HIV Pathogenesis and
Natural Course of the Disease
Unit 4
HIV Care and ART: A Course for Physicians
Learning Objectives
■ Discuss HIV molecular biology and virology
■ Describe immunological response against
infections
■ Explain the effect of HIV on the immune system
and how HIV establishes a chronic infection
■ Identify characteristics that make HIV disease
chronic and incurable
■ Understand the natural course of the disease
Pathogenesis and Natural Course of the Disease
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Virology of HIV
Pathogenesis and Natural Course of the Disease
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Characteristics of HIV
■ Classification
■ Family of retroviruses (RNA -> DNA -> RNA)
■ Subfamily of lente (slow) viruses
■ Cytopathic to cells that replicate it
■ Infects many cells types and is latent in some cells
■ Infects and depletes CD4 lymphocytes
■ Causes cell-mediated immunosuppression
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HIV Strains
■ HIV-1 Group M (main), the cause of the AIDS
epidemic
■ HIV-2, a less virulent retrovirus causing an
epidemic in West Africa
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HIV-1 and HIV-2 Differ in Multiple
Ways
■ Accessory genes
■ HIV-1 vpu
■ HIV-2 vpx
■ Distribution
■ HIV-1 – global pandemic
■ HIV-2 – West Africa
■ Rate of progression of severe immunosuppression
■ HIV-1 – median time to AIDS = 10 years
■ HIV-2 – median time to AIDS = longer, but ?
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Classification of HIV-1
■ Groups
■ M (major) with 9 subtypes (clades)
■ O (outlier)
■ N (reported only in Cameroon)
■ Group M’s clades (related viruses)
■ Named with letters A to K, with many recombinants between parts of
HIV from two clades
■ Differ in geographic distribution
■ Differ from each other by about 30% in the env coding sequences
and 14% of the gag code sequences
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HIV Clades
■ HIV rapidly evolves by two mechanisms:
■ Mutation - changes in single nucleosides of the RNA
■ Recombination – combinations of long RNA sequences from two
distinct HIV strains
■ Distinct genetic subgroups, or clades, of the M group of HIV
have evolved and become dominate in specific geographic
regions
■ A in Central Africa
■ B in North American and Europe
■ C in Southern and Eastern Africa
■ Several clades (e.g., A/G ad A/E) are recombinants
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Geographic Distribution
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Structure of HIV
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Characteristics of HIV
■ HIV infect cells that express CD4 receptor
molecules
■ CD-4 receptor molecules are expressed by Thelper cells and monocyte-macrophage cell lines
■ Successful entry of the virus to a target cell also
requires cellular co-receptors
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Characteristics of HIV (2)
■ A fusion co-receptor is designated CXCR5 for Tcell tropic stain and CCR4 for monocytemacrophage tropic strains
■ The receptor and co-receptors of CD4 cells interact
with HIV’s gp-120 and gp-41 proteins during entry
into a cell
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HIV and Cellular
HIV
HIVReceptors
Receptors
Receptors
Levy JA, NEJM, 335(20); 1528-1530
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13
Role of Chemokine Receptors in HIV Entry
Host Cell Membrane Fusion Via CXCR4
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Pathogenesis and Natural Course of the Disease
16
Pathogenesis and Natural Course of the Disease
17
Cell cytoplasm
Cell nucleus
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Pathogenesis and Natural Course of the Disease
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Life Cycle of HIV: Replication
■ Reverse transcription converse HIV RNA into proviral DNA
■ Importation to cell nucleus
■ Integration of proviral to host-cell DNA
■ Cellular activation causes transcription (copying) of HIV
DNA back to RNA
■ Some RNA translated to HIV proteins
■ Other RNA moved to cell membrane
■ HIV assembled under cell membrane and budded from cell
■ Proteases convert immature to infectious HIV
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Summary of Life
Cycle
of HIV and Sites of
HIV
life cycle
Drug Action
Fusion-Inhibitors
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22
Characteristics of HIV
Once infection is established, the virus homes itself
mainly in the lymphoid and, to a lesser extent, in the
circulation.
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Early Phases of HIV Entry and Replication
at Mucosal Surfaces
Cell free
HIV
CD40—CD40
T-cell
Immature Dendritic
cell
Skin or
mucosa
PEP
24 hours
1.
Burst of HIV
replication
Via lymphatics or
circulation
HIV co receptors,
CD4 + chemokine
receptor CC5
48 hours
2.
Selective of
macrophagetropic HIV
Pathogenesis and Natural Course of the Disease
3.
