the target cell. This is followedby a conformational change that allows gp41 to mediatefusion of the viral envelope with the host cell membrane.

2 Once viral nucleic material is released into hostcytoplasm reverse transcription of the viral RNA occursin the cytoplasm producing double-stranded DNA.

3 and 4 The double-stranded DNA migrates to the nucleuswhere it is integrated in to the host genome and transcribed.

5 Assembly of the newly produced viral proteins andgenomic RNA occurs in the cytoplasm, and the new virusparticle is released by budding from the cell surface.

6 Cleavage of the viral polyproteins is required for thefunctional maturation of the virus particle.

Immature viralparticle

Proteasecleavage

61

5

3

4

2

Entryand

fusion

Mature viralparticle

CD4 receptor

CXCR4/CCR5

Reversetranscription

RNA

DNA

Nucleus

Latentprovirus

Activeprovirus

Rev

Gag

PolAssembly and

budding

TatRev

Nef

Integration


2.8 Distribution of the HIV-resistant CCR5-Δ32 allele. Only the frequencies in native populations have been evidenced inAmerica, Asia, Africa, and Oceania. (Adapted from Faure E, et al., 200813.)

R5 X4

Co-receptor CCR5 CXCR4

Natural ligands MIP-1α, MIP-1β, RANTES SDF-1

Cellular targets Macrophages Many cell types including:Subset of memory CD4 T-cells naïve CD4 T-cellsNaïve CD4 T-cells must be activated to memory CD4 T-cellsa memory phenotype to become a target macrophages

Acute infection Dominant Rare

Chronic infection Dominant Rare

Advanced disease Reduced dependence on high CD4/CCR5 Emerge in 40–60% of infected patients, levels for entry, decreased susceptibility to coinciding with expanded cell tropism, inhibition by RANTES, enhanced increased viral replication, immunological pathogenicity deterioration, and disease progression

Host genetics Homozygotes for a 32 bp deletion in CCR5 (CCR5-Δ32) are resistant to infection, heterozygotes have delayed disease progression

Table 2.3 HIV tropism


No data

0.03

0.05

0.07

0.09

0.11

0.13


2.9 Interaction between gp120 and the CCR5co-receptor.

2.10 The HIV envelope glycoprotein 12015–17.


• Has low fidelity, with an estimated error rate of 10-4

nucleotides.• Lacks proof-reading activity therefore nucleotide mis-

incorporations become fixed in the newly producedgenome as point mutations. All mutations can occurdaily, and while some mutants are not functional, otherspersist in plasma and within integrated proviral DNA.Duplications and insertions also occur.

• A further mechanism of genetic diversification isrecombination between virus strains infecting the samecell to produce hybrid progeny virus, mediated by RTjumping between RNA templates during replication20.

Because of the continuous genetic diversification, eachinfected person hosts a variety of related but diverging virusstrains referred to as the viral ‘quasispecies’. Within thecirculating quasispecies, some virus strains predominatewhereas others are present as low-frequency species. At anygiven time, dominant strains are those with the best abilityto infect and replicate, properties defining the viral ‘fitness’.Due to its diversity, the quasispecies can adapt rapidly tochanging ‘environmental’ circumstances such as immuno -logical or drug pressure, or availability of cell targets. Thedynamics of HIV infection are described in Table 2.4.

HIV tropism can be determined in vitro usingrecombinant viruses containing the env gene sequence fromthe patient’s plasma viral RNA to infect cells expressing theCD4 receptor with either CCR5 or CXCR412. Results arereported as R5, X4, or dual tropic/mixed (D/M), and do notdistinguish between dual tropic virus and mixed populationsof R5 and X4 strains. HIV tropism can also be predictedfrom the sequence of the V3 loop in gp120 (2.9, 2.10). Thisis the major determinant of co-receptor use, reflecting thestructural homology between the crown of the V3 loop andthe beta2-beta3 loop in the natural chemokine ligands14.

HIV replication dynamics, geneticvariability, and fitness

HIV infection is characterized by:• High levels of virus replication.• Ongoing genetic diversification. • Rapid virus clearance by the immune system18,19.

The RT enzyme, which is responsible for the productionof double stranded DNA from the viral RNA templateduring virus replication:

Residues involved in CD4 bindingResidues involved in coreceptor binding

gp120

CCR5

C

N

V1/V2

V3

V4

V5


Table 2.4 Dynamics of HIV infection


outcomes. Plasma HIV RNA load (‘viral load’) provides animmediate measure of treatment success, acting as asurrogate marker for immunological and clinicalresponses29. Commercial assays show excellent correlationand reliably detect and quantify all major HIV-1 group Msubtypes and CRFs30. The Abbott assays also detect groupO viruses, but no commercial assay is available for thequantification of group N HIV-1 or for HIV-2.

