Tissue reservoirs of HIV

Abstract

Purpose Tissue reservoirs of HIV may promote the persistent immunopathology responsible for non-AIDS morbidity and data support multifocal reactivation from tissues as the source of viral rebound during ART interruption. The heterogeneity of tissue reservoirs and incomplete knowledge about their composition are obstacles to an HIV cure. Recent findings In addition to the higher concentration of infected CD4+ T cells found in both central lymphoid tissues and gut, specific subsets of CD4+ T cells appear to play a disproportionate role in HIV persistence. Recently, a subset of central memory T cells enriched in lymphnode germinal centers called T-follicular helper cells have been identified that express more viral RNA and occupy an anatomic niche inaccessible to CTL killing. Additional observations suggest that ARV concentrations may be lower in some tissues raising the possibility for localized, low-level viral replication. Finally, some recent data implicate the persistence of infected, non-CD4+ T cell types in tissues during ART. Summary The retention of infected cells in a wide variety of tissues, often with distinct viral and cellular characteristics, underscores the importance of studying tissue reservoirs in the development and assessment of cure strategies. Both inhibitory ARVs and latency reversing drugs must reach these sites and novel strategies may be needed to attack virus in cells as variable as Tfh and macrophages.

HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms

“…Major CD4 + T cell alterations occur in gut-associated lymphoid tissues (GALT) rapidly upon HIV transmission (4,5), and these alterations persist despite viral suppressive ART (3,6), even in patients treated during acute HIV infection (7). The GALT is considered an important site of HIV replication and viral reservoir persistence during ART (8). GALT-infiltrating CD4 + T cells represent optimal HIV targets, likely due to their high expression of CCR5 (4,5,8), a major coreceptor for HIV entry (9)(10)(11), and integrin α4β7, a gut-homing molecule (12) identified as an HIV-binding molecule (13).…”

“…The GALT is considered an important site of HIV replication and viral reservoir persistence during ART (8). GALT-infiltrating CD4 + T cells represent optimal HIV targets, likely due to their high expression of CCR5 (4,5,8), a major coreceptor for HIV entry (9)(10)(11), and integrin α4β7, a gut-homing molecule (12) identified as an HIV-binding molecule (13). Very recently, integrin α4β7-blocking Abs proved efficacy in controlling viral replication upon ART interruption in an SIV infection model (14), indicative that interfering with HIV replication in gut-homing α4β7…”

Exploring HIV latency using transcription profiling

“…Furthermore, gut and blood compartments differ in levels of T cell activation and its relationship with HIV transcription 12 . Considering that the gut harbors up to 85% of all lymphoid tissue and over 90% of all lymphocytes 14,15 , it is imperative to investigate how mechanisms of HIV persistence and latency differ between gut and blood in vivo.…”

“…Although much HIV latency research utilises in vitro models or cells from peripheral blood, prior work has highlighted differences between the gut and blood in the phenotype of infected T and non-T cells 12,13 . Furthermore, gut and blood compartments differ in levels of T cell activation and its relationship with HIV transcription 12 .…”

“…Latent HIV has been primarily found in long-lived memory CD4 + T cells, which can survive for decades and expand the viral reservoir by cell proliferation [8][9][10][11] . These latently infected cells are considered to be the main barrier to HIV eradication 4 and their reactivation in vivo likely contributes to sustained immune activation observed during suppressive ART 12 .…”