Mature Dendritic
cell in regional LN
undergoes a single
replication, which
transfers HIV to Tcell
24
Spread of HIV in Host Tissues
Enhanced: Dendritic Cell’s HIV Infectivity
to CD4 T-cell
CD4
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Immunology and HIV
Infection
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Types of Normal Immune Responses
■ Innate – non-specific, “natural,” no prior contact
required
■ Mediated through neutrophils, macrophages, circulating
binding proteins, and natural killer lymphocytes
■ Acquired – specific, learned from contact with
pathogens
■ Mediated through T (cellular signalizing) and B (antibody
producing) lymphocytes and macrophages
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The Normal Immune Response
■ Normal host defense in response to a foreign
antigen culminates in a rapid and efficient
elimination of a non-self substance
■ The process of elimination of a foreign antigen
involves effector-cell activity and their interaction
through soluble cellular secretions (cytokines)
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Specific Normal Immune Response
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Normal Immune-Cell Interaction
plasma
CD-4-4
CTL
CTL
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Specific Immune Response
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32
Peculiar Characteristics of HIV
HIV is a unique infection in that:
■ The virus is not cleared, except partially in the
early period of infection
■ A chronic infection is established, and it persists
with varying degrees of viral replication. The viral
replication continues for about eight to ten years
before bringing in significant immuno-suppresion
■ There is no virological latency
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Infected CD4 T-lymphocyte
HIV
Modified; South Carolina Medical Library
Viral Dynamics of HIV Infection
■ Viral replication is continuous in all stages (early,
during clinical latency and in advanced stages)
■ Half life of a virion is about 6 hours, while an
infected cell has a life span of 1.6 days
■ Daily about 1010 virions are produced and cleared
from the circulation
■ Average generation time of HIV is 2.6 days
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Viral Set Point
■ The level of steady-state viremia (set-point) at six
months to one year after infection has and
important prognostic implication for progression of
HIV disease
■ Those with a high viral set-point have faster
progression to AIDS, if not treated
Pathogenesis and Natural Course of the Disease
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Reasons for Persistent Viremia
Despite robust immune reaction, HIV evades
elimination by the immune system due to:
■ High level of viral mutation
■ Large pool of latently infected cells that cannot be
eliminated by viral-specific CTLs
■ Virus homes in lymphoid organs, while antibody is in the
circulation
■ Exhaustion of CD8 T-lymphocytes by excessive antigen
stimulation
Pathogenesis and Natural Course of the Disease
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Reasons for Persistent Viremia (2)
■ Down regulation of HLA-1 molecule in HIV infected cells
■ HIV attacks CD-4 T-cells, which are central to both
humoral and-cell mediated immunity
■ HIV seeds itself in areas of the body where sufficient
antibodies might not reach, e.g., the central nervous
system
Pathogenesis and Natural Course of the Disease
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Pathogenesis of HIV
■ HIV infection is a disease characterized by a
profound immunodeficiency from progressive
decline of T-helper cells
■ The pathogenetic mechanism of HIV disease is
multifactorial and multiphasic and it differs in
different stage of the disease
Pathogenesis and Natural Course of the Disease
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Effects of Cellular Activation
■ Quiescent but infected CD4 T-cells start to
transcript, making viral spread more efficient
■ Cellular activation induces expression of receptors
for HIV
■ Chronic stimulation favors programmed cell death
(apoptosis) to CD4, CD8 and B-cells
■ Significant increase in the release of cytokines
Pathogenesis and Natural Course of the Disease
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Effects of Cellular Activation (2)
■ Brings about up-regulation of viral expression and
cellular activation
■ Initiates auto-immune phenomena
■ Brings about compromised immune response to
broad spectrum of antigens
■ Co-infection (TB, CMV, etc.) also induces viral
replication
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41
Cytokines in HIV
■ The immune system is regulated by a complex of
immuno-regulatory cytokines
■ Cytokines are cellular products that induce or
suppress cellular activity
■ Inducers of HIV expression include: IL-1, IL-2, IL-3,
IL-6, IL-12, TNF-Alfa, TNL-beta, M-CSF and GMCSF
■ The most potent inducers are pro-inflammatory
cytokines, TNF-Alfa, IL-1and IL-6, which are
products of macrophages
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Cytokines in HIV (2)
■ T-helper cells are classified as TH-1 and TH-2
based on the type cytokines they release
■ TH-1 type secrete IL-2 and INF-Alfa, which favor
cell-mediated immune response
■ TH-2 type secrete IL-4, IL-5 and IL-10, which favor
humoral immune response
■ HIV-infected individuals show decreased TH-1 type
response in relation to TH-2
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Effect of IL-2
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T-cell Abnormalities
■ Late in the course of illness, there are qualitative
and quantitative abnormalities
■ T-cell abnormalities detected in the course of the
illness are manifested as CD4 and CD8
abnormalities
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CD4 Cell Abnormalities
■ Defective T-cell cloning and colony-forming
efficiency
■ Impaired expression of IL-2
■ Defective IL-2 and INF-Alfa production