Molecular viral load assays in routine use in high-incomecountries require expensive instruments and reagents,sophisticated laboratory facilities to minimize the risk ofcontamination, regular and stable electricity supply, andhighly skilled laboratory technicians proficient in molecularbiology techniques (Table 2.6). These factors limit theirimplementation in resource-limited settings. The CavidiExaVirTM Load assay employs a modified ELISA format tomeasure the viral RT enzymatic activity, which in turncorrelates with plasma RNA levels. The assay is suitable foruse in settings with limited infrastructure as it requiressimple equipment and is relatively inexpensive and easy toperform.

HIV replicates preferentially in activated CD4 T-cells.Although most infected cells have a short lifespan, afraction of cells survive long enough to revert to a restingmemory state, thereby allowing HIV persistence as a stable,integrated, and transcriptionally silent provirus, which isunaffected by antiretroviral therapy21,22. In viraemicindividuals, the reservoir is continuously replenished,creating an archive for all viral quasispecies. Latentlyinfected cells can resume full virus production onceactivated, which represents the main barrier to eradicatingthe infection23–25.

Virological assays used to diagnose andmonitor HIV infection

The virological assays listed in Table 2.5 below are used inclinical practice for diagnosis, staging, and monitoring ofthe infection26.

Plasma viral loadVirological monitoring is required during therapy to ensureearly detection of treatment failure and optimal long-term

Virus production:

Half-life of free virus in plasma:

Half-life of virus-producing cells:

Frequency of latently infected cells:

Loss of infected cells:

Reverse transcriptase error rate:

Recombinant events:

Quasispecies:

Viral fitness:

Mutant virus:

Wild-type virus:

Recombinant virus:

109–1010 virus particles per day

A few hours

Less than 1 day

1 in 106 resting CD4 T-cells

108–109 per day

~1 mis-incorporation per genome round

7–30 events per genome round

Swarm of related but divergent strains

Ability to replicate and infect

Virus carrying a mutation of interest

Virus not carrying a mutation of interest

Hybrid progeny of two different parental strains


Assay Application Comment

Antibody Diagnosis Detected 21–25 days after infection

Detects HIV-1 groups M and O

Combined antibody/p24 antigen Diagnosis p24 detected ~6 days earlier than antibody

p24 antigen Diagnosis

Antibody avidity Disease staging Low avidity identifies infection within the previous 4–6 months27,28

Plasma HIV-1 RNA load Diagnosis Acute infection‘viral load’ Detected 9–11 days after infection

Detects HIV-1 groups M ± O

Monitoring Predicts rapidity of CD4 declineMeasures treatment successCorrelates with infectivity

Proviral DNA Diagnosis No commercial assaysVertical HIV transmission or indeterminate antibody status

Resistance testing Monitoring Detection of drug resistance

Tropism testing Monitoring Prior to using CCR5 antagonists

Table 2.5 Assays commonly used to diagnose and monitor HIV-1 infection

Assay type Assay model Quantification range

(copies/ml)

Branched chain DNA Bayer VERSANT HIV-1 RNA assay v. 3.0 50–500,000

Reverse-transcription PCR Roche Amplicor Monitor assay v. 1.5 400–750,000 or

50–75,000

Ligase chain reaction Abbott LCX assay 50–1,000,000

Nucleic acid sequence based BioMérieux Nuclisens HIV-1 QT assay 50–3,000,000

amplification (NASBA)

NASBA + real-time molecular BioMérieux NucliSens EasyQ assay 50–3,000,000

beacon detection

Real-time reverse-transcription PCR Roche COBAS® TaqMan® HIV-1 v.2 assay 20–10,000,000

Abbott RealTime HIV-1 assay 40–10,000,000

RT enzymatic activity measured in Cavidi ExaVir Load v.3 assay ~200–600,000

ELISA format

Table 2.6 HIV-1 viral load assays



Advantages Disadvantages

Rapid, provide results in <30 min Expensive

Detect antibodies against: Show reduced sensitivity in early infection compared with

Group M and Group O HIV-1 and HIV-2 laboratory assays

Require simple equipment Prone to operator errors

Easy to perform and interpret Subjective interpretation of results

Avoid venopuncture May give false-positive results

Include a positive control Reactive results require immediate laboratory confirmation

