Pathogenesis of HIV disease

and markers of progression

Anjie Zhen, PhD
 Summary
• Overview of HIV life cycle
• Overview human immune responses
• HIV pathogenesis
– Acquisition of HIV
– Acute infection
– Chronic infection and markers of progression
– AIDS
 Overview of HIV life cycle

HIV life cycle:

1. Binding and Fusion
2. Entry
3. Reverse transcription
4. Integration
5. Viral RNA and protein expression
6. Assembly and budding
7. Maturation

HIV target cells:

CD4T cells,
Macrohpages,
Dendritic cells
 Overview of adaptive immunity

Nonspecific Specific
Clearance of viral infection
 HIV disease progression –
clinical latency
AIDS and
Primary Acute Asymptomatic Death
infection (clinical latency)
Levels (Separate Scales)

CD8+ T cell HIV viral load

Neutralizing Antibodies

CD4+ T cell
4–8 Years
weeks
HIV disease progression
–Acute infection
Primary infection of cells in blood or mucosa
(HIV directly infects T cells and microphages
oris carried to those cells by dendritic cells)

Viral replication in the regional lymph nodes

leads to Exponential viral growth and
widespread dissemination

Development of anti-viral responses and

symptoms of acute infection occur

Decrease in plasma viral load and symptoms

of acute infection resolve
 HIV disease progression --
Clinical Latency

• During this period of the disease, the immune

systems remains competent at handling most
infections with opportunistic microbes
• Few or no clinical manifestation.
• Steady destruction of CD4+ T cells and
steady decline of circulating blood CD4+ T
cells
Mechanism of CD4 T cell depletion in HIV infection
 Mechanism of CD4 T cell depletion in HIV infection

• Infection and killing of infected cells only explain part of the T cells loss
• Chronic immune activation and disrupted T cell homeostasis
 HIV Specific T Cell Responses

R
T
R
R T
T
R
R
T R
T
T
R
R R
T
T T
R
T
HIV Infected Cells
Killing of HIV R
T
R

Infected Cells R
T
R
T

HIV-Specific
T Cell
Mature
T-Cells Incomplete Clearance
Stem Cell of HIV Infected Cells
Expansion of and Exhaustion
HIV-Specific
Cells

Thymus Periphery
 HIV disease progression --
AIDS

• Acquired Immune Deficiency Syndrome:

• Catastrophic breakdown of host defenses,
marked increase in viremia and clinical
disease.
• CD4+ cell count less than or equal to 200 per
microliter
• Clinical Features:
• Opportunistic infection
• Neoplasms
• CNS involvement
 HIV disease progression –
clinical latency
AIDS and
Primary Acute Asymptomatic Death
infection (clinical latency)
Levels (Separate Scales)

CD8+ T cell HIV viral load

Neutralizing Antibodies

CD4+ T cell
4–8 Years
weeks
 Markers of HIV disease progression

• CD4 T cell counts

• Viral load

• Markers of immune activation

 Markers of disease progression: CD4 cell count

• Major Factor to initiate therapy

– CD4<350: strongly recommended (Data from randomized trials)
– <350<CD4<500: strongly recommended (Data from well designed non-
redomized trials or observational cohort studies)
– Cd4>500: moderately recommended
• Prophylaxis against opportunistic infection is based on CD4 counts

The Lancet Volume 360, Issue 9327 2002 119 - 129

 Markers of disease progression: Viral load
• The HIV-1 viral load measurement indicates the number of copies of
HIV-1 RNA per milliliter of plasma.
• Viral load is an accurate reflection of the burden of infection and the
magnitude of viral replication.
• It is critical in monitoring virologic response to ART.

The Lancet Volume 360, Issue 9327 2002 119 - 129

Prognosis according to CD4 cell count and viral
load in the pre-HAART and HAART eras

The Lancet Volume 360, Issue 9327 2002 119 - 129

Markers of disease progression: Viral load set point
 Markers of disease progression: Immune activation
markers
• Chronic immune activation is a characteristic of HIV disease progression.
• Activation markers expressed on cell surface: CD69, CD25, and MHC class II, CD38,
etc.
 Questions
• List key stages for HIV disease progression?
• While CD4 T cells are progressively depleted
during untreated HIV infection, what happens
to CD8 T cells?
• List one important laboratory marker of HIV
disease progression other than CD4 cell count
 Questions
• List key stages for HIV disease progression?
• Acute infection, clinical latency, AIDS.
• While CD4 T cells are progressively depleted during untreated HIV
infection, what happens to CD8 T cells?
• In early HIV infection, CD8 T cells tend to increase in number, in response
to viral infection. However, at advanced stages of HIV disease, CD8 cells
also decline precipitously.
• List one important laboratory marker of HIV disease progression other
than CD4 cell count
• Viral load.
 Discussion

• How will effective anti-retroviral therapy

affect our immune responses?