■ Decreased help to B-cells in production of
immunogloblins
■ Marked reduction in their number
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46
CD8 Cell Abnormalities
■ Remain high after primary infection and throughout
the latent period
■ In advanced stage, there is marked reduction
■ HIV-specific clones of CD8 CTLs that are present
in the early phase of illness disappear in advanced
period
■ In the face of depleting CD4, the homeostatic
mechanism responsible for maintaining total T-cells
in a normal range replaces CD8, leading to CD8
lymphocytosis
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Mechanism of CD4 Cell Depletion
■ HIV-mediated direct cytopathicity (singe cell killing)
■ HIV-mediated syncytia formation
■ Defect in CD4 T-cell regeneration in relation to the
rate of destruction
■ Maintenance of homeostasis of total T-lymphocytes
(decreased CD4, increased CD8)
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Mechanism of CD4 Cell Depletion (2)
■ HIV-specific immune response (killing of virally
infected and innocent cells)
■ Auto-immune mechanism
■ Programmed cell death (apoptosis)
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Apoptosis (Programmed Cell Death)
Guisoppe et.al. NEJM 328,1993
B-cell Activity in HIV
■ There is no quantitative abnormality
■ Has abnormal activation with spontaneous
proliferation and IG, IL-6 and TNF-Alfa secretion
■ B-cells are defective for antigen stimulation
■ HIV can directly stimulate B-cells leading to
hypergammaglobulinemia
■ Cannot mount sufficient humoral immunity to
common bacterial antigen
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Monocyte Macrophage Activity
■ Circulating monocytes are generally normal in HIV
infection
■ Cytopathic effect of HIV to monocyte macrophage
is low
■ HIV can intensely replicate in monocyte
macrophage cell line
■ There is defective function, like in antigen
presentation, chemotaxis, secretion of IL-1 and in
induction of T-cell response
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Humoral Immune Response
■ Neutralizing antibodies appear following primary
viremia with CTLs
■ Antibodies are produced to multiple epitopes of
HIV
■ HIV antibodies are used as diagnostic tool
■ Generally their preventive role is unknown
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53
Primary HIV Infection
■ Following primary infection there is initial viremia
■ The phenomena of dissemination of virus to
lymphoid organs is the major factor in
establishment of chronic and persistent infection
■ Whatever the route of entry the virus, it reaches a
lymphoid organ, where it bases itself and replicates
extensively
■ Intense replication brings about a burst of viremia
which triggers HIV-specific antibody
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Primary HIV Infection (2)
■ Primary viremia lasts several weeks
■ The set-point (steady state) plasma viremia at six
months to one year correlates with disease
progression (those with low set point develop
advanced disease slowly)
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Pathogenesis of HIV Infection: No
Progression with Low-level Viremia
Primary HIV Chronic Non-progressive HIV Infection
CD4
RNA Set Point ~ 103
RNA
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Pathogenesis: Average Progression
with Median-Level Viremia
Primary HIV
Slowly Progressive HIV
AIDS
RNA Set Point ~104
RNA
CD4
1
5
10
Years
Pathogenesis and Natural Course of the Disease
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Pathogenesis: Rapid Progression
with High-Level Viremia
Primary HIV
RNA
AIDS
RNA Set Point ~ 106
CD4
3
2
Years
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HIV RNA Levels Predict Progression to
AIDS
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Relating Disease Progression to Plasma
HIV-1 RNA Level and CD4 Cell Count
Viral Load
1,000
100
10,000
200
100,000
300
400
1000
900
800
700
600
500
+
CD4 COUNT
Adapted with permission from Coffin. AIDS. 1996;10(suppl 3):S75-S84.
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60
Chronic and Persistent Infection
■ HIV-specific antibody partially clears the virus
■ There is clinical latency
■ Initial clones of CD8 lymphocytes CTLs, which
partially control viremia, are later lost
■ There is progressive drop in CD4 T-cells
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Advanced HIV Disease
■ CD4 cells fall below critical level: <200cells/ml
■ Patients present with OIs or malignancy
■ Higher degree of viremia due to destruction of
lymphoid organs
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Natural History of HIV Disease from HIV
Transmission to Death (no ARV)
•
Fauci AS, Pantaleo G, Stanley, Weissman D. Immunopathogenic
mechanisms of HIV infection. Ann Intern Med 1996;124:654-63.
Window Period: Untreated Clinical
Course
Primary Acute HIV syndrome
HIV
infection
Asymptomatic
antibody
viremia
--------------------------------------------PCR
P24
ELISA
a
b
Time from a to b is the window period
0
2
3 4
Weeks since infection
years
Source: S Conway and J.G Bartlett, 2003
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Laboratory Markers of HIV Infection –
Immune Suppression
Markers of immunologic damage by HIV: subsets of
T-lymphocytes
■ Functional surface proteins (CD4 and CD8) used
to count
■ Normal Values
■ Helper / CD4 + cell count = 400-1200
■ Suppressor/ CD8 + cell count = 400-800
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Key Points
■ HIV infection is a chronic disease
■ The immune system is the target of HIV
■ Clinically there are different stages based on
immunocompetence
■ During clinical latency, there is no virological
latency
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Key Points (2)
■ The effect of immune system delays the onset of
clinical disease
■ HIV can be suppressed, but there is no cure
■ Ultimately the immune system is destroyed, with a
few exceptions
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