CD8 lymphocytes mitigate HIV-1 persistence in lymph node follicular helper T cells during hyperacute-treated infection

Abstract

HIV persistence in tissue sites despite ART is a major barrier to HIV cure. Detailed studies of HIV-infected cells and immune responses in native lymph node tissue environment is critical for gaining insight into immune mechanisms impacting HIV persistence and clearance in tissue sanctuary sites. We compared HIV persistence and HIV-specific T cell responses in lymph node biopsies obtained from 14 individuals who initiated therapy in Fiebig stages I/II, 5 persons treated in Fiebig stages III-V and 17 late treated individuals who initiated ART in Fiebig VI and beyond. Using multicolor immunofluorescence staining and in situ hybridization, we detect HIV RNA and/or protein in 12 of 14 Fiebig I/II treated persons on suppressive therapy for 1 to 55 months, and in late treated persons with persistent antigens. CXCR3+ T follicular helper cells harbor the greatest amounts of gag mRNA transcripts. Notably, HIV-specific CD8+ T cells responses are associated with lower HIV antigen burden, suggesting that these responses may contribute to HIV suppression in lymph nodes during therapy. These results reveal HIV persistence despite the initiation of ART in hyperacute infection and highlight the contribution of virus-specific responses to HIV suppression in tissue sanctuaries during suppressive ART.

Targeting HIV persistence in the tissue

“…Therefore, strategies to enhance cellular trafficking towards these areas or block establishment of LT reservoirs may provide steps towards reservoir elimination. Persistence of HIV has been shown in LN of acute HIV infected patients despite early ART and plasma viral suppression [33]. This persistence is likely achieved through proliferation of infected cells [16 ▪ ,34 ▪ ].…”

“…LNs are highly structured secondary lymphoid organs organized in B cell areas, which include Tfh-rich germinal centers (GC), and T cell areas harboring T RM , amongst other cell types [12 ▪ ]. Whereas the pool of infected cells in LN during chronic infection has been shown to be highly heterogeneous, the majority of HIV infected cells within the LN are CD4 + Tfh cells [23 ▪ ,26 ▪ ], and higher levels of HIV RNA correlate with higher proportions of germinal center CXCR3 + Tfh cells [33]. However, cells carrying intact provirus were equally distributed between Tfh and CD4 + T RM , expressing higher levels of CD44, IL-21R, CD127, and CD28, which suggests enhanced cell survival [23 ▪ ].…”

Cytolytic CD8 + T cells infiltrate germinal centers to limit ongoing HIV replication in spontaneous controller lymph nodes

“…Spontaneous control of HIV infection in the absence of antiviral therapy, in which virus is not eliminated but actively held in check, provides an opportunity to more precisely determine the antiviral properties of fCD8s. In spontaneous HIV controllers, CD8 + T cellmediated immunity has been repeatedly associated with containment of viremia in studies of peripheral blood (PB) (36), but HIV replication primarily persists within LN follicular helper CD4 + T (T FH ) cells in these individuals (37,38), as it does in uncontrolled chronic infection (39)(40)(41)(42)(43)(44) and during antiretroviral therapy (ART) (45)(46)(47)(48)(49). Limited GC access of cytotoxic CD8 + T cells is thought to contribute to this persistent viral replication (13,19,20,(50)(51)(52)(53)(54)(55)(56).…”

Persistence of intact HIV-1 proviruses in the brain during antiretroviral therapy

“…Much less is currently known about HIV-1 reservoir cells in other body compartments that are more difficult to access for analytic purposes. Lymph nodes and lymphoid tissues in the gastrointestinal tract harbor the vast majority of all lymphocytes and are likely to represent a prime location for the persistence of virally infected cells ( Estes et al, 2017 ; Baiyegunhi et al, 2022 ; Kroon et al, 2022 ; Beckford-Vera et al, 2022 ); however, studies that interrogate viral reservoir cells in these tissues remain limited. Even less is known about HIV-1 persistence in other organs, and, in particular, in the CNS, although recent studies have started to explore viral reservoir cells in such specific body compartments ( Cochrane et al, 2022 ).…”