People with HIV (PWH) require lifelong antiretroviral therapy (ART) to maintain systemic viral suppression, yet integrated HIV DNA persists within long-lived cellular reservoirs in blood and tissues. These integrated genomes—proviruses—can be distributed across multiple compartments and are central to the barrier that prevents HIV cure. The reservoir is heterogeneous: a minority of proviruses are replication-competent, while the majority are defective proviruses that contain genetic lesions preventing production of replication-competent virus.
Most integrated HIV proviruses carry defects such as large internal deletions, G-to-A hypermutation, defects in packaging signals, aberrant splice sites, or other mutations that preclude generation of infectious virions. Although these genomes are replication-incompetent by sequence-defined criteria, they are not necessarily biologically inert. Multiple studies summarized in the review indicate defective proviruses accumulate rapidly during acute infection and dominate the proviral landscape in chronic infection and during ART. Importantly, some defective genomes retain transcriptional competence and, in selected cases, can be translated into viral proteins or peptides that are detectable by immune effectors.
Recent evidence reviewed shows the brain is a stable reservoir that contains both intact and defective proviruses, even in persons who are virally suppressed on ART. Postmortem and tissue-based studies have detected proviral DNA in brain tissue and have characterized proviral sequences consistent with both replication-capable and defective genomes. Intact replication-capable proviruses in the brain are of concern because they have the potential to produce infectious virus locally and to elicit cell activation and pathology. The review emphasizes that the brain reservoir persists despite systemic ART and that its composition includes a preponderance of defective proviruses similar to other compartments.
Although defective proviruses cannot restore systemic infectivity, many retain the capacity for transcription. The review highlights that defective genomes with large deletions or hypermutation may still be transcribed and, in some instances, translated into viral proteins. Studies cited report that defective proviral transcripts can be present during ART, and that cytotoxic T lymphocytes can recognize peptides derived from defective proviruses. This transcriptional and translational activity means defective proviruses contribute antigenic material and molecular signals to local immune environments.
Transcriptionally active defective proviral DNA in the brain has been linked with persistent immune activation during ART. The review posits that antigen persistence from defective genomes, together with localized transcriptional activity, may contribute to chronic neuroinflammation, antigen-driven immune responses, and neuropathology in ART-suppressed PWH. While intact proviruses can directly cause cell activation and pathology through production of viral products, defective proviruses may contribute indirectly by sustaining antigenic stimulation and inflammatory signaling without producing infectious virus. These mechanisms could underlie ongoing neurological complications observed in some PWH despite effective systemic viral suppression.
Defective HIV proviruses constitute the majority of the proviral reservoir across blood and tissue compartments, including the brain. The review underscores that although these proviruses are replication-incompetent, their capacity for transcription and in some cases translation makes them potential contributors to chronic inflammation, antigen persistence, and neuropathology in ART-suppressed individuals. The brain’s role as a reservoir of both intact and defective proviruses reinforces the need to consider tissue-specific reservoir biology when evaluating strategies for HIV remission or cure.
The source article is a review summarizing recent findings; specific experimental details, quantitative prevalence data, and methodological descriptions are reported in the cited primary studies and references. Where the review did not provide numerical prevalence estimates or experimental parameters, those details were not reported in the source.