Pathogenesis of HIV Disease - PH.docx

Unit-3

1. Unit 3. Pathogenesis of HIV Disease and Natural History of HIV Infection
Participant Handbook HIV Care and ART: A Course for Pharmacists 3-1




Unit 3


Pathogenesis of HIV Disease
And
Natural History of HIV Infection


Participant Handbook


By Salahadin M.Ali

2. Unit 3. Pathogenesis of HIV Disease and Natural History of HIV Infection
Participant Handbook HIV Care and ART: A Course for Pharmacists 3-2
Aim: The aim of this session is to create basic understanding of the pathogenesis of HIV disease and
the natural history of the HIV virus.
Learning Objectives: By the end of this unit, participants will be able to:

• 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

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

3. Unit 3. Pathogenesis of HIV Disease and Natural History of HIV Infection
Participant Handbook HIV Care and ART: A Course for Pharmacists 3-3

 PowerPoint Slides

The following pages contain the slides to be used during this course as well as the corresponding
notes.

1. Unit 3. Pathogenesis of HIV Disease and Natural History of HIV Infection

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

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 r treatment is given

Notes
Since the initial description of the human immunodeficiency virus type I (HIV-1) in 1983 and
HIV-2 in 1986, these two viruses have been identified for almost 20 years as the primary cause
of the acquired immunodeficiency syndrome (AIDS) and HIV-1 is the major cause of AIDS in
the world today.

Blood cells contain RBCs, Platelets (Thrombocytes), and WBCs (Leucocytes).
WBCs are divided into:

Granulocytes, which do have granules in their cytoplasm
o Neutrophils,
o Esinophils, and
o Basophils,
Lymphocytes
o B-lymphocytes (B-cells),
o T-lymphocytes (T-cells)), and
Monocytes, which leave the blood and become macrophages (phagocytic cells).
T-cells (Crescent disc shape cells =CD1 to CD10) are divided into three as to their function to
perform, otherwise they all look alike under microscope;
 Inflammatory T-cells, which recruit macrophages,
 Cytotoxic T-cells, which kills virus infected and tumor cells, and

4. Unit 3. Pathogenesis of HIV Disease and Natural History of HIV Infection
Participant Handbook HIV Care and ART: A Course for Pharmacists 3-4
 Helper T-cells, which enhance production of antibodies by B-cells.

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 a type of white blood cell that ‘switch on’ the immune system to
fight disease
• HIV uses CD4 cells for reproduction

Note:
Viruses need a receptor on the cell surface in order to attach themselves and get inside. In
order for a cell to be infected by HIV, there must be CD4 receptor molecules present. These
receptors occur on T-cells and other cells in the monocot-macrophage cell lines.

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

Note:
Fusion co-receptor CXCR5 or CCR4 is needed for entry. In some people with naturally
occurring genetic defects at this cellular level, HIV infection can be prevented or lessened. For
most, however, this co-receptor allows HIV to enter the CD4 cell (or other cell).
The gp-120 and gp-41 (glycoprotein layer that we saw on the diagram of the AIDS virus) are
needed for entry into the CD4 cell (or other cell).

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

7. Target Cells of HIV

• Numerous organ systems are infected by HIV:
– Brain: macrophages and glial cells

5. Unit 3. Pathogenesis of HIV Disease and Natural History of HIV Infection
Participant Handbook HIV Care and ART: A Course for Pharmacists 3-5
– 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

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

Note:
Pathogenesis can be grouped by general mechanism of injury

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

Note:
• The effects of HIV on the human immune system are extensive and complex, resulting
in both depletion and dysfunction of all elements of the immune system.

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

11. Syncytium Formation

6. Unit 3. Pathogenesis of HIV Disease and Natural History of HIV Infection
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• 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

Note:
Viral gp 120 can be found on the surface of infected host cells after fusion of viral envelope
and cell membrane, with retention of viral proteins at the cell surface.

12. Apoptosis
12
Courtesy of CDC

Note:
• Apoptosis (pronounced “apoh-toh-sis”) means programmed cell death. CD4 cells may
undergo apoptosis in the presence of HIV infection when they cross-link with other CD4
molecules either by gp-120 alone or gp-120 in complex with anti-gp120 antibodies.
• This cross linking provides the first of two signals required for apoptosis.
• The second signal is the activation of the cell through the T-cell antigen receptor by
either conventional antigen or superantigen.

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

7. Unit 3. Pathogenesis of HIV Disease and Natural History of HIV Infection
Participant Handbook HIV Care and ART: A Course for Pharmacists 3-7
– 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
Note:
Not only does the virus destroy and disrupt the immune system, the virus can manipulate the
immune system to its own replicative advantage. This is achieved by immune activation.
Clinically, this is demonstrated by the observation that viral load transiently increases in the
presence of intercurrent illnesses, such as TB.

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)
Note:
The immune system activation (and disruption) by HIV is mediated by various cytokines

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
Note:
Decline in immune status parallels the decline in CD4 number and function. Loss of these
cells results in failure of normal Th1 response and cell-mediated immunity that is necessary for
controlling intracellular infections.

16. Natural History of HIV Infection

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

8. Unit 3. Pathogenesis of HIV Disease and Natural History of HIV Infection
Participant Handbook HIV Care and ART: A Course for Pharmacists 3-8
– Patients homozygous for the CCR5 mutation are relatively resistant to
transmission

Note:
Study of HIV ”exposed uninfected” individuals revealed the presence of a mutated CCR5
receptor in some people. Patients homozygous for this mutation are relatively resistant to the
virus.

18. Early Phases of HIV Infection of Mucosal Surfaces

Note:
HIV establishes infection across the skin or mucosal surfaces like the cervix or urethra within in
72 hours of its introduction. This information suggests that PEP (post-exposure prophylaxis
with antiretroviral drugs after high-risk blood or sexual contacts) should be immediate.

