HIV Promoters Isolated from Brain and Peripheral Tissue of Virally Suppressed PWH Are Phylogenetically and Functionally Similar

Despite viral suppression with antiretroviral therapy (ART), reservoirs of Human Immunodeficiency Virus (HIV) persist in anatomical compartments throughout the body, including the brain. We have previously demonstrated that the HIV long terminal repeats (LTRs) isolated from the brains of non-virally suppressed people with HIV (PWH) are phylogenetically and functionally distinct from those isolated from matched peripheral tissue. While intact, transcriptionally competent HIV genomes persist within the brains of virally suppressed PWH, whether HIV LTRs are intact, functional, and compartmentalized relative to the periphery, as in non-virally suppressed PWH, remains unclear. HIV LTRs were extracted from frontal cortex post-mortem brain and matched peripheral tissues of virally suppressed PWH (n = 5). Following single-genome amplification, sequences were phylogenetically analyzed and transcriptional activity was assessed. In contrast to non-virally suppressed PWH, LTR sequences failed to compartmentalize between the brain and peripheral compartments. Identical LTR sequences were observed across brain and peripheral tissues in 2/5 PWH. While the LTRs remain transcriptionally active, mutations, insertions and deletions predicted to reduce transcription factor binding affinity at key binding sites, including C/EBP, NF-κB, and Sp1 sites, were observed and found to result in reduced basal transcriptional activity. The role of these mutations in latency and viral persistence remains unclear.