The Other AIDS Virus:A Brief Overview of HIV-2 infection

(Epidemiology, Transmission, Viral Load & Variability)

Geoffrey S. Gottlieb, MD PhDAssociate Professor

Allergy & Infectious DiseasesDepartment of MedicineUniversity of Washington

Seattle, USA

IAS, Rome 2011ANRS Satellite:

HIV-2: A model of attenuated HIV Infection

HIV-2: Discovery/Origins• 1985: serum from Senegalese FSW cross-reacts

with SIVmac. (Barin et al. Lancet 1985)

• 1986: HIV-2 isolated from AIDS patients in Guinea- Bissau and Cape Verde. (Clavel et al. Science 1986)

• Retrospective look shows HIV-2 in stored serum from 1960s in West Africans and Portuguese Nationals who visited West Africa in the 1960s. (Kawamura et al. Lancet. 1989, Bryceson et al. Lancet 1988.)

• Phylogenetic dating HIV-2 introduction in humans to 1930-40s (Lemey et al. PNAS 2003, Wertheim et al. PloS Comp Bio 2009. )

A global view of HIV infection33.4 million people [31.1‒35.8 million] living with HIV, 2009

>25 million deaths

2.4

No WHO estimate of HIV-2 infections

HIV-2 Epidemiology (I)

Countries reporting HIV-2 infections

HIV-2 Epidemiology (II)

Sources: Pubmed & LANL

Prevalence of HIV-2 in Sub-Saharan Africa?

Arien et al. JVI 2005

HIV-2 Epidemiology (III)

HIV-2 Seroprevalence in the 1980-90s

HIV-2 Epidemiology (IV)

Source: US Census Bureau

Masson et al. STI 2007

Bruhn & Gilbert Lancet ID 2011

Hamel et al. ARHR 2007

Prevalence Incidence

van der Loeff et al. IJE 2006

Senegal

The Gambia

Guinea-Bissau

HIV-2: Molecular Epidemiology & Variability

• HIV-2: 8 groups : A-H – Groups A and B most common

• Group A-B recombinants reported rarely– Groups C-H have only been isolated very rarely

• Closely related to SIVsm (Sooty mangabey, Cercocebus atys)

• Each HIV-2 group probably represents a separate zoonotic transmission from Sooty mangabeys to humans – Similar to HIV-1 groups

• M, N, O (chimps) • P (gorillas?)

Sooty mangabey

(Cercocebus atys)

www.bushmeat.org

Phylogenetic Relationship of HIV-2, HIV-1 & SIVs

Los Alamos HIV Database

Santiago et al. JVI 2005

HIV-2 groups (subtypes) in HIV- Database (LANL)(accessed JAN-2010)

HIV-2 Transmission & Genital Tract Shedding• Modes of HIV-2 transmission same as HIV-1

– Sexual (F<->M, MSM), IDU, MTCT, Blood borne• Sexual Transmission HIV-2 << HIV-1 (Kanki et al. Lancet 1994)

– Risk estimates: HIV-1: 3-4 fold greater than HIV-2.• MTCT transmission HIV-2 << HIV-1 (Matheron et al. Lancet 1990;

Adjorlolo-Johnson et al. JAMA 1994)

– ~0-4% for HIV-2 vs ~25-35% for HIV-1• Male & Female genital tract shedding HIV-2 << HIV-1

(Gottlieb et al. AIDS 2006, Hawes et al. AIDS 2008)

Gilbert et al. Stat Med. 2003

Senegal- FSW

Gottlieb et al. AIDS 2006

Senegal-Males at SMIT CHU Fann

HIV-2 Natural History & Clinical Outcomes• HIV-2 infection causes AIDS (Brun-Vezinet et al. Lancet. 1987; Clavel et al. NEJM

1987; many others)

• HIV-2 is generally less pathogenic/virulent than HIV-1 (Marlink et al. Science 1994; many others)

• Most HIV-2 patients are “long term non-progressors” (LTNP) – Longer asymptomatic stage– Slower decline in CD4 count– Lower mortality rate due to AIDS

MTCT

Mortality hazards compared to HIV-negative HIV-1=9.9 (95% CI 5.2–19)HIV-2=3.9 (95% CI, 1.2–12)

Schim van der Loeff et al. AIDS 2003

Adults

Hansmann et al. JAIDS 2005

Clinical Manifestations of HIV-2 infection • OI’s & AIDS-associated malignancies are generally similar

to those reported for HIV-1– OI’s & AIDS-AM in HIV-2 may occur at higher CD4 counts than

HIV-1 (Martinez-Steele et al. AIDS 2007)

• Due to slower CD4 cell loss? – Kaposi’s Sarcoma may occur less frequently in HIV-2 (Ariyoshi et al. J

Hum Virol. 1998)

– Invasive cervical cancer, severe CMV disease, HIV encephalitis and cholangitis may occur more frequently in HIV-2 infected individuals. (Hawes et al. JID 2003, Lucas et al. AIDS 1993)

