Mononuclear phagocyte activation and its role in HIV-1 pathogenesis
Three decades into the HIV-1 pandemic, it is increasingly apparent that generalized immune activation is a key pathogenic determinant of AIDS. Studies of immune activation, in the setting of HIV-1, have focused primarily on the adaptive immune response despite the role of monocytes and macrophages as key regulators of inflammatory responses. In this thesis, I focused on the relationships between mononuclear phagocyte activation and HIV-1 pathogenesis, both in vitro using model systems and in
... l systems and in vivo in African patients with AIDS, Using a monocyte-derived macrophage (MDM) model of Ml and M2a polarization, I found that activation transiently altered the capacity of macrophages to support productive HIV-1 infection and that the level of viral inhibition was dependant on the polarization phenotype. Ml and M2a polarized MDM also differed in the capacity to transmit virus to CD4+ T cells with M2a cells efficiently transmitting HIV-1 via a DC-SIGN dependant mechanism. In a cohort of treatment-naive AIDS patients, in vivo activation of circulating monocytes and intestinal macrophages was strongly associated with HIV-1 pathogenesis. Monocyte activation in these patients was differentially regulated by HIV-1 and circulating LPS (marker of microbial translocation) and was associated with two clearly distinct activation profiles. At the tissue level, HIV-1 was associated with alterations in intestinal macrophage distribution, frequency and phenotype. In the colon, macrophage activation was negatively correlated with viral load and positively correlated with microbial translocation suggesting that, although inflammatory macrophages in the intestine may contribute to the control viral replication, they may also enhance microbial translocation and systemic activation.