HIV, Intermediate Monocytes, and Endothelial Colony Forming Cells



 DESCRIPTION (provided by applicant): Cardiovascular disease is a leading cause of morbidity and mortality in the HIV-infected population. Accumulating evidence suggests that the systemic inflammation, particularly involving inflammatory monocytes, may contribute to accelerated atherosclerosis in HIV. But the mechanisms by which these monocytes lead to cardiovascular disease in HIV (HIV-CVD) remain unclear. Our group has pioneered the study of endothelial progenitor cells as a key component of the atherosclerotic pathway. We have now established a widely acknowledged method which correctly isolates 'true' endothelial progenitor cells, which we call endothelial colony forming cells (ECFC) because of their ability to generate endothelium and vessels in vivo. Our preliminary data suggest that HIV infection may lead to greater numbers of ECFC in order to repair HIV-induced endothelial damage but that this ECFC response may be inappropriately blunted in those with greater inflammatory monocyte burdens. Given the high interest in endothelial progenitor cells in the development of HIV-CVD, the proposed 'next step' investigations in this application are of potentially high significance by investigating the role o ECFC in HIV. Thus, the central objective of this application is to determine the pathologic relationships between intermediate CD14++CD16+ monocytes and ECFC in HIV as a completely new avenue of research towards understanding and preventing HIV-CVD. This objective will be addressed by meeting the following Specific Aims: Specific Aim #1: To determine the relationships between HIV, intermediate monocytes, and ECFC numbers. We hypothesize that circulating CD14++CD16+ monocytes levels will negatively correlate with ECFC levels in both ART-naïve and integrase inhibitor-treated HIV-infected patients but not in uninfected controls. Importantly, ECFC will be measured by flow cytometry and validated by colony forming assays in the 23 participants in each of these three study groups. Specific Aim #2: To determine the effects of intermediate monocytes on ECFC function in HIV. Using whole blood samples from the same three groups in Aim #1, we will test the hypothesis that ex vivo CD14++CD16+ cells from both groups of HIV-infected patients will inhibit ECFC proliferative capacity in culture more than CD14++CD16+ cells from uninfected controls. Isolated monocytes will be co-cultured with uninfected control ECFC, and the potential detrimental effects of CD14++CD16+ cells on ECFC clonal proliferative assays and capillary forming ability will be assessed. Our multidisciplinary group of translational investigators has the expertise and resources to meet these Aims. These studies will generate the needed preliminary data to establish a new pathologic model of HIVCVD. As such, this application clearly meets the objectives of RFA-HL-14-029.