HIV-Nef and ADAM17-Containing Plasma Extracellular Vesicles Induce and Correlate with Immune Pathogenesis in Chronic HIV Infection

• Viremic and non-viremic HIV patients harbor high levels of plasma extracellular vesicles.
• Besides inflammatory factors they contain Nef and Vpu, hinting at ongoing viral activity despite efficient ART.
• The level of Nef vesicles correlates with immunactivation and low CD4 levels in chronic HIV infection.Lee et al. found high levels of extracellular vesicles in plasma (pEV) in HIV infection that did not decline under treatment and analyzed a possible correlation with HIV pathogenesis. The pEV contained inflammatory factors and HIV proteins. This was unexpected as viral replication is efficiently suppressed by treatment. The pEV content and viral proteins correlated stringently with symptoms of chronic HIV disease, including low T cell count and increased inflammation. Analyzing the cytokine pattern of HIV pEV it seemed that they were secreted by a so far unknown cell compartment. Suppressing pEV secretion may greatly improve the treatment of chronic HIV infection.

Antiretroviral therapy (ART) efficiently suppresses HIV replication but immune activation and low CD4 T cell counts often persist. The underlying mechanism of this ART-resistant pathogenesis is not clear. We observed that levels of plasma extracellular vesicles (pEV) are strongly elevated in HIV infection and do not decline during ART. Surprisingly, these vesicles contained the viral accessory proteins Nef and Vpu, which are assumed to be not expressed under efficient ART, as well as pro-inflammatory effectors, including activated ADAM17. HIV pEV were characterized by the presence of activated αvβ3 and absence of CD81 and Tsg101. Correlating with immune activation, peripheral monocytes ingested large amounts of pEV, giving rise to an increased population of CD1c+ CD14+ cells that secreted inflammatory cytokines. Importantly, the pro-inflammatory content, particularly ADAM17 activity, correlated with low T cell counts. Preliminary evidence suggested that HIV pEV derived from peripheral mononuclear cells and from an unknown myeloid cell population. In summary we propose an important role of pro-inflammatory pEV in chronic HIV infection due to ongoing viral Nef activity.