HIV pathogenesis

The course of HIV infection 1. Acute Phase 2. Intermediate (asymptomatic) phase -viral load stabilizes at a “set point”. 3. Late (symptomatic) phase Acute AIDS Asymptomatic

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

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 From Brenchley et al. JEM 200, The ileum before and after HIV ---Malabsorption, diarrhea, weight loss---Malabsorption, diarrhea, weight loss

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 non- pathogenic SIV infection

Sooty mangabeys SIVsm Rhesus macaques SIVmac Humans HIV-1 AIDSNo disease African green monkeys SIVagm

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. ---Immune activation is low. In sooty mangabeys:

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

Plasma LPS levels are a quantitative indicator of microbial translocation What about non-pathogenic infection? Increased plasma LPS levels in HIV + individuals

No evidence for microbial translocation in non-pathogenic natural SIV infection of sooty mangabeys Non-Pathogenic Natural SIV Infection

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 drives a cycle of immune activation, CD4 T-cell infection and death, and immune deficiency HIV pathogenesis Cytopathicity AICD Pyroptosis of abortively infected cells Targeting of Th17 and Tcm cells

Question What happens in non-pathogenic SIV infections e.g. sooty mangabeys, AGMs?