Figure 2

Relationship between macrophages and T lymphocytes in HIV-1 infection. Macrophages harboring HIV-1 play an important role in HIV pathogenesis. Nef stimulates the release of soluble factors ICAM and CD23 which makes uninfected CD4+ T cells more susceptible to HIV infection, thereby favoring the expansion of the viral reservoir (a). In addition, Nef induces the expression of Fas ligand (FasL, CD95L) on HIV-infected cells. Interaction of CD95L and its receptor (Fas) present on uninfected CD4+ T cells results in apoptosis (b). On the other hand in infected CD4+ T cells, Nef inhibits the expression of proteins involved in apoptosis including ASK1, caspase 8 and caspase 3 (c), protects infected CD4+ T cells from cell death and further expands the viral reservoir. HIV regulatory protein Tat stimulates the production and release of TRAIL from the infected macrophages. TRAIL binds with its receptor (DR5) present on uninfected CD4+ T cells and induces apoptosis (d). Furthermore, gp120 interaction with CXCR4 receptor increases the expression of TNF-α on macrophages which interacts with TNFR2 present on CD8+ T cells. This interaction results in the down regulation of the anti-apoptotic protein Bcl-XL and ultimately leads to apoptosis (e). Moreover, HIV infection in macrophages is known to induce macrophage colony stimulating factor (M-CSF) which inhibits the expression of TRAILR1 on macrophages and upregulates the expression of anti-apoptotic proteins (f), favoring the resistance to apoptosis of infected macrophages. Therefore, targeting M-CSF has been suggested to increase apoptosis in infected macrophages.