Grant: Operating Grant - PA: HIV/AIDS Research Initiative - Biomedical/Clinical Stream

The goal of the research is to characterize the role of exosomes in acute HIV-1 infection. Exosomes are nanovesicles released from many cell types and bear certain similarities to HIV-1 particles. Serving generally as garbage cans, they carry proteins or microRNA, which means they could also regulate complex functions including immune response by acting as intercellular communicators. Since they are released from HIV-1-stimulated dendritic cells (DCs) or CD4 T lymphocytes (CD4TL), we think they are active participants in the early events of HIV-1 pathogenesis. Initial interaction between HIV-1 and DCs occurs through virus-associated lectin attachment factors, for which we have identified the dendritic cell immunoreceptor (DCIR). This allows the virus to escape from the immune response and be transported to the lymphoid organs, where it gains entry into CD4TL by cell-to-cell transmission from DCs. Subsequent replication leads to severe and irreversible depletion of CD4TL (TH17), which appears to be a major factor in the ineffectiveness of the immune response to HIV-1. The chronic inflammation due to increased microbial translocation and possibly associated with defective neutrophil function, another early sign of AIDS progression, also appears to result from TH17 depletion. The so-called early events involve complex interactions between HIV-1, DC, CD4TL and neutrophils, and exosomes might serve as intercellular communicators between them and hence as biomarkers of different disease stages. We therefore propose to investigate the following hypotheses: 1) that exosomes are involved in communication between TH17 and neutrophils; (2) that binding of HIV-1 to DCIR leads to the release of exosomes from DCs and CD4TL and (3) that proteins and microRNA contained in these exosomes are useful biomarkers for the development of AIDS.