HIV pathogenesis

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HIV pathogenesis
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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
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HIV-1 phenotypes and disease
Acute
AIDS
Asymptomatic
R5 virus
R5X4, X4
50 of AIDS patients
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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

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The importance of gut-associated lymphoid tissue
(GALT)

• GALT is the bodys 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.

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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

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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.
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How are CD4 T-cells lost?
Is it the virus? Or an indirect mechanism?
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Causes of CD4 T-cell death

• Direct killing by HIV infection. HIV-1 is
  cytopathic.
• CTL killing of infected cells.
• Bystander cell death. HIV-1 proteins and toxic
  factors induced by immune activation induce
  apoptosis of uninfected cells.
• Indirect killing via chronic immune activation.
  (Activation induced cell death.)
• Aborted infection results in pyroptosis of
  T-cells

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What causes AIDS?

• Logically, high levels of virus replication must
  be related to causing AIDS

This view is not supported by studies of
non-pathogenic SIV infection
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Sooty mangabeys SIVsm
Rhesus macaques SIVmac
Humans HIV-1
African green monkeys SIVagm
AIDS
No disease
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Sooty Mangabeys do not develop disease
---High levels of virus replication. ---Continuou
s rounds of viral replication with infected cells
dying as quickly as in HIV infections. ---No
disease and minimal CD4 T-cell depletion. Conclus
ion HIV/SIV replication alone is not sufficient
to cause lymphocyte depletion or AIDS
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• 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.
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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?

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Microbial translocation is a cause of systemic
immune activation in chronic HIV infection.
Brenchley et al. Nature Med. 12 1365, 2006.
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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
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Increased plasma LPS levels in HIV individuals
Plasma LPS levels are a quantitative indicator of
microbial translocation What about
non-pathogenic infection?
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Non-Pathogenic Natural SIV Infection
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CD4 T cell depletion allows bacteria to cross
the mucosa

• Are CD4 T cells involved in control of bacteria?
  

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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.
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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.
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HIV pathogenesis
HIV drives a cycle of immune activation, CD4
T-cell infection and death, and immune deficiency
Cytopathicity AICD Pyroptosis of
abortively infected cells Targeting of Th17 and
Tcm cells
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Question What happens in non-pathogenic SIV
infections e.g. sooty mangabeys, AGMs?