Perform well compared with laboratory Quality assurance requires complex arrangements

methods

Table 2.7 Point-of-care HIV antibody tests


References

1 Hahn BH, et al. AIDS as a zoonosis: scientific and publichealth implications. Science 2000;287(5453):607–14.

2 Lemey P, et al. Tracing the origin and history of theHIV-2 epidemic. Proc Natl Acad Sci USA2003;100(11):6588–92.

3 Keele BF, et al. Chimpanzee reservoirs of pandemic andnonpandemic HIV-1. Science 2006;313(5786):523–6.

4 Geretti AM. HIV-1 subtypes: epidemiology andsignificance for HIV management. Curr Opin Infect Dis2006;19(1):1–7.

5 Osmanov S, et al. Estimated global distribution andregional spread of HIV-1 genetic subtypes in the year2000. J Acquir Immune Defic Syndr2002;29(2):184–90.

6 Feng Y, et al. HIV-1 entry cofactor: functional cDNAcloning of a seven-transmembrane, G protein-coupledreceptor. Science 1996;272(5263):872–7.

7 Berger EA, Murphy PM, Farber JM. Chemokinereceptors as HIV-1 coreceptors: roles in viral entry,tropism, and disease. Ann Rev Immuno l1999;17:657–700.

8 Connor RI, et al. Change in coreceptor use correlateswith disease progression in HIV-1-infected individuals. JExp Med 1997;185(4):621–8.

9 Kinter A, et al. Chemokines, cytokines and HIV: acomplex network of interactions that influence HIVpathogenesis. Immunol Rev 2000;177:88–98.

Rapid HIV antibody assays for point-of-caretestingRapid HIV tests for point-of-care or near-patient testing useeither capillary blood collected by finger-prick or thecrevicular transudate from capillaries collected beneath thetooth-gum margin (‘oral fluid’). They are most useful:• In settings where rapid availability of results can

immediately guide management (e.g. in pregnantwomen who present during labour, or prior to the use ofpost-exposure prophylaxis).

• In clinical settings where a significant proportion ofpersons tested by laboratory methods fail to return fortheir results.

• Or in out-reaching initiatives to provide testing outsideof traditional clinical settings31.

Second-generation assays combine the detection ofantibodies and p24 antigen, thereby increasing sensitivity inearly infection.

The advantages and disadvantages of point-of-care HIVantibody tests are shown in Table 2.7.



25 Han Y, et al. Experimental approaches to the study ofHIV-1 latency. Nat Rev Microbiol 2007;5(2):95–106.

26 Branson BM. State of the art for diagnosis of HIVinfection. Clin Infect Dis 2007;45(Suppl 4):S221–S225.

27 Suligoi B, et al. Precision and accuracy of a procedurefor detecting recent human immunodeficiency virusinfections by calculating the antibody avidity index by anautomated immunoassay-based method. J ClinMicrobio l 2002;40(11):4015–20.

28 Chawla A, et al. Human immunodeficiency virus (HIV)antibody avidity testing to identify recent infection innewly diagnosed HIV type 1 (HIV-1)-seropositivepersons infected with diverse HIV-1 subtypes. J ClinMicrobiol 2007;45(2):415–20.

29 Mellors JW, et al. Prognosis in HIV-1 infectionpredicted by the quantity of virus in plasma. Science1996;272(5265):1167–70.

30 Schutten M, et al. Multicenter evaluation of the newAbbott RealTime assays for quantitative detection ofhuman immunodeficiency virus type 1 and hepatitis Cvirus RNA. J Clin Microbiol 2007;45(6):1712–17.

31 Roberts KJ, Grusky O, Swanson AN. Outcomes ofblood and oral fluid rapid HIV testing: a literaturereview, 2000–2006. AIDS Patient Care STDS2007;21(9):621–37.

10 O’Brien SJ, Moore JP. The effect of genetic variation inchemokines and their receptors on HIV transmission andprogression to AIDS. Immunol Rev 2000;177:99–111.

11 Kwa D, et al. Increased in vitro cytopathicity of CCchemokine receptor 5-restricted human immuno -deficiency virus type 1 primary isolates correlates with aprogressive clinical course of infection. J Infect Dis2003;187(9):1397–403.

12 Coakley E, Petropoulos CJ, Whitcomb JM. Assessingchemokine co-receptor usage in HIV. Curr Opin InfectDis 2005;18(1):9–15.

13 Faure E, Royer-Carenzi M. Is the European spatialdistribution of the HIV-1-resistant CCR5-Delta32 alleleformed by a breakdown of the pathocenosis due to thehistorical Roman expansion? Infec t Genet Evo l2008;8(6):864–74.

