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HIV Pathogenesis and Natural
Course of the Disease
Unit 4
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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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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Spread of HIV in Africa, 1990-2005
Source: UNAIDS, 2006
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The HIV Epidemic Unfolds
 Sudden outbreak in USA of opportunistic infections and
cancers in homosexual men in 1981
 Pneumocystis carinii pneumonia (PCP), Kaposi’s 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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11
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HIV at Surface
of CD4
Lymphocyte
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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
HIVReceptors
Receptors
HIV and Cellular
Receptors
Copyright © 1996 Massachusetts Medical Society. All rights reserved.
15
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
Extracellular
infection
APC
Intracellular
infection
MHC I presentation
of endogenous
antigen
Free antigen
MHC II
presentation of
exogenous antigen
Naïve
T8 cell
Naïve
B-Cell
Naïve T4
helper 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 naïve 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
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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


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
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
T-cell
Immature
Dendritic cell
Skin or
mucosa
HIV co-receptors,
CD4 + chemokine
receptor CC5
Burst of HIV
replication
Via lymphatics or
circulation
24 hours
1.
PEP
2.
48 hours
Selective of
macrophagetropic HIV
3.
Mature Dendritic cell in
regional LN undergoes
a single replication,
which transfers HIV to
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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
2
3
b
Time from a to b is the window period
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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