Early Antiretroviral Therapy Prevents Viral Infection of Monocytes and Inflammation in Simian Immunodeficiency Virus-Infected Rhesus Macaques.

Despite early antiretroviral therapy (ART), treatment interruption is associated with viral rebound, indicating early viral reservoir (VR) seeding and absence of full eradication of human immunodeficiency virus type 1 (HIV-1) that may persist in tissues. Herein, we address the contributing role of monocytes in maintaining VRs under ART, since these cells may represent a source of viral dissemination due to their ability to replenish mucosal tissues in response to injury. To this aim, monocytes with classical (CD14+), intermediate (CD14+ CD16+), and nonclassical (CD16+) phenotypes and CD4+ T cells were sorted from the blood, spleen, and intestines of untreated and early-ART-treated simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) before and after ART interruption. Cell-associated SIV DNA and RNA were quantified. We demonstrated that in the absence of ART, monocytes were productively infected with replication-competent SIV, especially in the spleen. Reciprocally, early ART efficiently (i) prevented the establishment of monocyte VRs in the blood, spleen, and intestines and (ii) reduced systemic inflammation, as indicated by changes in interleukin-18 (IL-18) and IL-1 receptor antagonist (IL-1Ra) plasma levels. ART interruption was associated with a rebound in viremia that led to the rapid productive infection of both CD4+ T cells and monocytes. Altogether, our results reveal the benefits of early ART initiation in limiting the contribution of monocytes to VRs and SIV-associated inflammation.IMPORTANCE Despite the administration of antiretroviral therapy (ART), HIV persists in treated individuals and ART interruption is associated with viral rebound. Persistent chronic immune activation and inflammation contribute to disease morbidity. Whereas monocytes are infected by HIV/SIV, their role as viral reservoirs (VRs) in visceral tissues has been poorly explored. Our work demonstrates that monocyte cell subsets in the blood, spleen, and intestines do not significantly contribute to the establishment of early VRs in SIV-infected rhesus macaques treated with ART. By preventing the infection of these cells, early ART reduces systemic inflammation. However, following ART interruption, monocytes are rapidly reinfected. Altogether, our findings shed new light on the benefits of early ART initiation in limiting VR and inflammation.

Despite early antiretroviral therapy effector memory and follicular helper CD4 T cells are major reservoirs in visceral lymphoid tissues of SIV-infected macaques.

Whereas antiretroviral therapy (ART) suppresses viral replication, ART discontinuation results in viral rebound, indicating the presence of viral reservoirs (VRs) established within lymphoid tissues. Herein, by sorting CD4 T-cell subsets from the spleen, mesenteric and peripheral lymph nodes (LNs) of SIVmac251-infected rhesus macaques (RMs), we demonstrate that effector memory (TEM) and follicular helper (TFH) CD4+ T cells harbor the highest frequency of viral DNA and RNA, as well of early R-U5 transcripts in ART-naïve RMs. Furthermore, our results highlight that these two CD4 T cells subsets harbor viral DNA and early R-U5 transcripts in the spleen and mesenteric LNs (but not in peripheral LN) of RMs treated with ART at day 4 post infection suggesting that these two anatomical sites are important for viral persistence. Finally, after ART interruption, we demonstrate the rapid and, compared to peripheral LNs, earlier seeding of SIV in spleen and mesenteric LNs, thereby emphasizing the importance of these two anatomical sites for viral replication dynamics. Altogether our results advance understanding of early viral seeding in which visceral lymphoid tissues are crucial in maintaining TEM and TFH VRs.

Mucosal T follicular helper cells in SIV-infected rhesus macaques: contributing role of IL-27.

Mesenteric lymph nodes (MLNs), that drain the large and small intestine, are critical sites for the induction of oral tolerance. Although depletion of CD4 T cells in the intestinal lamina propria is a hallmark of HIV infection, CD4 T cell dynamics in MLNs is less known due to the lack of accessibility to these LNs. We demonstrate the early loss of memory CD4 T cells, including T follicular helper cells (Tfh) and a remodeling of MLN architecture in SIV-infected rhesus macaques (RMs). Along with the loss of Tfh cells, we observe the loss of memory B cells and of germinal center B cells. Tfh cells display a Th1 profile with increased levels of the transcription factors that negatively impact on Tfh differentiation and of Stat5 phosphorylation. MLNs of SIV-infected RMs display lower mRNA transcripts encoding for IL-12, IL-23, and IL-35, whereas those coding for IL-27 are not impaired in MLNs. In vitro, IL-27 negatively impacts on Tfh cells and recapitulates the profile observed in SIV-infected RMs. Therefore, early defects of memory CD4 T cells, as well of Tfh cells in MLNs, which play a central role in regulating the mucosal immune response, may have major implications for Aids.