14 Soulie C, et al. Comparison of two genotypic algorithmsto determine HIV-1 tropism. HIV Med 2008;9(1):1–5.

15 Kraulis PJ. MOLSCRIPT: a program to produce bothdetailed and schematic plots of protein structures. JApplCryst 1991;24:946–50.

16 Merritt EA, Bacon DJ. Raster3D: photorealisticmolecular graphics. Methods Enzymol 1997;277:505–24.

17 Neurath AR, et al. Punica granatum (Pomegranate)juice provides an HIV-1 entry inhibitor and candidatetopical microbicide. BMC Infect Dis 2004;4:41.

18 Wei X, et al. Viral dynamics in human immuno -deficiency virus type 1 infection. Nature1995;373(6510):117–22.

19 Markowitz M, et al. A novel antiviral intervention resultsin more accurate assessment of human immuno -deficiency virus type 1 replication dynamics and T-celldecay in vivo . J Virol 2003;77(8):5037–8.

20 Ramirez BC, et al. Implications of recombination forHIV diversity. Virus Res 2008;134(1-2):64–73.

21 Chun TW, et al. Quantification of latent tissue reservoirsand total body viral load in HIV-1 infection. Nature1997;387(6629):183–8.

22 Wong JK, et al. Recovery of replication-competent HIVdespite prolonged suppression of plasma viremia.Science 1997;278(5341):1291–5.

23 Siliciano JD, et al. Long-term follow-up studies confirmthe stability of the latent reservoir for HIV-1 in restingCD4+ T cells. Nat Med 2003;9(6):727–8.

24 Strain MC, et al. Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: intrinsic stabilitypredicts lifelong persistence. Proc Natl Acad Sci USA2003;100(8):4819–24.


2.11 HIV transmission and early immunological events.

2.12 Natural history of HIV infection in: (A) untreatedprogressors; (B) untreated nonprogressors; (C) treatedprogressors.


chronic phase. Although historically T-cells (in particularCD4 T-cells) have been viewed as the main target of thevirus, all major lymphocyte populations and components ofthe immune system, including B cells, are affected by HIV-1.

Apart from a small minority of patients known as HIV-1controllers or long-term nonprogressors, prolonged long-term control of viral replication with the maintenance ofCD4 T-cell counts and the absence of clinical progression isnot achieved in the absence of ART or after the discon -tinuation of treatment. In recent years, progress has beenmade in understanding the immune correlates and geneticfactors involved in the protection against AIDS. Greatinsights in particular have been gained from studies in thepopulation of HIV-1 long-term nonprogressors (2.12)2–4.

HIV transmission andimmunopathogenesis

Infection with HIV-1 is characterized by chronic viralreplication and progressive immunodeficiency with the lossof CD4 T-cells. In the absence of combinationantiretroviral treatment (ART), continued loss of CD4 T-cells results in the development of opportunistic infectionsand malignancies, ultimately leading to death1.

Dendritic cells are the earliest targets of HIV-1. They arefound within the mucosal epithelium and act as antigen-presenting cells. Within the first 48 hours of successfultransmission via skin or mucosal surfaces, HIV-1 can bedetected in regional lymph nodes and by 72 hours, HIV-1can be detected in the plasma (2.11)1.

Immunopathology occurs within the first few weeks ofinfection following viral entry and sets the scene for the

HIV and the immune systemS Kinloch-de Loes and C Cellerai

AHIV-1 virus

Skin or mucosa

1 Infection ofimmaturedendritic cell

Maturedendritic cell

2 Fusion ofmature dendritic

cell and T-cell

3 Transport ofvirus to regional

lymph nodes

4 Infection of activated

T-cells

48 hours

72 hours

T-cell

1,0009008007006005004003002001000

1,0009008007006005004003002001000

1,0009008007006005004003002001000

1,200,000

1,000,000

800,000

600,000

400,000

200,000

0

1,200,000

1,000,000

800,000

600,000

400,000

200,000

0

1,200,000

1,000,000

800,000

600,000

400,000

200,000

0

B

C

CD4 T-cells (cells/mm3)

Plasma HIV-1 RNA (copies/ml)


2.13 Overview of adaptive immuneresponses.

lymphocytes (Th) play a very important role in cell-mediated responses. CTLs arise from naïve T-cells and areable to eliminate infected cells. Th cells, on the other hand,enhance CTL-mediated activity by helping CD8lymphocytes to differentiate into active CTLs2,6,7.

Although HIV-1 specific T-cells are unable to fullysuppress viral replication, they are understood to have animportant role in virological control. Initial studies lookingat interferon-gamma (IFN-γ) production by T-cells andtheir effector function found no correlation between themagnitude of IFN-γ-producing HIV-1-specific T-cellresponses and virological control or clinical progression.

