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HIV Pathogenesis and Natural Course of the Disease

HIV Care and ART: A Course for Physicians

Learning Objectives
• Describe the origin and basic virology of HIV-1 • Describe the normal immunological response to HIV-1 • List the mechanisms used by HIV-1 to evade the normal immune responses • Explain the principles of HIV-1 pathogenesis • Describe the natural course of HIV-1

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HIV-1 Virology

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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“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 5 .Transfer of SIV to Humans (2) • “Human error” theory (Edward Hooper.

1990-2005 Source: UNAIDS. 2006 6 .Spread of HIV in Africa.

Kaposi’s sarcoma. developed in 1986 • Exploding pandemic  Has infected more than 50 million people around the world  Has killed over 22 million people 7 .The HIV Epidemic Unfolds • Sudden outbreak in USA of opportunistic infections and cancers in homosexual men in 1981  Pneumocystis carinii pneumonia (PCP). zidovudine. USA) • HIV diagnostic tests developed in 1985 • First antiretroviral drug. Paris) and Robert Gallo (NIH. Bethesda.Luc Montanier (Pasteur Institute. and non-Hodkins lymphoma • HIV isolated in 1984 .

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.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. causes AIDS much more slowly than HIV-1 but otherwise clinically similar 8 .

Classification of HIV-1 • HIV-1 groups M (major): cause of current worldwide epidemic O (outlier) and N (Cameroon): rare HIV-1 groups that arose separately • HIV-1 M subgroups (clades) >10 identified (named with letters A to K) Descended from common HIV ancestor One clade tends to dominate in a geographic region Clades differ from each other genetically Different clades have different clinical and biologic behavior 9 .

A/G ad A/E) are recombinants • Geographic distribution of HIV group M clades A in Central Africa B in North American.Origin and Distribution of HIV-1 Clades • HIV-1 rapidly evolves by two mechanisms: Mutation: changes in single nucleosides of the RNA Recombination: combinations of RNA sequences from two distinct HIV strains Several common clades (e. Australia.g. and Europe C in Southern and Eastern Africa (Ethiopia) 10 ..

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HIV at Surface of CD4 Lymphocyte 13 Courtesy of CDC .

and microglial cells  Binding to CD4 is not sufficient for entry • V3 loop of gp120 env protein binds to co-receptor  CCR5 receptor .used by macrophage-tropic HIV variants  CXCR4 receptor .How HIV Enters Cells • gp120 env protein binds to CD4 molecule  CD4 found on T-cells macrophages.used by lymphocyte-tropic HIV variants • Binding of virus to cell surface results in fusion of viral envelope with cell membrane • Viral core is released into cell cytoplasm 14 .

15 .HIV Receptors HIV Receptors HIV and CellularReceptors Copyright © 1996 Massachusetts Medical Society. All rights reserved.

6 days • HIV can lie dormant within a cell for many years.Viral-host Dynamics • About 1010 (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. unlike other retroviruses 16 . especially in resting (memory) CD4 cells.

HIV Immunology .

Samuel Anderson .Overview of Adaptive Immune Response APC Intracellular infection MHC I presentation of endogenous antigen Extracellular infection Free antigen MHC II presentation of exogenous antigen Naïve T8 cell Naïve T4 helper cell Naïve B-Cell Cell-mediated (CTLs) Th1 Th2 Humoral (plasma cells / antibodies) 18 Diagram courtesy of Dr.

most important  Humoral (antibody-mediated) • Virus: subverts the immune system  Infects CD4 cells that control normal immune responses  Integrates into host DNA  High rate of mutation  Hides in tissue not readily accessible to immune system  Induces a cytokine environment that the virus uses to its own replicative advantage • Achieved by “activation” of the immune system 19 .General Principles of Viral-host Interactions: • Host: mounts HIV-specific immune responses  Cellular (cell-mediated) .

which recognize viral antigens in context of MHC class I presentation Directly destroy infected cell Activity augmented by Th1 response 20 .Cellular Immune Responses to HIV • CD8 Cytotoxic T lymphocyte (CTL) Critical for containment of HIV Derived from naïve T8 cells.

activate B lymphocytes. promoting cellmediated immunity • Th2 .activate Tc (CD8) lymphocytes. promoting antibody mediated immunity 21 .Cellular Immune Responses to HIV • CD4 Helper T Lymphocyte (Th) Plays an important role in cell-mediated response Recognizes viral antigens by an antigen presenting cell (APC) • Utilizes major histocompatibility complex (MHC) class II Differentiated according to the type of “help” • Th1 .

