Howell, Bonnie J.

Anti-retroviral therapy (ART) has greatly improved the quality and length of life for people living with HIV, but immune activation does not normalize during ART, and persistent immune activation has been linked to increased morbidity and mortality. We report a comparison of assays of two potential sources of immune activation during ART: rare cells producing HIV and the virus’ major viral protein, p24, benchmarked on a cell model of active and latent infections and a method to visualize HIV-producing cells.

The expansion and accumulation of HIV-infected BCL6 + Tfh CD4 + T cells are thought to contribute to the persistence of viral reservoirs in infected subjects undergoing ART. Two mechanisms have been raised for the preferential retention of HIV within Tfh CD4 + T cells: (i) antiretroviral drugs have limited tissue distribution, resulting in insufficient tissue concentration and lower efficacy in controlling HIV replication in lymphoid tissues, and (ii) cytotoxic CD8 + T cells within lymphoid tissues express low levels of chemokine receptor (CXCR5), thus limiting their ability to enter the GCs to control/eliminate HIV-infected Tfh cells. Our results indicate that the BCL6 inhibitor FX1 can not only repress HIV infection of tonsillar Tfh ex vivo but also suppress HIV infection and reactivation in primary, non-Tfh CD4 + T cells. Our study provides a rationale for targeting BCL6 protein to extend ART-mediated reduction of persistent HIV and/or support strategies toward HIV remission beyond ART cessation.