More recently, the emphasis has shifted on to thefunctional qualities rather than the frequency of virus-specificT-cells. The term ‘monofunctional’ is used to define the typeof HIV-1-specific T-cells with sole effector function (IFN-γor TNF-α production and cytotoxic activity) in contrast to‘polyfunctional’ cells that in addition to typical effectorfunction, also produce interleukin-2 (IL-2) upon stimulationand retain proliferative capacity. These ‘polyfunctional’ cellsare often associated with disease control and thereforerepresent a correlate of protective antiviral immunity6,7.

The importance of genetic factors in generatingprotective virus-specific T-cells and their association withsome HLA-B alleles (B*5701/02/03, B*2705, B*5801,B*5101, and B*1302) has recently been highlighted (Table2.8)8. HLA-A and -C may play a role in host control aswell, although the evidence is not as strong as HLA-B.


With effective ART on board, the control of viralreplication is achieved and some HIV-related immuneabnormalities are reversed as immune reconstitutionoccurs. The extent of immune recovery, however, largelydepends on the stage of the infection when treatment isinitiated and on its duration5.

Immune responses

In general terms, the human host is protected frominfectious pathogens by two types of defence mechanism:• Innate immune responses.• Adaptive immune responses.

The innate immune response provides an immediate,nonspecific response to infection while the adaptiveimmune re sponse is a delayed antigen-specific one.Although equally important, most studies seeking tounderstand the immunopathogenesis of HIV-1 infectionhave focused on the adaptive immune response.

Adaptive immune responsesThese consist of both cell-mediated (cytotoxic T-cells) andantibody-mediated (humoral) responses (2.13).

Cell-mediated immune responsesCD8 cytotoxic T lymphocytes (CTL) and CD4 helper T

Naïve B-cell

Naïve T4 helper

cell

Naïve T8 helper

cell

Intracellularinfection

Extracellularinfection

Cell-mediatedimmunity

Humoral immunity

Th1 Th2

Free antigen

MCH IIMCH I


Slow

HLA-B*2705

HLA-B*5701/02/03

HLA-B*1302

HLA-B*5801

HLA-B*5101

Fast

HLA-B*3502/03

HLA-B*5301

HLA-B*5802

HLA-B*18

Table 2.8 HLA-B alleles associated with slow orrapid progression of HIV infection

2.14 HIV replication and immunity.


of infection is governed by a balance between the immuneresponse generated and attempts by the virus to escapedetection and destruction (2.14)13.

Innate immune responseNK cells and dendritic cells (DC) are importantcomponents of the innate immune response. NK cellsrapidly expand in number during acute infection, precedingthe development of adaptive HIV-1-specific CD8 T-cells.However, NK cell defective cytotoxicity and cytokinesecretion occur during the course of chronic infection andappear to be correlated with viraemia. It remains unclearwhether effective suppression of viral replication by ARTcan fully restore NK cell function14,15.

Recent data have demonstrated slower diseaseprogression in patients who express KIR3DS1, a killerimmunoglobulin-like receptor in conjunction with HLA-Bw4-80I (a putative ligand with an isoleucine at position80), suggesting a role for NK cells in chronic viral control.Several studies have described an impairment in theinteraction between NK cells and DCs that is proportionalto the level of viraemia and has been suggested to interferewith the development of an effective immune response.

Both HIV-1-specific CD4 and CD8 T-cells have areduced ability to proliferate upon antigen encounter inHIV-progressors, which has been ascribed to their impairedability to secrete IL-2. Defective cytotoxic activity of HIV-1-specific CD8 T-cells is also observed in chronic HIVinfection and may result from mechanisms such as skewedmaturation, senescence, and exhaustion.

Humoral immune responsesThe role of B-cells and neutralizing antibodies in thecontrol of HIV remains unclear. B-cell exhaustion hasrecently been described in association with a reduced abilityto produce high-quality antibodies in the context of HIVinfection. Some but not all of these abnormalities recoverwith ART, potentially explaining the improvement inhumoral immunity with virological control9–11.

The role of neutralizing antibodies (NAb) in the controlof HIV replication remains controversial. Some studieshave shown higher titres of heterologous NAb in HIV-controllers compared with HIV-progressors, but these mayhave only a limited effect in vivo on viral replication.

The role of antibody-related mechanisms, such asantibody-dependent cellular cytotoxicity (ADCC), whereantibodies stimulate natural killer (NK) cells to destroyinfected cells still deserves further investigation12.