Humoral Immune Response to HIV • Neutralization Antibodies bind to surface of virus to prevent attachment to target cell • Antibody-dependent cell-mediated cytotoxicity (ADCC) Fc portion of antibody binds to NK cell Stimulates NK cell to destroy infected cell 22 .

.g.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. the central nervous system 23 . e.

Pathogenesis of HIV .

semen.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. duodenum. rectum: chromaffin cells Lung: alveolar macriphages 25 . vaginal fluids: macrophages Bone marrow: lymphocytes Skin: langerhans cells Colon.

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 26 .

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 27 .

Mechanisms of CD4 Depletion and Dysfunction • Direct Elimination of HIV-infected cells by virus-specific immune responses Loss of plasma membrane integrity because of viral budding Interference with cellular RNA processing • Indirect Syncytium formation Apoptosis Autoimmunity 28 .

• These syncytium are highly unstable.Syncytium Formation • Observed in HIV infection. 29 . most commonly in the brain • Uninfected cells may then bind to infected cells due to viral gp 120 • This results in fusion of the cell membranes and subsequent syncytium formation. and die quickly.

Apoptosis 30 Courtesy of CDC .

Role of Cellular Activation in Pathogenesis of HIV • HIV induces immune activation Which may seem paradoxical because HIV ultimately results in severe immunosuppression • Activated T-cells support HIV replication Intercurrent infections are associated with transient increases in viremia The magnitude of this increase correlates inversely with stage of HIV disease Accounts for why TB worsens underlying HIV disease 31 .

IL-12 Necessary for modulating effective cell-mediated immune responses (CTLs and NK cells) 32 . IFN-gamma Associated with up-regulation of HIV replication • HIV results in disruption and loss of immunoregulatory cytokines IL-2. IL-1.Role of Cytokine Dysregulation in Pathogenesis of HIV • HIV is associated with increased expression of pro-inflammatory cytokines TNF-alpha. IL-10.IL-6.

pox viruses EBV-related lymphomas 33 . JC virus. VZV. Legionella Leishmania. Toxoplama. Cryptosporidium. Salmonella.Consequence of Cell-mediated Immune Dysfunction • Inability to respond to intracellular infections and malignancy Mycobacteria. Microsporidium PCP. Histoplamosis HSV.

Natural History of HIV Infection .

Transmission • Modes of infection Sexual transmission at genital or colonic mucosa Blood transfusion Mother to infant Accidental occupational exposure • Viral tropism Transmitted viruses is usually macrophage-tropic Typically utilizes the chemokine receptor CCR5 to gain cell entry Patients homozygous for the CCR5 mutation are relatively resistant to transmission 35 .

T-cell PEP Burst of HIV replication Mature Dendritic cell in regional LN undergoes a single replication. Selective of macrophagetropic HIV Via lymphatics or circulation 48 hours 3. which transfers HIV to 36 T-cell . CD4 + chemokine receptor CC5 2.Early Phases of HIV Infection of Mucosal Surfaces Cell free HIV Immature Dendritic cell Skin or mucosa 24 hours 1. HIV co-receptors.

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) 37 .

Spread of HIV in Host Tissues Copyright © 1998 Massachusetts Medical Society. All rights reserved. 38 .

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 mononucleosislike symptoms (fever. rash. swollen lymph glands) • Primary infection resolves as body mounts HIV-specific adaptive immune response  Cell-mediated response (CTL) followed by humoral  Patient enters “clinical latency” 39 .

Window Period: Untreated Clinical Course Acute HIV syndrome Primary HIV infection Asymptomatic antibody viremia --------------------------------------------PCR P24 ELISA a 0 b Time from a to b is the window period 2 3 4 years Weeks since infection Source: S Conway and J.G Bartlett. 2003 40 .

1996 41 .Natural History of HIV-1 Fauci As.

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 42 .

CD4 T-cell Count and Progression to AIDS • In contrast to VL. patients will develop opportunistic infections Develop in a sequence predictable according to CD4 count WHO Staging system 43 . as the CD4 count declines over time. baseline CD4 is not a good predictor of time to progression to AIDS Unless CD4<321 cells/ml • However.

capable of integrating into host genome and establishing chronic infection • HIV can be classified into subgroups (clades) which have characteristic geographic distribution • The important steps in the lifecycle of HIV include cell entry.Key Points • HIV is a retrovirus. reverse transcription. integration. and maturation/assembly • Cell-mediated immunity is critical for containment of HIV infection and other intracellular infections • HIV evades host immunity by a variety of mechanisms 44 .

Key Points (2) • HIV activates the immune system to increase its own replication • CD4 count declines by both direct and indirect mechanisms • HIV RNA set point predicts rate of progression to AIDS • CD4 count decline is associated with a predictable sequence of opportunistic infections 45 .

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