19. Laboratory Markers of HIV Infection

• Viral load
– Marker of HIV replication rate
– Number of HIV RNA copies/mm
3
plasma
• CD4 count
– Marker of immunologic damage
– Number of CD4 T-lymphocytes cells/mm
3
plasma
– Median CD4 count in HIV negative Ethiopians is significantly lower than that
seen in Dutch controls
• Female 762 cells/mm
3
(IQR 604-908)
• Male 684 cells/mm
3
(IQR 588-832)
Note:
The average CD4 T cell count in HIV-1 uninfected Ethiopians reportedly ranged from 591 ×
10*6 to 775 × 10*6 cells/L

20. Spread of HIV in Host Tissues

9. Unit 3. Pathogenesis of HIV Disease and Natural History of HIV Infection
Participant Handbook HIV Care and ART: A Course for Pharmacists 3-9



Notes:
• Early Events in Transmucosal HIV-1 Infection
• The arrows indicate the path of the virus. The viral-envelope protein binds to the CD4
molecule on dendritic cells. Entry into the cells requires the presence of CCR5, a surface
chemokine receptor. Dendritic cells, which express the viral co-receptors CD4 and CCR5,
are selectively infected by R5 (macrophage-tropic) strains. Within two days after mucosal
exposure, virus can be detected in lymph nodes. Within another three days, it can be
cultured from plasma.



21. HIV Disease Progression

10. Unit 3. Pathogenesis of HIV Disease and Natural History of HIV Infection
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0
100
200
300
400
500
600
700
800
900
1000
0369121234567891011
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


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”

Note:
For about half of patients, in the period immediately after infection, virus titer rises (about 4 to
11 days after infection) and continues at a high level over a period of a few weeks. The patient
often experiences some mononucleosis-like symptoms (fever, rash, swollen lymph glands) but
none of these is life-threatening. Level of viremia is associated with severity of symptoms,
degree of initial CD4 depletion and viral set point during chronic infection.

By this time, infection is already established. Viral replication is already occurring in infected T-
cells, T-cells are dying and latent virus is already hidden in the sanctuaries of the lymphoid
organs, the central nervous system, and latent CD4 cells. Chronic and persistent infection has
been established, and if no intervention the patient will eventually die.

23. Window Period: Untreated Clinical Course

11. Unit 3. Pathogenesis of HIV Disease and Natural History of HIV Infection
Participant Handbook HIV Care and ART: A Course for Pharmacists 3-11 23
--------------------------------------------PCR
P24
ELISA
0 234
Weeks since infection
a bTime 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

Note:
• The window period begins at the time of infection and can last 4 to 8 weeks.
• During this period, a person is infected, infectious and viremic, with a high viral load and
a negative HIV antibody test.
• The point when the HIV antibody test becomes positive is called the point of
seroconversion.

24. Natural History of HIV- 1 24FauciAs, 1996



Note:

12. Unit 3. Pathogenesis of HIV Disease and Natural History of HIV Infection
Participant Handbook HIV Care and ART: A Course for Pharmacists 3-12
• Acute (primary) retroviral syndrome is the initial event after infection, which is characterized
by a rapid decline in CD4 cell count and high plasma viremia.
• Development of cytotoxic T-cell (CTL) response results in clinical recovery of acute
infection and a reduction in plasma viremia. The virus reaches “set point” as a result of this
immune response. The viral load at this “set point” correlates with the rate of CD4 decline
and disease progression. Overtime, HIV RNA levels gradually increase.
• In parallel, the CD4 cell count gradually declines over several years, but rapidly drops 1.5
to 2 years before an AIDS-defining diagnosis.
• When the CD4 count falls below 200, patients develop opportunistic infections, tumors, and
neurological complications. The median survival after the CD4 count has fallen to <200 is
3.7 years, if untreated.

25. Relative Control of HIV: Viral Set Points
25Year 1
Viral load
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


Note:

13. Unit 3. Pathogenesis of HIV Disease and Natural History of HIV Infection
Participant Handbook HIV Care and ART: A Course for Pharmacists 3-13
• The rate of disease progression - is determined by the patient’s viral load.
• With levels between 1,000 and 10,000 viral copies, the likelihood of AIDS in 5 years is 8%.
• At 10,000 to approximately 50,000, the likelihood is 26%.
• At 50,000 to <100,000 it is 49%.
• Between 100,000 to 1,000,000 the likelihood is 62% at 5 years.


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

28. Patterns of HIV Disease Progression
28
HIV HIV
InfectionInfection
LongLong--termterm
NonNon--progressorsprogressors
Rapid ProgressorsRapid Progressors
TypicalTypicalProgressorsProgressors
<<33yearsyears
77--1010yearyearss
>>1010--1515yryrss
NormalNormal,,Stable CDStable CD44
9090%%
<<55%%
<<1010%%

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)


30. Acute Retroviral Syndrome

14. Unit 3. Pathogenesis of HIV Disease and Natural History of HIV Infection
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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

31. Acute Retroviral Syndrome
Lab markers

• 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

• 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

33. 33
VIRAL TRANSMISSION
VIRAL TRANSMISSION
ACUTE RETROVIRAL SYNDROME
ACUTE RETROVIRAL SYNDROME
RECOVERY AND SEROCONVERSION
RECOVERY AND SEROCONVERSION
2-3 WEEKS
2-3 WEEKS or longer



34. Clinical Latency

15. Unit 3. Pathogenesis of HIV Disease and Natural History of HIV Infection
Participant Handbook HIV Care and ART: A Course for Pharmacists 3-15

• 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.)

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 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