Martinez-Steele et al. AIDS 2007

Survival after AIDS Dx. in The Gambia

HIV-2: Diagnosis & Testing1. Screening:• HIV-1/HIV-2 ELISA/EIA

2. Confirmation: • “Rapid” tests that distinguish HIV-2

from HIV-1: • Immunocomb II, Multispot, Genie II, SD Bioline

• HIV-2 EIA• HIV-2 western blot• HIV-2 viral load testing

• Not commercially available or US-FDA approved• Generally not available in RLS• Collaborative efforts to standardize and QA/QC HIV-

2 through the ACHI EV2E network.(Damond et al. JCM 2008 & 2011)(http://etudes.isped.u-bordeaux2.fr/achiev2e/)

HIV-2 viral loads • HIV-2 Plasma RNA << HIV-1 (Simon et al. AIDS 1993, De Cock et al. JAMA

1993, many others)

• ~25% have “undetectable” plasma RNA (<50-100 copies/ml)

• Model for “elite control”? • HIV-2 PBMC DNA ~ HIV-1

Thiébaut et al. AIDS 2011

French HIV-2 CohortHIV Plasma RNA HIV PBMC DNA

Gottlieb et al. JID 2002

Senegal Cohort

HIV-2 plasma RNA viral load predicts CD4 decline & disease progression.

Gottlieb et al. JID 2002-Senegal

Ariyoshi et al. AIDS 2000

The Gambia

Schim van der Loeff et al. Retrovirology 2010Guinea-Bissau

Mortality hazard rate increased by 2.12 for each log10 increase in RNA load (95% CI, 1.3–3.5; p = 0.0023)

Dual HIV-1/HIV-2 seropositivity & infection• Dual HIV-1/HIV-2 infection first reported in 1980’s

(Rayfield et al. JID 1988)

• Difficult to differentiate cross-reactive serology from true infection without HIV-1 and HIV-2 specific PCR.– ~40-80% of dual-sp confirmed dually infected,

depending on the screening algorithm and PCR methods. (Walther-Jallow et al. ARHR 1999, Rouet et al. JCM 2004)

• Prevalence of Dual-SP/I is ~5-15% of HIV cases in West Africa

• Dual Infection order: Co-infection? or Super-infection– HIV-1 -> HIV-2 -> dual– HIV-2 -> HIV-1 -> dual

• Correct Assessment has implications for ART & biologic-immunological studies.

Does HIV-2 protect against HIV-1?

• Senegalese CSW w/ HIV-2 have a RR= 0.32 of subsequent acquisition of HIV-1 (Travers et al. Science 1995)

• Subsequent studies conducted in Guinéa-Bissau (Aaby et al. 1997; Norrgren et al. 1999, van der Loeff et

al. 2001), and the Ivory Coast (Wiktor et al. 1999), did not show any protective effect.

Does HIV-1/HIV-2 dual infection affect disease course?

• In vitro: HIV-1/HIV-2 super-infection interference (Hart et al. 1990, Le Guern et al. 1992, von Dalnok et al. 1993) and transcriptional inhibition (Arya et al. 1996, Al-Harthi et al. 1998, Browning et al. 1999)

• In vivo: HIV-2 pro-viral loads < in dually infected patients (Sarr et al. 1999), HIV-1 RNA viral loads lower in dually infected patients (Andersson et al. 2000, Alabi et al. 2003, Hawes et al. -unpublished)

• Mortality: HIV-1 ~ HIV-1/HIV-2 duals >> HIV-2 (Schim van der Loeff et al. AIDS 2002, Holmgren et al. Retrovirology 2007, Alabi et al. 2003)

Summary:• HIV-2 prevalence, disease progression &

transmission are significantly less than HIV-1.• HIV-2 “attenuation” is likely due to lower HIV-

2 RNA viral loads.• The underlying mechanisms that lead to low

HIV-2 RNA viral loads remains to be determined…

• Determination of the underlying HIV-2 disease mechanisms may provide further insight into HIV-1 disease control.

UW-Dakar HIV-2 Study GroupSenegal

Papa Salif SowMacoumba Toure

Selly BaCheikh Tidiane Ndour

Mery Dia BadianeLouise Fortes

Jacques Ndour Fatou NiasseFatou Traore

Habibatou Diallo AgneNdeye Rokhaya Fall

Sophie Chablis Marie Pierre SyMame Dieumba

Mbaye Ndoye Khady Diop Fatima Sall

Amadou Bale Diop Cheikh Gueye

Boubacar Diamanka Marianne Ndiaye

Marie Cisse ThioyeFatou Cisse

Madeleine Mbow Marianne Fadam Diome

Marie Diedhiou

UW

Nancy KiviatSteve Hawes

Donna KenneySteve Cherne

Josh SternQinghua Feng

Bob SmithDana Raugi

Charlotte PanBeruk AsfawBrad ChurchMatt Coyne

Alexandra HernandezKara Parker

Bob CoombsMing Chang

Joan Dragavon

Jim Mullins

GrazieThank you

Funding:Royalty Research Fund