Loss of Niemann Pick type C proteins 1 and 2 greatly enhances HIV infectivity and is associated with accumulation of HIV Gag and cholesterol in late endosomes/lysosomes.

BACKGROUND: Cholesterol pathways play an important role at multiple stages during the HIV-1 infection cycle. Here, we investigated the role of cholesterol trafficking in HIV-1 replication utilizing Niemann-Pick Type C disease (NPCD) cells as a model system. RESULTS: We used a unique NPC2-deficient cell line (NPCD55) that exhibited Gag accumulation as well as decreased NPC1 expression after HIV infection. Virus release efficiency from NPCD55 cells was similar to that from control cells. However, we observed a 3 to 4-fold enhancement in the infectivity of virus released from these cells. Fluorescence microscopy revealed accumulation and co-localization of Gag proteins with cholesterol in late endosomal/lysosomal (LE/L) compartments of these cells. Virion-associated cholesterol was 4-fold higher in virions produced in NPCD55 cells relative to virus produced in control cells. Treatment of infected NPCD55 cells with the cholesterol efflux-inducing drug TO-9013171 reduced virus infectivity to control levels. CONCLUSIONS: These results suggest cholesterol trafficking and localization can profoundly affect HIV-1 infectivity by modulating the cholesterol content of the virions.

Antibody against integrin lymphocyte function-associated antigen 1 inhibits HIV type 1 infection in primary cells through caspase-8-mediated apoptosis.

HIV-1 infection induces formation of a virological synapse wherein CD4, chemokine receptors, and cell-adhesion molecules such as lymphocyte function-associated antigen 1 (LFA-1) form localized domains on the cell surface. Studies show that LFA-1 on the surface of HIV-1 particles retains its adhesion function and enhances virus attachment to susceptible cells by binding its counterreceptor intercellular adhesion molecule 1 (ICAM-1). This virus-cell interaction augments virus infectivity by facilitating binding and entry events. In this study, we demonstrate that inhibition of the LFA-1/ICAM-1 interaction by a monoclonal antibody leads to decreased virus production and spread in association with increased apoptosis of HIV-infected primary T cells. The data indicate that the LFA-1/ICAM-1 interaction may limit apoptosis in HIV-1-infected T cells. This phenomenon appears similar to anoikis wherein epithelial cells are protected from apoptosis conferred by ligand-bound integrins. These results have implications for further understanding HIV pathogenesis and replication in peripheral compartments and lymphoid organs.