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.
Binding and Fusion (let me in!)
Reverse transcription (I’m weird)
Integration (I am not going
anywhere!)
4. Viral RNA and protein expression
(Make more viruses!)
5. Assembly and budding
(go and infect more cells!)
6. Maturation
HIV target cells:
CD4T cells,
Macrohpages,
Dendritic cells
Overview of adaptive immunity
Nonspecific
Specific
Overview of adaptive immunity
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
Virus escapes immune surveillance
R
T
Escape
Immune
pressure
T cell exhaustion during persistent infection
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 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
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 to improve our immunity against HIV?
Engineer HIV resistant cells
1) Entry
C4
6 2) Uncoating
CCR5
Trim5a
3) Reverse
transcription
9) Budding,
maturation
8) Assembly
7) Translation
4) Integration
6) RNA export
5) Transcription
ZFN
s
ZFNs
CCR5
siRNA/
ribozyme
Restriction factors
inhibitor
C46
Rh-hu Trim5a
Stem-cell-based gene therapy for HIV infection. Zhen A, Kitchen S1.
Broad neutralizing antibodies
CD4-Zeta Chimeric Antigen Receptor
D
1
D
2
CD4
D
3
D
4
CD4-Tm
TCR
Zeta
 Contains the CD4 molecule extracellular
and transmembrane domains,CD3 zeta
signaling domain.
 Recognizes HIV gp120 independent of
HLA restriction.
 Ligation induces T cell receptor
signaling/activation.
 Previously used in peripheral T cells in
multiple clinical trials: stable, safe
engraftment and persistence >10 years.
 Modest clinical efficacy due to functional
defects in modified peripheral T cells
 Virus unlikely to be able to escape its
recognition
Stem cell based approach with Protective CD4 chimeric antigen receptor:
Summary
5’ LTR
H1
CCR5
CCR5
sh1005
HIV
R
T
Protected
from Infection
CD4
7SK
sh516
UbC
EGFP
2A
CD4-zeta
ΔLTR
CD3-zeta
CCR5 siRNA
5’
LTR
H
1
CCR5
sh100
5
HIV siRNA
7S
K
sh5
16
Pro-inflammatory cytokines
CTL
Ub
C
EGFP
2
A
CD4-zeta
ΔLT
R
Resistant to HIV infection
Differentiate into effector
cells and expand upon HIV
infection
Killing of infected T cells
HIV infection
EGFP