Solving the Puzzle: HIV-1 Restriction by Innate-associated HLA-Mediated Mechanisms

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Remarkable advances have helped to determine how immune responses act to contain HIV-1 infection, but precise immune correlates of protection still remain largely uncharacterized. The HLA region is a major determinant of genetics linked to viral control. HLA-B*57+ individuals are known to progress slowly to disease, and this allele is overrepresented in elite controllers. My preliminary results show a reduced replicative capacity of HIV-1 in PBMC from seronegative HLA-B*57+ subjects, in comparison to PBMC from subjects carrying HLA-B*35, an allele associated with rapid disease progression. In addition, my preliminary results show that HLA-B*57+ individuals have higher gene expression levels of anti-HIV-1 restriction factors, such as APOBEC3A, APOBEC3B, BST2/tetherin and ISG15, correlating with lower viral replication in these latter individuals. Since some HLA-B*57+ individuals can also progress more rapidly to disease, I hypothesize that additional unreported intrinsic anti-HIV-1 factors are at play in the control of viremia in HLA-B*57+ people. I propose to quantify the expression of 14 intrinsic anti-HIV-1 restriction factors in purified CD4+ T cells and monocyte/macrophages using real-time quantitative PCR and quantitative western blotting. Purified cells will be used in in vitro infection assays, and I will investigate several stages of HIV-1 life cycle (reverse transcription, integration and production), aiming at pinpointing which stage is restricted in HLA-B*57+ individuals. I will have access to a cohort of 70 seronegative individuals: 35 homozygous HLA-B*35+ and 35 homozygous HLA-B*57+. Generated results will be analyzed used standard statistical tools, such as the Mann- Whitney Test and Spearman correlations. I anticipate, over the course of 12 months, to elucidate unreported differences in host associated anti-retroviral restriction factors, and determinants in HIV-1 replication in HLAB* 57+ subjects. It is my goal to provide invaluable insights into natural protection mechanisms and immunity against HIV-1, which is of crucial importance to better design an effective HIV-1 vaccine.