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Pathogenesis of HIV Disease.ppt
1. Pathogenesis of HIV Disease
and
Natural History of HIV Infection
Unit 3
HIV Care and ART: A Course for
Healthcare Providers by
Salahadin M.Ali
1
2. Learning Objectives
• Describe the characteristics of HIV
• Understand how HIV attacks the body’s
immune system
• Explain how the body’s immune system
responds to HIV infection
• Discuss the natural course of HIV disease and
its clinical implications
2
3. Characteristics of HIV
• HIV is a chronic viral infection with no cure
• HIV primarily affects the CD4 lymphocyte
• When CD4 cells are destroyed, a person’s
immunity is impaired
• As immune function decreases, opportunistic
infections increase
• HIV progresses over time to death, if no
treatment is given
3
4. Characteristics of HIV (2)
• HIV infects cells that express CD4 receptor
molecules
– T4-lymphocytes (T-helper cells)
– Monocyte-macrophage cell lines
• T4-lymphocytes are type of white blood cell
that ‘switch on’ the immune system to fight
disease
• HIV uses CD4 cells for reproduction
4
5. Characteristics of HIV (3)
• Successful entry of the virus to a target cell
also requires cellular co-receptors
• A fusion co-receptor is designated CXCR4 for
T-cell tropic strain and CCR5 for monocyte-
macrophage 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
5
6. How does HIV disseminate?
• One of the cell types first encountered HIV-1 following sexual
transmission are dendritic cells (DC)
• DC capture HIV-1 through C-type lectin receptors, of which
the best studied example is DC-SIGN(CD209), which mediates
HIV-1 internalization
• DC can keep the virus infectious for several days and are able
to transmit HIV-1 to CD4 T cells.
• Subsequent transmission to T cells takes place via an
“infectious synapse,” but a virus that has not been
internalized can also be transmitted to T cells
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7. Target Cells of 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 macrophages
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8. 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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9. 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
9
10. 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
10
11. Syncytium Formation
• A mass of protoplasm containing several
nuclei
• 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. 11
13. 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
13
14. 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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15. 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
15
17. Transmission
• Modes of infection
– Sexual transmission at genital or colonic mucosa
– Blood transfusion
– Mother to infant
– Accidental occupational exposure
• Viral tropism
– Transmitted viruses are 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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18. Cell free
HIV
Skin or
mucosa
24 hours 48 hours
1. HIV co-receptors,
CD4 + chemokine
receptor CCR5
Immature
Dendritic cell
3. Mature Dendritic cell in
regional LN undergoes
a single replication,
which transfers HIV to
T-cell
Via lymphatics or
circulation
T-cell
PEP
Burst of HIV
replication
2. Selective of
macrophage-
tropic HIV
Early Phases of HIV Infection of Mucosal
Surfaces
18
19. 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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21. 0
100
200
300
400
500
600
700
800
900
1000
0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11
weeks years
CD4+ cells
modified after Pantaleo et al., NEJM, 1993
Primary HIV infection
Acute HIV Syndrome
(Acute RetroviralS~)
clinical
latency*
constitutional
symptoms
plasma
viremia
AIDS
very
early disease
early disease
advanced disease
* high rate of replication
in lymphoid tissue
steady state
21
HIV Disease Progression
22. 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)
• 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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23. Window Period: Untreated Clinical Course
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--------------------------------------------PCR
P24
ELISA
0 2 3 4
Weeks since infection
a b Time from a to b is the window period
viremia
antibody
Asymptomatic
Acute HIV syndrome
Primary
HIV
infection
Source: S Conway and J.G Bartlett, 2003
years
25. Relative Control of HIV: Viral Set Points
25
Year 1
Predictor for:
-Disease progression
-Risk of transmission
Low set point = slower
disease progression
High set point = faster
disease progression
26. 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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27. 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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28. Patterns of HIV Disease Progression
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HIV
Infection
Long-term
Non-progressors
Rapid Progressors
Typical Progressors
<3 years
7-10 years
>10-15 yrs
Normal, Stable CD4
90 %
<5 %
<10 %
29. Immune Response in Children
• Absolute CD4 cell count age-dependent (disease
progression expressed as CD4%)
• Variability in disease progression similar to adults
• Viral set point is higher in children
25-30 % die within 1 year (rapid progressors)
• 50-60 % die within 3 to 5 years
• 5-25 % live beyond 8 years (slow
progressors)
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30. Acute Retroviral Syndrome
Clinical
• Non-specific ‘flu-like’ symptoms, which do
not lead directly to the diagnosis of HIV
infection and which are not present in all
patients
• Fever
• Fatigue
• Pharyngitis
• Lymphadenopathy
• Rash
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31. Acute Retroviral Syndrome
Lab markers
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• HIV test May be Negative
• HIV RNA levels (usually >50 000 copies)
Period of extreme infectiousness
Be aware of false negatives
• Using rapid tests >95% of patients will
test positive within 6 months
32. Acute Retroviral Syndrome:
Management
32
• Clinical management is primarily
symptomatic, unless serious and prolonged
seroconversion illness (e.g. meningitis):
HAART
• Goal is to give appropriate counseling and
education to prevent further spread
• Issues to consider:
• Patient’s self-reproach
• Implication for patient’s lifestyle
• Patients are most likely to transmit HIV during
the early stage of infection
34. Clinical Latency
• At CD4 cell counts over 500 cells/ml, many
complications overlap with conditions found in
the general population (malaria, bacterial
pneumonia, tuberculosis, minor skin
conditions) although they may be more
frequent
• At CD4 counts between 200 and 500 cells/ml,
other conditions, or opportunistic infections,
begin to appear (Kaposi’s sarcoma, oral or
vaginal candidiasis, herpes zoster, etc.)
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35. Key Points
• HIV is a retrovirus, capable of integrating into host genome
and establishing chronic infection
• 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
• HIV activates the immune system initially 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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