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HIV's ability to persist during suppressive antiretroviral therapy is the main barrier to cure. Immune privileged tissues such as the testes may constitute distinctive sites of HIV persistence, but this has been challenging to study in humans. We analyzed proviral burden and genetics in blood and testes of 10 individuals on suppressive therapy who underwent elective gender-affirming surgery. HIV DNA levels in matched blood and testes were quantified by qPCR and subgenomic proviral sequences ( region) were characterized from single templates. HIV diversity, compartmentalization and immune escape burden were assessed using genetic and phylogenetic approaches. Diverse proviruses were recovered from blood (396 sequences; 354 -intact) and testes (326 sequences; 309 -intact) of all participants. Notably, the frequency of identical HIV sequences varied markedly between and within individuals. Nevertheless, proviral loads, within-host unique HIV sequence diversity, and immune escape burden correlated positively between blood and testes. When all intact  sequences were evaluated, 60% of participants exhibited significant blood-testes genetic compartmentalization, but none did so when restricting to unique sequences per site, suggesting that compartmentalization, when present, is attributable to clonal expansion of HIV-infected cells. Our observations confirm the testes as a site of HIV persistence and suggest that individuals with larger and more diverse blood reservoirs will have larger and more diverse testes reservoirs. Furthermore, while the testes microenvironment may not be sufficiently unique to facilitate the seeding of  viral populations therein, differential clonal expansion dynamics may be at play, which may complicate HIV eradication.Two key questions in HIV reservoir biology are whether immune privileged tissues, such as the testes, harbor distinctive proviral populations during suppressive therapy, and if so by what mechanism. While our results indicated that blood-testes HIV genetic compartmentalization was reasonably common (60%), it was always attributable to differential frequencies of identical HIV sequences between sites. No blood/tissue dataset retained evidence of compartmentalization when only unique HIV sequences per site were considered; moreover, HIV immune escape mutation burdens were highly concordant between sites. We conclude that the principal mechanism by which blood and testes reservoirs differ is  via seeding of divergent HIV sequences therein, but rather due to differential clonal expansion of latently-infected cells. Thus, while viral diversity and escape-related barriers to HIV eradication are of broadly similar magnitude across blood and testes, clonal expansion represents a challenge. Results support individualized analysis of within-host reservoir diversity to inform curative approaches.

HIV Diversity and Genetic Compartmentalization in Blood and Testes during Suppressive Antiretroviral Therapy