HIV-I modulates the survival and proliferation of microglia in HIV encephalitis and in a culture model

Abstract

Despite the advent of HAART, HIV-associated dementia remains a significant disease in AIDS patients. Productive infection of parenchymal microglia in HIV encephalitis (HIVE) has been recognized, but its relative importance (compared with infection of perivascular macrophages) has been challenged in a study of Simian Immunodeficiency Virus (SIV) encephalitis (SIVE). Williams et al. reported that only perivascular macrophages expressed CD14 and CD45, as well as SIV proteins, and that microglia are not infected based on the lack of marker expression. Thus, my first goal was to quantitatively analyze the pathology of HIVE to determine (1) the relative contribution of perivascular macrophages and parenchymal microglia in productive HIV infection and (2) the usefulness of the myeloid lineage markers CD14 and CD45 as tools to distinguish macrophages from microglia. Our data demonstrate that microglia constitute approximately two-thirds of the infected cell population in HIVE and that both CD14 and CD45 are expressed in activated microglia, as well as in perivascular macrophages.;I tested the hypothesis that HIV expression influences cell fate in infected macrophages and microglial cells in HIVE. White matter sections of HIVE and control brains were analyzed using the TUNEL assay and the macrophage and microglial marker CD68. We found more TUNEL+/CD68+ cells in HIVE compared to controls; however, due to the increase in the number of total CD68+ cells in HIVE, the frequency of apoptotic macrophages was similar in HIVE and control brains. More importantly, there was a tendency for fewer TUNEL+/p24+ cells compared to TUNEL+/CD68+ cells, indicating that HIV-infected macrophages and microglia are resistant to apoptosis. Thus, HIV modulation of cell survival may contribute to viral persistence and the formation of a viral reservoir.;My third objective was to examine how HIV infection affects the proliferation of infected cells. Surprisingly, it was found that p24+ microglia are negative for the proliferation marker Ki-67, indicating a G0/G1 arrest. Furthermore, infection with VSV-g env pseudotyped HIV demonstrated a similar cell cycle arrest in HIV-expressing astrocytes in vitro. In vivo double labeling analysis demonstrated that the incidence of Ki-67+ cells was lower in the infected (p24+) cell population compared to that in the total macrophage (CD68+) population. Currently, studies are ongoing to determine the role of viral proteins (Nef and Vpr) and the host cell mechanisms responsible for HIV-mediated growth arrest. These results suggest that activation of cell cycle machinery may be disadvantageous for virus production. (Abstract shortened by UMI.).