Although the host mounts an HIV-specific cell-mediatedand antibody-mediated response, viral replication is nothalted in the absence of treatment. The eventual outcome

Host Virus

Cell-mediated response

Humoral-mediatedresponse

Infection anddestruction of

infected CD4 cell

Rapid replication(integration into

host DNA)

Latent reservoirs

Immune activation


2.15 CD4 depletion in the gut. (From Plos Med 2006.3(12), with permission.)

2.16 Chronic immune activation. Tem: effector memory T-cells; Tcm: central memory T-cells. (Adapted fromDouek D. Immune Effects at HIV-infected MucosalSurfaces. Abstract 20. 18th CROI; 2009; Montreal,Canada.)

AIDS


CD4 T-cell depletion

During the acute phase of the infection, CD4 T-cellsdecrease in the peripheral blood as a result of high levels ofviral replication. However, the most dramatic loss of thesecells occurs at the gut level (2.15)1, and although numbersin peripheral blood tend to temporarily recover in theensuing weeks, the decline in effector memory CD4 T-cellsremains a hallmark of chronic infection. While CD4 T-cellsdecrease during chronic infection, the number of CD8 T-cells in peripheral blood remains increased and results in aninverted CD4/CD8 ratio.

The extent of CD4 T-cell loss during the course of theinfection is more profound than the estimated number ofHIV-1-infected cells (estimated at 1 in 100 to 1 in 1000cells). In addition to the direct cytopathic effect of the virus,other mechanisms such as immune activation as well asvirally-derived and autoimmune factors have been putforward to explain the dramatic loss of these cells. Amongthese, immune activation is now considered to be the majorplayer in HIV-induced immune dysregulation andprogressive loss of CD4 T-cells leading to AIDS16,17.

Chronic immune activation

Generalized and persistent immune activation is one of thehallmarks of chronic HIV infection (2.16). Its mainmanifestations include:• Increased T-cell turn-over.• Increased expression of markers of activation on T

lymphocytes.• High levels of activation-induced apoptosis in uninfected

T-cells.• Polyclonal B-cell activation.

The above occur in a context of increasedproinflammatory cytokines and chemokines. B-cells, NKcells, and macrophages also show an increased rate ofproliferation.

One of the strongest arguments in favour of the directrole of chronic immune activation in AIDS pathogenesiscomes from animal models where it is a prerequisite for theprogression to AIDS in the presence of high viral loads. Inthese models, the predictive value of immune activation interms of disease progression is higher than that of HIV-1viral load.

Events taking place at the gut mucosal level (the site ofmajor CD4 T-cell destruction and intestinal barrierdamage) during primary HIV infection set the scene for

Gut

ImmuneactivationTem

Tcm

Target cells

Reduceddelivery

Microbialtranslocation

CD4 deletionenteropathy

HIV



later immune dysregulation. Infection and depletion of thecritical central memory CD4 T-cell pool result in reducedtissue delivery of effector memory CD4 T-cells and furtherloss of immune control at mucosal level. These events areunderstood to lead to chronic microbial translocation withthe involvement of the Toll-like receptor (TLR) pathwayand to contribute to chronic immune activation. Therehave been contradictory reports regarding the role of Tregulatory cells (Tregs) in this phenomenon18–22.

HIV-1 prophylactic vaccine

Unfortunately efforts at developing an HIV-I prophylacticvaccine have not been successful. Over the last few years theemphasis has shifted from the development of vaccines ableto generate NAbs towards a cell-mediated type of vaccinethat would generate HIV-specific T-cells.

In a recent phase-IIb trial (STEP trial) a vaccinecontaining Merck’s adenovirus serotype 5 vector (MRKAd5) was tested in 3,000 high-risk individuals. Unhappily,the results were disappointing – the vaccine did not workand individuals with pre-existing immunity to Ad5appeared to have an increased risk of HIV transmission.However, the positive results from the RV144 trialperformed in Thailand with a canary pox-based vaccine(ALVAC-HIV [V1521]) and AIDSVAX B/E showed a 31%decrease in the rate of infections in vaccinated subjectsversus those who received placebo will help to providecorrelates of protection to help vaccine development23.

Renewed efforts are focusing on different types of vectorand viral antigen combination in the vaccine. A prime-boost strategy has been used in recent trials in an effort toincrease the levels of immune response towards the virus.Progress in the understanding of neutralization sites couldpromote this line of vaccine development and produce newvaccine candidates24.

