In the three decades of the HIV epidemic, it has become clear that HIV-1 can be well controlled by drugs, but not eliminated. Alternative strategies, which target host factors important in HIV infection and offer protection from or cure of HIV-1 infection, need to be developed. Genome-wide association studies (GWAS) in HIV infected patients have identified a multitude of host genetic determinants of HIV viral control and/or disease progression. However, the majority of the disease-associated SNPs identified are in non-coding regions and the functional mechanisms mediating these associations are still unknown. Therefore, these potentially vital host factors could not be utilized as vaccine or drug targets. A single nucleotide polymorphism (SNP; rs1015164) in close genomic proximity of a long intergenic non-coding RNA (lincRNA) gene associated with HIV viral control and progression to AIDS in two distinct GWAS studies. The rs1015164 A allele, which associated with higher viral loads and more rapid disease progression, correlated with higher expression levels of the novel lincRNA, CCRL2-5'AS. We have found that the lincRNA (CCRL2-5'AS) augments expression of an HIV co-receptor, CCR5. Thus, variation in expression of CCRL2-5'AS may contribute to HIV viral control through enhanced CCR5 expression and greater susceptibility to HIV infection. We propose following specific aims;
Aim 1 : Elucidate mechanisms of lincRNA mediated CCR5 regulation, Aim 2: Identify and characterize novel lincRNA(s) that influence HIV viral control, Aim 3: Determine the influence of lincRNA expression on host gene regulation and viral replication. The proposed study will fuel discovery of novel non-coding RNAs and their poorly understood role in HIV pathogenesis. These data are likely to result in the finding of yet undiscovered host factors important in HIV viral control that could be targeted for future therapy/vaccine development.
The majority of host genetic determinants of HIV viral control identified in genome-wide association studies are in the non-coding regions and the functional mechanisms mediating these associations are still unknown. We are investigating functional impact of these non-coding RNAs on HIV viral control. Outcomes from the study outlined in this proposal will likely provide new therapeutic targets that can be manipulated in order to control HIV infection.
