HIV pathogenesis The course of HIV infection AIDS

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 R 5 virus R 5 X 4, X 4 50% of AIDS patients

The acute phase of replication 1. Massive replication occurs in gut lymphoid tissue 2. CD 4+ CCR 5+ 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, CD 4+ CCR 5+ memory T-cells, the preferred targets for R 5 virus replication. • Rapid depletion of these T-cells from the GALT can occur even when there is NO DETECTABLE LOSS of CD 4+ T-cells from the peripheral blood.

Asymptomatic phase 1. Viral replication is continuous. 2. CD 4 cell depletion in gut is maintained. 3. All lymphoid tissue is affected. 4. Slow decline of CD 4+ T-cells detected in blood. 5. Ability to maintain homeostasis is undermined

AIDS CD 4 cell number is insufficient to maintain immune control over opportunistic infections. CXCR 4 -using variants emerge in some patients. R 5 viruses may become more aggressive. CD 4 T-cells decline rapidly.

How are CD 4+ T-cells lost? Is it the virus? Or an indirect mechanism?

Causes of CD 4+ 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 CD 4 T-cell depletion. Conclusion: HIV/SIV replication alone is not sufficient to cause lymphocyte depletion or AIDS

Sousa et al. 02 CD 4+ 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, CD 4 cell turnover, immune activation, CD 4 cell depletion. • Non-pathogenic: Profound viremia, CD 4 cell turnover, little immune activation, CD 4 depletion low. • Immune activation may undermine the renewal of CD 4+ 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

CD 4+ T cell depletion allows bacteria to cross the mucosa Are CD 4+ T cells involved in control of bacteria?

Control of Extracellular Microbial Pathogens Neutrophils Th 17 cells • Memory CD 4 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) Th 17 cells are depleted in HIV-infection.

Th 17 cells and other critical CD 4+ T-cell populations are preserved in non-pathogenic infections SM and AGM T-helper memory cells express lower levels of CCR 5. AGM T-helper cells down regulate CD 4 as they enter the memory pool. BUT still function effectively as helper cells. RESULT. Critical cell populations resist SIV replication. These populations include Th 17 and Tcms.

HIV pathogenesis HIV drives a cycle of immune activation, CD 4 T-cell infection and death, and immune deficiency Cytopathicity AICD Pyroptosis of abortively infected cells Targeting of Th 17 and Tcm cells

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