Dendritic Cells Pulsed with HIV-1 Release Exosomes that Promote Apoptosis in Cd4+ T Lymphocytes

Abstract

Loss of mucosal CD4TL (CD4 + T lymphocyte) cells is a salient characteristic of infection by the human immunodeficiency virus-1 (HIV-1). While several mechanisms promoting T cell apoptosis have been proposed, they fail to explain fully the observed T cell loss. Dendritic cells (DCs) are thought to play a pivotal role in the spread of HIV-1 throughout the organism, both establishing and maintaining the infection. DCs capture virions, enclose them in late endocytic compartments and subsequently deliver them to target cells. Internalized viral particles are found in cellular compartments that also contain nanovesicles known as exosomes. These vesicles and virions are released together by DCs. Whether or not exosomes are benign in HIV-1 pathogenesis is unknown. We therefore examined the effect of exosomes derived from HIV-1-infected DCs on CD4TL viability and HIV infectivity in CD4TL. DCs exposed to HIV-1 release more exosomes into the extra-cellular media than do control cells. By processing culture supernatant of infected DCs to separate HIV-1 from exosomes, we showed that the latter produce a pro-apoptotic profile in CD4TL. The purified HIV-1 fraction allows greater viability of CD4TL but is more infectious than the exosome-containing fraction. Altogether, our results suggest that exosomes derived from HIV-1-infected DCs can bring about apoptosis of CD4TL and might thereby limit HIV infectivity in the infectious synapse. Exosome release appears to be an important immune modulator mechanism while appearing paradoxically to contribute to the T-cell depletion observed following HIV infection.