Retroviridae

• The Retroviridae are a family of enveloped

(+) sense ssRNA viruses that have been

intensely studied because of their

association with cancers, leukemias and

the AIDS syndrome

Human Immunodeficiency

Virus

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Transfer of SIV to Humans

• “Natural transfer” theory (Science 2000)

– SIV was transferred to humans through

hunting and handling of chimpanzees

– The epidemic required urbanization and

increased population mobility

– Most scientific-based theory

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Transfer of SIV to Humans (2)

• “Human error” theory (Edward

Hooper,“The River” 2000)

– Oral polio vaccine used in West Africa during

the late 1950s may have been contaminated

with SIV

– SIV has not been recovered from this vaccine

in subsequent studies

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Classification of HIV

• HIV class: Lentivirus– Retrovirus: single stranded RNA transcribed

to double stranded DNA by reverse transcriptase

– Integrates into host genome– High potential for genetic diversity– Can lie dormant within a cell for many years,

especially in resting (memory) CD4+ T4 lymphocytes

• HIV type (distinguished genetically)

– HIV-1 -> worldwide pandemic (current ~ 40 M

people)

– HIV-2 -> isolated in West Africa; causes AIDS

much more slowly than HIV-1 but otherwise

clinically similar

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surface transmembrane

matrix protein

capsid protein

nucleocapsid protein

RT

Integrase

protease

HIV Structure

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Retroviral Proteins• gag, pol, and env

– Gag protein proteolytically processed into• MA (matrix)• CA (capsid)• NC (nucleocapsid)

– Pol protein encodes enzymes• PR (protease) • RT (Reverse Transcriptase which has both DNA polymerase and

RNase H activities)• IN (Integrase)

– Env protein encodes• SU surface glycoprotein• TM transmembrane protein

• “Accessory” genes (in Complex Retroviruses) - regulate and coordinate virus expression; function in immune escape

HIV genome organization

Env Proteins: Surface (SU)• Glycoprotein (gp, followed by apparent molecular weight)• Attaches to a specific receptor on cell surface• Major neutralizing antigen on retrovirus, also often highly

variable (EIAV, HIV). Hard to make vaccines.

SU (gp120)

TM (gp 41)

Lipid Bilayer(derived from cell)

CXCr4 is the major coreceptor for T-cell-tropic strains

CCr5 is the major coreceptor for macrophage-tropic strains

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Retroviruslife cycle:

HIV integration:

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HIV at Surface of CD4

Lymphocyte

Courtesy of CDC

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Viral-host Dynamics

• About 10 (10 billion) virions are produced daily

• Average life-span of an HIV virion in plasma is ~6 hours

• Average life-span of an HIV-infected CD4 lymphocytes is ~1.6 days

• HIV can lie dormant within a cell for many years, especially in resting (memory) CD4 cells, unlike other retroviruses

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HIV Evasion Methods

• Makes 10 billion copies/day -> rapid mutation of HIV antigens

• Integrates into host DNA • Depletes CD4 lymphocytes • Down-regulation of MHC-I process• Impairs Th1 response of CD4 helper T

lymphocyte • Infects cells in regions of the body where

antibodies penetrate poorly, e.g., the central nervous system

Pathogenesis of HIV

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Primary HIV Infection• The period immediately after infection

characterized by high level of viremia (>1

million) for a duration of a few weeks

• Associated with a transient fall in CD4

• Nearly half of patients experience some

mononucleosis-like symptoms (fever, rash,

swollen lymph glands) Patient enters “clinical

latency”

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Cells Infected by HIV

• Numerous organ systems are infected by HIV:– Brain: macrophages and glial cells– Lymph nodes and thymus: lymphocytes and

dendritic cells– Blood, semen, vaginal fluids: macrophages– Bone marrow: lymphocytes– Skin: langerhans cells– Colon, duodenum, rectum: chromaffin cells– Lung: alveolar macriphages

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General Mechanisms of HIV Pathogenesis

• Direct injury– Nervous (encephalopathy and peripheral

neuropathy)– Kidney (HIVAN = HIV-associated

nephropathy)– Cardiac (HIV cardiomyopathy) – Endocrine (hypogonadism in both sexes)– GI tract (dysmotility and malabsorption)

• Indirect injury– Opportunistic infections and tumors as a

consequence of immunosuppression

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General Principles of Immune Dysfunction in HIV

• All elements of immune system are affected• Advanced stages of HIV are associated with

substantial disruption of lymphoid tissue– Impaired ability to mount immune response to

new antigen– Impaired ability to maintain memory

responses– Loss of containment of HIV replication – Susceptibility to opportunistic infections

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Consequence of Cell-mediated Immune Dysfunction

• Inability to respond to intracellular infections and malignancy– Mycobacteria, Salmonella, Legionella– Leishmania, Toxoplama, Cryptosporidium,

Microsporidium– Histoplamosis– HSV, VZV, JC virus, pox viruses– EBV-related lymphomas

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Transmission

• Modes of infection

– Sexual transmission at genital or colonic

mucosa

– Blood transfusion

– Mother to infant

– Accidental occupational exposure

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Laboratory Markers of HIV Infection• Viral load

– Marker of HIV replication rate– Number of HIV RNA copies/mm3 plasma

• CD4 count – Marker of immunologic damage – Number of CD4 T-lymphocytes cells/mm3

plasma– Median CD4 count in HIV negative Ethiopians

is significantly lower than that seen in Dutch controls • Female 762 cells/mm3 (IQR 604-908)• Male 684 cells/mm3 (IQR 588-832)

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HIV RNA Set Point Predicts Progression to AIDS

• HIV RNA viral loads after infection can be used in the following ways:– To assess the viral set point – To predict the likelihood of progression to

AIDS in the next 5 years• The higher the viral set point:

– The more rapid the CD4 count fall – The more rapid the disease progression to

AIDS

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CD4 T-cell Count and Progression to AIDS

• In contrast to VL, baseline CD4 is not a good predictor of time to progression to AIDS – Unless CD4<321 cells/ml

• However, as the CD4 count declines over time, patients will develop opportunistic infections – Develop in a sequence predictable according

to CD4 count – WHO Staging system

THE END

R.DOROST@yahoo.com

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