Quiet but not silent: assessing the impact of intact and defective HIV proviral DNA in the brain.
PURPOSE OF REVIEW People with HIV (PWH) require lifelong antiretroviral therapy (ART) to maintain viral suppression, yet integrated HIV DNA persists in long-lived cellular reservoirs in blood and tissues. Most integrated proviruses are defective, meaning they contain deletions, hypermutation, packaging-signal defects, splice defects, or other defects that prevent production of replication-competent viruses. However, these genomes are not necessarily biologically inert as many remain capable of transcription and, in some cases, translation of viral proteins. RECENT FINDINGS Recent evidence has demonstrated that the brain is a stable reservoir of both intact and defective HIV despite viral suppression with ART. Whilst intact replication capable proviruses are known to induce cell activation and pathology, recent studies suggest that defective proviruses with large internal deletions and hypermutation can remain transcriptionally, and in some cases, translationally active and have now been linked with persistent immune activation during ART. Therefore, transcriptionally active defective proviral DNA may be a contributor to underlying neuropathogenesis in ART-suppressed PWH. SUMMARY Defective HIV proviruses make up the majority of the proviral reservoir across blood and tissue compartments. Although they are replication-incompetent, many remain transcriptionally and translationally competent and may contribute to chronic inflammation, antigen persistence, and neuropathology in ART-suppressed PWH.