During infection, part of the cellular environment rewired by HIV-1 is composed by endogenous retroviruses. Studies that have revealed the HIV mediated increase of HERV-K HML-2 proteins, underscored HERV-K potential as an excellent source of antigenic targets for anti-HIV therapy. We have found that during HIV-1 infection of primary CD4+ T-cells, the high expressing HERV-K HML-2 elements are those that are unable to autonomously produce proteins. This creates a conundrum about which are the elements that are at the root of HIV-1 dependent HERV-K HML-2 protein production and by what mechanism they achieve it. We will investigate the mechanism by which HIV-1 mediates HERV-K HML-2 protein upregulation during infection. Furthermore, the repetitive nature of HERV-K HML-2 family has undermined their study in relation to the effect they have on HIV-1, as conventional analysis systems are often insufficient. By combining HERV-K-specific RNA and protein expression analyses we have devised an approach that not only can accurately establish the HERV-K expression profile of different cell types, but also determines which of those expressed HERV-Ks produces proteins and peptides. The identity of the specific elements responsible for HERV-K HML-2 protein expression is essential to investigate the consequences of their expression on HIV-HERV-K interaction, as small differences in amino acid sequence have been demonstrated to have important repercussions on their function. Taken together, this proposal will contribute to a better understanding of the relation between HIV-1 infection and HERV-K protein production, and provide the tools to assess specific HERV-K HML-2 as potential HIV-1-dependent antigenic targets for antiviral therapy.
This proposal describes a plan aimed at exploring the hypothesis that during infection, HIV-1 directly mediates human endogenous retroviruses (HERV) protein production from HERV RNAs that are intrinsically unable to do so. Most of the human endogenous retroviruses (HERVs) are inert, due to either structural or transcriptional roadblocks and these studies will provide insight to which HERV elements are at the root of HERV protein production during HIV-1 infection as well as the mechanism by which HIV-1 mediates such HERV protein production. The results we will obtain are important because they will provide fundamental new knowledge regarding the nature of the HERV-K function and the tools to assess specific HERVs as potential HIV-1- dependent peptide-based biomarkers.