Despite antiretroviral therapy, HIV-1 persists in memory CD4+ T cells creating a barrier to cure. The majority of HIV-1 proviruses are defective due to packaging signal deletions, APOBEC-mediated G-to-A hypermutations, large internal deletions, and point mutations. These defective proviruses are considered clinically irrelevant. Using cells from HIV-1-infected individuals and reconstructed patient-derived defective proviruses, we show that defective proviruses can be transcribed to RNAs that are spliced and translated into viral antigens. Proviruses with defective major splice donors (MSDs) can activate novel splice sites to produce HIV-1 transcripts. Cells with HIV-1 proviruses containing defective MSDs can be recognized by HIV-1-specific cytotoxic T lymphocytes (CTLs). Surprisingly, cells with proviruses containing lethal mutations upstream of CTL epitopes can also be recognized by CTLs potentially through aberrant translation. Thus, expression of defective proviruses complicates the measurement of the latent reservoir. CTLs may change the landscape of HIV-1 proviruses by preferential targeting cells with specific types of defective proviruses. The scope of potential CTL targets may be bigger than the size of the latent reservoir.
Yale University School of Medicine