CNAR inhibits HIV replication by impairing transcriptional initiation

Dalibor Blazek, University of California, San Francisco
Molecular Biology

In this proposal I will study the mechanism by which the CD8+ cell non-cytotoxic antiviral response (CNAR) inhibits the replication of the human immunodeficiency virus (HIV). CNAR is demonstrated by mixing CD8+ cells from healthy HIV-infected individuals with normal primary CD4+ cells acutely infected with HIV. HIV replication is inhibited by more than 90 % and this inhibition is believed to be a transcription block. In preliminary results, I have found that in CNAR treated HIV-infected CD4+ cells there is significantly less RNA-polymerase II (RNAPII) on the HIV coding region as well as on the promoter in comparison to HIV-infected CD4+ not treated with CNAR. This result provides important insight into the mechanism by which CNAR reduces HIV replication in healthy HIV-infected individuals. In this fellowship proposal I will test two hypotheses: 1) that CNAR mediates inhibitions of HIV transcription at the level of chromatin deacetylation and nucleosome remodeling or 2) that CNAR inhibits the transcriptional initiation complex assembly.