Conclusion

Although great progress has been made recently in theunderstanding of the mechanisms underlying HIV-1immunopathogenesis, there remain large gaps in ourunderstanding of the main immune correlates of protectionagainst the development of AIDS. Efforts continue toconcentrate on the development of an HIV-1 vaccine usingboth innate and adaptative immunity.

References

1 Brenchley JM, Price DA, Douek DC. HIV disease:fallout from a mucosal catastrophe? Nat Immunol 2006Mar;7(3):235–9.

2 Pantaleo G, Koup RA. Correlates of immune protectionin HIV-1 infection: what we know, what we don’t know,what we should know. Nat Med 2004Aug;10(8):806–10.

3 Fellay J, Shianna KV, Ge D, Colombo S, Ledergerber B,Weale M, et al. A whole-genome association study ofmajor determinants for host control of HIV-1. Science2007 Aug 17;317(5840):944–7.

4 Betts MR, Nason MC, West SM, De Rosa SC, MiguelesSA, Abraham J, et al. HIV nonprogressors preferentiallymaintain highly functional HIV-specific CD8+ T cells.Blood 2006 Jun 15;107(12):4781–9.

5 Robbins GK, Spritzler JG, Chan ES, Asmuth DM,Gandhi RT, Rodriguez BA, e t al. Incompletereconstitution of T cell subsets on combinationantiretroviral therapy in the AIDS Clinical Trials Groupprotocol 384. Clin Infect Dis 2009 Feb 1;48(3):350–61.

6 Rehr M, Cahenzli J, Haas A, Price DA, Gostick E,Huber M, et al. Emergence of polyfunctional CD8+ Tcells after prolonged suppression of humanimmunodeficiency virus replication by antiretroviraltherapy. J Virol 2008 Apr;82(7):3391–404.

7 Addo MM, Yu XG, Rathod A, Cohen D, Eldridge RL,Strick D, et al. Comprehensive epitope analysis ofhuman immunodeficiency virus type 1 (HIV-1)-specificT-cell responses directed against the entire expressedHIV-1 genome demonstrates broadly directed responses,but no correlation to viral load. J Viro l 2003Feb;77(3):2081–92.

8 Kiepiela P, Leslie AJ, Honeyborne I, Ramduth D,Thobakgale C, Chetty S, et al. Dominant influence ofHLA-B in mediating the potential co-evolution of HIVand HLA. Nature 2004 Dec 9;432(7018):769–75.

9 Moir S, Fauci AS. Pathogenic mechanisms of B-lymphocyte dysfunction in HIV disease. J Allergy ClinImmunol 2008 Jul;122(1):12–19.

10 Moir S, Ho J, Malaspina A, Wang W, Dipoto AC,O’Shea MA, et al. Evidence for HIV-associated B cellexhaustion in a dysfunctional memory B cellcompartment in HIV-infected viremic individuals. J ExpMed 2008 Aug 4;205(8):1797–805.

11 Moir S, Malaspina A, Ho J, Wang W, Dipoto AC,O’Shea MA, et al. Normalization of B cell counts andsubpopulations after antiretroviral therapy in chronicHIV disease. J Infect Dis 2008 Feb 15;197(4):572–9.



17 Sousa AE, Carneiro J, Meier-Schellersheim M,Grossman Z, Victorino RM. CD4 T cell depletion islinked directly to immune activation in the pathogenesisof HIV-1 and HIV-2 but only indirectly to the viral load.J Immunol 2002 Sep 15;169(6):3400–6.

18 Rowland-Jones S, Dong T. Dying T cells triggerautoimmunity in HIV. Nat Med 2007Dec;13(12):1413–15.

19 Grossman Z, Meier-Schellersheim M, Sousa AE,Victorino RM, Paul WE. CD4+ T-cell depletion in HIVinfection: are we closer to understanding the cause? NatMed 2002 Apr;8(4):319–23.

20 Sodora DL, Silvestri G. Immune activation and AIDSpathogenesis. AIDS 2008 Feb 19;22(4):439–46.

21 Chang JJ, Altfeld M. TLR-mediated immune activationin HIV. Blood 2009 Jan 8;113(2):269–70.

22 Holmes D, Jiang Q, Zhang L, Su L. Foxp3 and Tregcells in HIV-1 infection and immuno-pathogenesis.Immunol Res 2008;41(3):248–66.

23 Koff W, Berkley SF. The renaissance in HIVE vaccinedevelopment – future directions. N Engl J Med 2010.

24 Barouch DH. Challenges in the development of an HIV-1 vaccine. Nature 2008 Oct 2;455(7213):613–19.

12 Deeks SG, Schweighardt B, Wrin T, Galovich J, Hoh R,Sinclair E, et al. Neutralizing antibody responses againstautologous and heterologous viruses in acute versuschronic human immunodeficiency virus (HIV) infection:evidence for a constraint on the ability of HIV tocompletely evade neutralizing antibody responses. J Virol2006 Jun;80(12):6155–64.

