Mucosal changes and microbial translocation

Enterocytes of the gut epithelium show evidence of apoptosis very early after HIV infection, with a peak 14 days following infection. This apoptosis is accompanied by increased epithelial proliferation and the development of regenerative villous enteropathy, which is characterised by villous atrophy plus micro-abscesses. This process is driven both by T cell activation and failure of mucosal regeneration.(Sankaran et al., 2008)  The compromised mucosal integrity may lead to an increase in circulating bacterial products, such as LPS, as described in graft-versus-host disease and inflammatory bowel disease. Gut permeability is increased 2 to 10 fold in people with HIV infection.(Brenchley et al., 2006b) Chronic HIV disease is associated with increased plasma levels of LPS, a marker of gram negative microbial products, compared with seronegative people and those with early HIV disease. Plasma levels of LPS detected in people with chronic HIV infection were also correlated with other markers of systemic immune activation including HLA-DR and CD38 expression on CD8+ T cells, and plasma levels of IFNα and soluble CD14 (sCD14). (Suffredini et al., 1999) LPS binds to monocytes via CD14, which is released as sCD14 by activated macrophages. (Douek)  Plasma levels of intestinal fatty acid binding protein (I-FABP) also correlate with microbial translocation and inflammation (Perkins et al., 2015) as does the levels of tryptophan metabolites. (Jenabian et al., 2015)  Microbial products may lead to enhanced immune activation by: increase in cytokine production by antigen presenting cells (IFNα and IL-15); increase in the production of cytokines IL-2, IL-4, IL-7 and IL-15 by lymph node cells; and direct activation of plasmacytoid DC. Direct ligation of TLR by bacterial products activates CD4+ and CD8+ T cells to express CD38, CD69 and to drive CD4+ T cells into cycle. TLR2 ligands have been shown to directly induce susceptibility to HIV infection, particularly by CCR5 using HIV-1.(Thibault et al., 2009) Thus, microbial translocation may also increase viral replication and induce T cell loss by indirect mechanisms.  Early use of cART reduces GIT infection and immune activation (Muir et al., 2016; Deleage et al., 2016)

Immune activation in non-pathogenic and pathogenic SIV infection of non-human primates

Further data on the role of immune activation in HIV disease pathogenesis come from African green monkey and sooty mangabey monkey models. Both these animals are infected naturally with SIV, and develop high SIV viral loads but do not lose CD4+ T cells or show development of AIDS. (Broussard et al., 2001)  In contrast, SIV infection of rhesus macaques leads to high SIV viral loads, CD4+ T cell depletion and the development of AIDS as found with HIV infection in humans. Levels of immune activation differ but even in those cases where sooty mangabey monkeys have persisting CD4+ T cell depletion there is no clinical disease. (Milush et al., 2007)  Interestingly, in sooty mangabey monkeys there is a rapid depletion of the gut-associated CD4+ T cells in common with pathogenic infection. (Gordon et al., 2007)

Immune activation in non-AIDS HIV disease and deaths

Immune activation may not only lead to CD4+ T cell decline and impaired host immune responses against opportunistic infections but may also lead to serious non-AIDS events. Chronic immune activation may lead to atherosclerotic vascular disease of the heart and brain, osteoporosis and renal disease that have become increasingly apparent since antiretroviral therapy reduced the incidence of most opportunistic infections and AIDS-related malignancies by up to 80%.