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.
2.
3.
4.
5.
6.
7.
Binding and Fusion
Entry
Reverse transcription
Integration
Viral RNA and protein expression
Assembly and budding
Maturation
HIV target cells:
CD4T cells,
Macrohpages,
Dendritic cells
Overview of adaptive immunity
Nonspecific
Specific
Clearance of viral infection
HIV disease progression –
clinical latency
Levels (Separate Scales)
Primary
infection
Acute
Asymptomatic
(clinical latency)
CD8+ T cell
AIDS and
Death
HIV viral load
Neutralizing Antibodies
CD4+ T cell
4–8
weeks
Years
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
T
R
T
R
T
R
T
R
T
R
T
R
T
R
T
R
T
HIV Infected Cells
Killing of HIV
Infected Cells
R
T
R
T
R
T
R
T
HIV-Specific
T Cell
Mature
T-Cells
Stem Cell
Expansion of
HIV-Specific
Cells
Thymus
Periphery
Incomplete Clearance
of HIV Infected Cells
and Exhaustion
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
Levels (Separate Scales)
Primary
infection
Acute
Asymptomatic
(clinical latency)
CD8+ T cell
AIDS and
Death
HIV viral load
Neutralizing Antibodies
CD4+ T cell
4–8
weeks
Years
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 nonredomized 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?