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 Fusion2.Entry3.Reverse transcription4.Integration5.Viral RNA and protein expression6.Assembly and budding7.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

(S

ep

ara

te S

cale

s)

CD4+ T cell

HIV viral loadCD8+ T cell

Neutralizing Antibodies

Years

AIDS and DeathAcute Asymptomatic

(clinical latency)

4 – 8 weeks

Primary infection

HIV disease progression –Acute infection

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

Stem Cell

MatureT-Cells

HIV Infected Cells

HIV-SpecificT Cell

Expansion ofHIV-Specific

Cells

Killing of HIV Infected Cells

Incomplete Clearance of HIV Infected Cells

and Exhaustion

HIV Specific T Cell Responses

Thymus Periphery

RT

RT

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RT

RT

RT

RT

RT

RT

RT

RT

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RT

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

(S

ep

ara

te S

cale

s)

CD4+ T cell

HIV viral loadCD8+ T cell

Neutralizing Antibodies

Years

AIDS and DeathAcute Asymptomatic

(clinical latency)

4 – 8 weeks

Primary infection

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

• Chronic immune activation is a characteristic of HIV disease progression.

• Activation markers expressed on cell surface: CD69, CD25, and MHC

class II, CD38, etc.

Markers of disease progression: Immune activation markers

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?