The mechanisms regulating the establishment/maintenance of HIV reservoirs are still to be determined, thus impeding the design of strategies limiting HIV persistence. Interleukin (IL)-10 is a key component of the host anti-inflammatory activities triggered by pathogen induced pro-inflammatory responses. IL-10 signaling inhibits the production of Th1 cytokines and stimulates the production of Th2 cytokines; upregulates the expression of co-inhibitory receptors such as PD-1 and CTLA-4; reduces antigen presentation and increases T cell anergy. As a result of these anti-inflammatory activities, we hypothesized that IL-10 can negatively impact on T cell function, lead to a status of immunosenescence, and favor HIV persistence.
15 RMs were infected with SIVmac239 and started on ART (tenofovir, emtricitabine, raltegravir, darunavir, and ritonavir) at day 58 post-infection (p.i.). ART was maintained for 7 months. Blood (PB), lymph node (LN), and rectal biopsy (RB) were collected longitudinally for flow cytometric and DNAscope analyses. Cell-associated SIV DNA was quantified in CD4 T cell subsets, including Tfh.
Plasma and LN levels of IL-10 increased upon SIV infection (p=0.0001 as compared to pre infection) and did not fully normalize with ART. Plasma IL-10 at pre-ART correlate with markers of disease progression such as plasma viremia (p=0.0016); the depletion of CD4 T cells in PB (p=0.0003) and RB (p=0.0422); and plasma IP-10 (p=0.0001). Additionally, plasma IL-10 at pre-ART correlates in LN with the percentage of Tfh cells proliferating (Ki-67+ ; p=0.0002) or harboring SIV-DNA (p=0.0256). We observed a selective enrichment during ART of SIV-DNA+ cells being IL-10+ in LN within the BCF (>85%; p=0.0095) as compared to untreated RMs, with the SIV-DNA+ IL-10+ cells being remarkably more stable between the pre- and on-ART time points than their IL-10 negative counterpart. Furthermore, plasma IL-10 at pre-ART predicts several key parameters of residual disease after 7 months of suppressive ART: CD4 T cell counts in PB (p=0.0305), %Ki-67+ CD4 T cells in PB (p=0.0163), %Tfh cells in LN (p=0.0002), SIV-DNA content in PB CD4 T cells (p=0.0218) and in RB (p=0.0383).
Plasma and LN content of IL-10, which is induced by SIV infection and not fully normalized with ART, critically contributes to SIV persistence by promoting maintenance of SIV-DNA+ cells, including TFH. Modulation of IL-10 represents a novel therapeutic avenue towards an HIV cure.