Multiple Origins of Virus Persistence during Natural Control of HIV Infection

Targeted HIV cure strategies require definition of the mechanisms that maintain the virus. Here, we tracked HIV replication and the persistence of infected CD4 T cells in individuals with natural virologic control by sequencing viruses, T cell receptor genes, HIV integration sites, and cellular transcriptomes. Our results revealed three mechanisms of HIV persistence operating within distinct anatomic and functional compartments. In lymph node, we detected viruses with genetic and transcriptional attributes of active replication in both T follicular helper (TFH) cells and non-TFH memory cells. In blood, we detected inducible proviruses of archival origin among highly differentiated, clonally expanded cells. Linking the lymph node and blood was a small population of circulating cells harboring inducible proviruses of recent origin. Thus, HIV replication in lymphoid tissue, clonal expansion of infected cells, and recirculation of recently infected cells act together to maintain the virus in HIV controllers despite effective antiviral immunity. [Display omitted] •In HIV controllers, both TFH and non-TFH lymph node CD4 T cells contain HIV•Lymph node viruses in both TFH and non-TFH have attributes of active replication•Rare, recently infected cells that produce virus upon stimulation circulate in blood•Archival proviruses predominant in clonally expanded blood cells can be inducible HIV persistence in people who can spontaneously control the infection involves different mechanisms within distinct anatomic and functional compartments.