Exosomes as New Players in HIV Pathogenesis - New Data from the IAS 2017.

Exosomes are nanovesicles that can be released into the extracellular medium by different cell types and are considered an important system of intercellular communication. In some instances, on secretion, exosomes break down and release their content into the extracellular space. Alternatively, intact exosomes can interact with other cells and discharge their content directly into the target cell cytoplasm. Exosomes are rich in endosome-associated proteins (i.e., the tetraspanin family) but also carry different molecules in their lumen including proteins, RNAs (i.e., microRNAs), and pathogenderived cargo. Indeed, the different biological functions of exosomes might depend on their cargo components. Several recent publications have identified exosomes as new players in the pathogenesis of HIV infection. This is an emerging field of growing interest that deserved a satellite symposium at the 9th IAS Conference held in Paris in July 2017, sponsored by the International Society for Extracellular Vesicles (EVs). Although the role of exosomes in HIV infection is not yet clarified, accumulating data suggest that exosomes may act at different levels of HIV pathogenesis by modulating immune responses, infectivity, or even by activating the latent viral reservoir. However, there are still methodological limitations that need to be resolved to advance our understanding of the role of exosomes in HIV infection. One particular limitation is to define an accurate and reproducible procedure for their isolation. A new strategy to separate exosomes from HIV-1-infected cells was proposed at this symposium. Martin-Jaular and colleagues (Institut Curie, France) used velocity centrifugation gradients and antibody labeling of specific endosome-associated protein markers (i.e., CD45+ and AChE+) to isolate pure exosomes from complex preparations of EVs. Separately, Arakelyan and colleagues (NIH, USA) used flow cytometry coupled with magnetic nanoparticles to characterize the antigenic composition of EVs and demonstrate that EVs carrying HIV envelope proteins facilitated HIV infection. This is an interesting observation that could lead to the discovery of new antiviral drugs targeting EVs that contain HIV-Env. Exosomes might also have an effect on the viral reservoir. Kashanchi et al. (George Mason University, USA) presented interesting results demonstrating how exosomes from HIV-uninfected cells could reactivate latent HIV-1 in infected cells. They proposed a mechanism in which exosomes might increase RNA polymerase II loading onto the HIV-1 promoter in the infected cells, thereby facilitating transcription and leading to an increase of cellular activation. These presentations represent just a small piece of the growing body of research focused on the role of exosomes in HIV infection. We stand at the beginning of a new source of knowledge of HIV pathogenesis that may provide novel strategies to control HIV infectivity, regulate HIV-reactive immune responses, and act against the HIV reservoir. The impact of exosomes on HIV infection at all these levels should be considered in ongoing and future approaches to achieve HIV remission and cure.