13 Huber M, Trkola A. Humoral immunity to HIV-1:neutralization and beyond. J Intern Med 2007Jul;262(1):5–25.

14 Kottilil S, Chun TW, Moir S, Liu S, McLaughlin M,Hallahan CW, e t al. Innate immunity in humanimmunodeficiency virus infection: effect of viremia onnatural killer cell function. J Infect Dis 2003 Apr1;187(7):1038–45.

15 Mavilio D, Lombardo G, Kinter A, Fogli M, La SA,Ortolano S, et al. Characterization of the defectiveinteraction between a subset of natural killer cells anddendritic cells in HIV-1 infection. J Exp Med 2006 Oct2;203(10):2339–50.

16 Hazenberg MD, Otto SA, van Benthem BH, Roos MT,Coutinho RA, Lange JM, et al. Persistent immuneactivation in HIV-1 infection is associated withprogression to AIDS. AIDS 2003 Sep 5;17(13):1881–8.


Initial assessment of the new HIV patient

The aim of initial consultation is to assess the patient’sunderstanding of HIV natural history, address issues suchas stigma and disclosure, the need for professionalcounselling, routes of transmission, potential contact

Chapter 3

Treatment of HIV infection AJ Rodger, N Marshall, AM Geretti and C Booth

31

tracing and testing of partners and children, promotion ofsafe sex practices through the use of condoms, and to assessstage of HIV disease and patient health (Table 3.1).

Table 3.1 Initial assessment of the new HIV patient (adapted from EACS and DHHS)1,2

History • HIV testing history• Routes of exposure – in UK or

overseas• Evaluation of social and

psychological support• Smoking, alcohol, and recreational

drug histories• Family history – CVD, HT,

diabetes• Social history • Details of partners and children

and their HIV testing history • Sexual health history• Vaccination history (see Table 3.2

for recommended vaccinations)• Complete medical history including

cardiovascular risk assessment• Current medications• Current symptomatology

Physical examination (3.1–3.11)• General: height, weight, BMI, waist

to hip ratio, blood pressure• Skin: KS (see Chapter 7)

(3.7–3.9), Molluscum contagiosum(3.1–3.3), seborrhoeic dermatitis(3.4), shingles scar, fungalinfection (3.5)

• Lymph nodes – site, size,consistency (3.6)

• Mouth – OHL, Candida, gumdisease, palatal KS (3.10)

• Cardiovascular, respiratory,abdominal, and neurogicalexaminations as standard

• Women: cervical pap smear• Urine dipstick for protein and

sugar• Sexual health screen

Laboratory evaluation • Confirmation of HIV antibody-

positive • Avidity and detuned assays if

available• Plasma HIV RNA• Resistance testing (genotype) with

determination of HIV subtype• CD4 absolute count + percentage

(optional: CD8 and %)• Full blood count, AST, ALT,

alkaline phosphatase, calcium,phosphate, glucose, creatinine,calculated creatinine clearance

• Antibody tests for Toxoplasma,CMV, VZV, hepatitis A, B, and C,and syphilis

• Fasting blood glucose and lipidsincluding fasting total LDL andHDL cholesterol, and triglycerides

• G6PD statusIf relevant:• HLA-B*5701 determination • HIV tropism


Treatment of HIV infection 32

3.1–3.3 Molluscum contagiosum. Characteristic waxy,dome-shaped, umbilicated flesh-coloured papules causedby the DNA pox virus. They are commonly located on theface, neck, axillae, and ano-genital regions.

3.4 HIV-related seborrhoeic dermatitis.

Vaccinations that are recommended for all HIV-infectedadults found to be susceptible on serological screening arehepatitis B (HBV), measles, mumps and rubella (if CD4count >200/mm3) and varicella (CD4 count >400/mm3).Further details on vaccination in HIV-positive adults isgiven in Table 3.2, adapted from the BHIVA guidance onvaccination (2008)3.

When to start treatment

Primary HIV infection Guidelines do not currently recommend treatment in acuteinfection unless symptoms are neurological in nature orsevere, as there is some indication that this may lead tomore rapidly progressive disease4. Duration of treatment isunclear, as is its effect on outcome or prognosis. The ShortPulse Anti Retroviral Therapy at HIV Seroconversion(SPARTAC) trial, which is a randomized prospective study


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