Defective HIV proviruses and Persistent Innate Immune Activation

Abstract/Summary CD4+ T cells and macrophages are infected by HIV and this infection correlates to more proinflammatory activities that drive HIV comorbidities and end organ diseases. Mechanisms that bias innate immune functions in HIV-infected cells towards chronic inflammation are poorly understood. We have demonstrated infected primary resting CD4+ T cells and macrophages harbor defective HIV-1 proviruses that, despite having deletions and mutations which attenuate provirus transcription, generate HIV-1 RNAs. The immunopathological consequences of persistent aberrant viral RNA expression have not been addressed. We hypothesize that HIV infection of CD4+ T cells and macrophages establishes a defective but transcriptionally competent proviral reservoir that expresses aberrant viral RNAs which perpetuate persistent inflammation. We will address this hypothesis in three specific aims: 1) Determine if persistent expression of cryptic HIV-1 RNAs promote innate immune activities; 2) Examine whether HIV-1 and HIV-2 have different propensities for generating intact proviral genomes and whether this influences immune activation; and 3) Determine if DNA damage response mechanisms lead to establishment of defective proviruses. Successful completion of these studies will provide general insights into the impact of HIV-1 persistence and expression in the context of CD4+ T cells and macrophages. Importantly, these studies will provide an understanding into mechanisms that contribute to HIV-1 comorbidities which persist even with antiretroviral treatments and could lead to new targets and strategies for treatments to improve the lives of people living with HIV.