HIV pathogenesis
The course of HIV infection
AIDS
Acute
Asymptomatic
1. Acute Phase
2. Intermediate (asymptomatic) phase -viral load stabilizes at
a “set point”.
3. Late (symptomatic) phase
HIV-1 phenotypes and disease
Acute
AIDS
Asymptomatic
R5 virus
R5X4, X4
50% of AIDS patients
The acute phase of replication
1. Massive replication occurs in gut lymphoid
tissue
2. CD4+ CCR5+ memory T-cells are main targets
for infection
3. Replication spills out into lymph nodes and
blood
The ileum before
and after HIV
From Brenchley et al. JEM 200,
749-759
-
The importance of gut-associated
lymphoid tissue (GALT)
• GALT is the body’s major reservoir of activated, CD4+ CCR5+
memory T-cells, the preferred targets for R5 virus replication.
• Rapid depletion of these T-cells from the GALT can occur even
when there is NO DETECTABLE LOSS of CD4+ T-cells from
the peripheral blood.
Asymptomatic phase
1. Viral replication is continuous.
2. CD4 cell depletion in gut is maintained.
3. All lymphoid tissue is affected.
4. Slow decline of CD4+ T-cells detected in
blood.
5. Ability to maintain homeostasis is
undermined
AIDS
CD4 cell number is insufficient to maintain
immune control over opportunistic
infections.
CXCR4-using variants emerge in some
patients.
R5 viruses may become more aggressive.
CD4 T-cells decline rapidly.
How are CD4+ T-cells lost?
Is it the virus?
Or an indirect mechanism?
Causes of CD4+ T-cell death
1. Direct killing by HIV infection. HIV-1 is cytopathic.
1. CTL killing of infected cells.
1. Bystander cell death. HIV-1 proteins and toxic
factors induced by immune activation induce
apoptosis of uninfected cells.
2. Indirect killing via chronic immune activation.
(Activation induced cell death.)
3. Aborted infection results in pyroptosis of T-cells
What causes AIDS?
Logically, high levels of virus replication must
be related to causing AIDS
This view is not supported by studies of nonpathogenic SIV infection
Sooty mangabeys
SIVsm
African green monkeys
SIVagm
No disease
Rhesus macaques SIVmac
Humans HIV-1
AIDS
Sooty Mangabeys do not develop disease
---High levels of virus replication.
---Continuous rounds of viral replication with infected cells
dying as quickly as in HIV infections.
---No disease and minimal CD4 T-cell depletion.
Conclusion: HIV/SIV replication alone is not sufficient to
cause lymphocyte depletion or AIDS
Sousa et al. 02
CD4+ T-cell depletion correlates more
closely with levels of immune activation
than viral load.
In sooty mangabeys:
---Immune activation is low.
Cause of pathogenic primate lentivirus
infections
• Pathogenic: Profound viremia, CD4 cell turnover,
immune activation, CD4 cell depletion.
• Non-pathogenic: Profound viremia, CD4 cell turnover,
little immune activation, CD4 depletion low.
• Immune activation may undermine the renewal of
CD4+ T-cells.
• What causes immune activation?
Microbial translocation is a cause of systemic
immune activation in chronic HIV infection.
Brenchley et al. Nature Med. 12: 1365, 2006.
The gut and immune activation in HIV
“Microbial Translocation” — translocation of gut-derived
microbes and/or microbial products to systemic circulation
without overt bacteremia (e.g. IBD)
Microbial Translocation correlates with the degree of systemic
immune activation in these conditions
Increased plasma LPS levels in HIV+ individuals
Plasma LPS levels are a quantitative indicator of microbial
translocation
What about non-pathogenic infection?
Non-Pathogenic Natural SIV Infection
No evidence for microbial translocation in non-pathogenic
natural SIV infection of sooty mangabeys
CD4+ T cell depletion allows bacteria to
cross the mucosa
Are CD4+ T cells involved in control of
bacteria?
Control of Extracellular Microbial Pathogens
Neutrophils
Th17 cells
• Memory CD4 T cells that produce IL-17
• IL-17 is thought to be important for anti-bacterial immunity
• Recruits neutrophils
• Induces production of anti-bacterial defensins
• Induces proliferation of GI enterocytes
• Induces expression of claudins (tight junction components)
Th17 cells are depleted in HIV-infection.
Th17 cells and other critical CD4+ T-cell populations
are preserved in non-pathogenic infections
SM and AGM T-helper memory cells express lower levels of
CCR5.
AGM T-helper cells down regulate CD4 as they enter the
memory pool. BUT still function effectively as helper cells.
RESULT. Critical cell populations resist SIV replication. These
populations include Th17 and Tcms.
HIV pathogenesis
HIV drives a cycle of immune activation, CD4 T-cell
infection and death, and immune deficiency
T-cell
T-cell
T-cell
T-cell
T-cell
T-cell
T-cell T-cell
Gut leakage
Microbial translocation
T-cell
Susceptible, activated
target cells
★Cytopathicity
cytopathicity
AICD
IMMUNE
DEFICIENCY
T-cell
★ pyroptosis of abortively
Pyroptosis
of abortively
infected
T-cells
infected cells
★Targeting
AICD of Th17
and Tcm cells
Question
What happens in non-pathogenic SIV infections
e.g. sooty mangabeys, AGMs?