A naturally occurring Tat R52W variant in brain-derived HIV attenuates transcription and may contribute to reservoir persistence

HIV-1 maintains a presence even with suppressive antiretroviral therapy (ART), but the role of natural genetic variation in viral transcription regulation has not been fully explored. Researchers have now discovered a naturally occurring HIV-1 variant, known as Tat R52W, that dampens viral transcription by interfering with the interaction between the Tat protein and TAR RNA.

Full-length HIV-1 genomes from brain microglia of a Last Gift donor, as well as peripheral viral sequences during ART, showed the presence of the R52W variant. This same variant was also found in another ART-suppressed donor within the same study group. A broader analysis of 3,440 clinical blood isolates from HIV-positive individuals revealed the R52W variant in 73 sequences (2.12%), including three individuals on ART and a therapy controller, across various viral subtypes.

Structural analysis demonstrated that the R52W variant weakens the binding between Tat and TAR, while functional tests revealed significantly reduced Tat-mediated transcriptional activity. This activity could be restored by reverting the R52W variant back to its original state (W52R). These findings establish a direct molecular mechanism by which a naturally occurring HIV-1 variant influences viral transcriptional output.

The study identifies transcriptionally attenuated HIV-1 variants in treated individuals and suggests that modulating Tat-dependent transcription could be an underrecognized factor contributing to viral persistence despite ART.