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

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

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

Spread of HIV in Africa, 1990-2005

Source: UNAIDS, 2006

The HIV Epidemic Unfolds

Sudden outbreak in USA of opportunistic infections and cancers in homosexual men in 1981
Pneumocystis carinii pneumonia (PCP), Kaposis sarcoma, and non-Hodkins lymphoma

HIV isolated in 1984 - Luc Montanier (Pasteur Institute, Paris) and Robert Gallo (NIH, Bethesda, USA) HIV diagnostic tests developed in 1985 First antiretroviral drug, zidovudine, developed in 1986 Exploding pandemic
Has infected more than 50 million people around the world Has killed over 22 million people
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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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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
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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.g., A/G ad A/E) are recombinants

Geographic distribution of HIV group M clades

A in Central Africa B in North American, Australia, and Europe C in Southern and Eastern Africa (Ethiopia)
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HIV at Surface of CD4 Lymphocyte

13 Courtesy of CDC

How HIV Enters Cells

gp120 env protein binds to CD4 molecule
CD4 found on T-cells macrophages, 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 - 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

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HIV Receptors HIV Receptors HIV and CellularReceptors

Copyright 1996 Massachusetts Medical Society. All rights reserved.

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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 ~1.6 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 Immunology

Overview of Adaptive Immune Response

APC
Intracellular infection
MHC I presentation of endogenous antigen

Extracellular infection Free antigen

MHC II presentation of exogenous antigen

Nave T8 cell

Nave T4 helper cell

Nave B-Cell

Cell-mediated
(CTLs)

Th1

Th2

Humoral
(plasma cells / antibodies)
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Diagram courtesy of Dr. Samuel Anderson

General Principles of Viral-host Interactions:

Host: mounts HIV-specific immune responses
Cellular (cell-mediated) - 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
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Cellular Immune Responses to HIV

CD8 Cytotoxic T lymphocyte (CTL)
Critical for containment of HIV Derived from nave T8 cells, which recognize viral antigens in context of MHC class I presentation Directly destroy infected cell Activity augmented by Th1 response

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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 - activate Tc (CD8) lymphocytes, promoting cellmediated immunity Th2 - activate B lymphocytes, promoting antibody mediated immunity
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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

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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
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Pathogenesis of HIV

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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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
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Syncytium Formation
Observed in HIV infection, 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. These syncytium are highly unstable, and die quickly.

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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

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Role of Cytokine Dysregulation in Pathogenesis of HIV

HIV is associated with increased expression of pro-inflammatory cytokines
TNF-alpha, IL-1,IL-6, IL-10, IFN-gamma Associated with up-regulation of HIV replication

HIV results in disruption and loss of immunoregulatory cytokines

IL-2, IL-12 Necessary for modulating effective cell-mediated immune responses (CTLs and NK cells)
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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 PCP, Histoplamosis HSV, VZV, JC virus, pox viruses EBV-related lymphomas

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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
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Early Phases of HIV Infection of Mucosal Surfaces

Cell free

HIV

Immature Dendritic cell Skin or mucosa 24 hours 1. HIV co-receptors, CD4 + chemokine receptor CC5 2. Selective of macrophagetropic HIV Via lymphatics or circulation 48 hours 3.

T-cell

PEP
Burst of HIV replication

Mature Dendritic cell in regional LN undergoes a single replication, which transfers HIV to 36 T-cell

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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Spread of HIV in Host Tissues

Copyright 1998 Massachusetts Medical Society. All rights reserved.

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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 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

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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
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Natural History of HIV-1

Fauci As, 1996

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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

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Key Points
HIV is a retrovirus, 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, 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
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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

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