While pioneering studies demonstrated that HIV replication and spreading mainly occur in lymphoid tissues, the identification of specific cell subsets harboring replication competent virus in lymphoid tissues has long time been neglected. In this context, we and others have recently shown that gut memory CD4 T cells, lymph node (LN) T follicular helper cells and tissue macrophages represent major HIV/SIV tissue reservoirs. LN dendritic cells (DCs) are endowed with an exceptional T-cell stimulatory potential and can either migrate from the periphery to the draining lymph node (migratory DCs) or locate in the LN for their entire life span (resident DCs). On the basis of these unique properties, long-term persistence of LN DCs infected with replication competent virus may represent the initial trigger of viral rebound post ART interruption and may therefore represent a major obstacle to HIV cure.
We therefore comprehensively assessed major virological parameters associated with HIV persistence in ex vivo isolated LN migratory and resident DCs isolated from viremic (N=3) and aviremic ART treated HIV-infected subjects (N=7).
LN migratory DCs harbored a much higher propensity for HIV infection in vitro than resident DCs (P<0.05) and supported HIV production, which was associated with significantly lower levels of SAMHD1 transcripts (P<0.05). Interestingly, LN migratory DCs isolated directly ex vivo from viremic individuals harbored higher frequencies of cells harboring integrated HIV DNA, unspliced gag and multi-spliced tat-rev HIV RNA as compared to resident DCs. In addition, LN migratory DCs supported higher reactivation of HIV production (in the absence of CD4) and replication (in the presence of CD4) in vitro as compared to resident DCs. Interestingly, HIV-infected LN migratory DCs were still detectable in treated HIV-infected individuals and were able to support much higher levels of HIV production and replication when co-cultured with target CD4 T cells in vitro as compared to LN resident DCs (P<0.05).
The present study underscored a yet underestimated role of LN DCs in HIV persistence and may therefore highlight the need to adapt the currently explored experimental strategies aiming at purging viral reservoirs.