Early antiretroviral therapy prevents viral infection of monocytes and inflammation in SIV-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 HIV-1 that may persist in tissues. Herein, we addressed 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 a classical (CD14+), intermediate (CD14+CD16+), and non-classical (CD16+) phenotype and CD4+ T cells were sorted from the blood, spleen and intestine of untreated and early ART-treated 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 intestine and ii) reduced systemic inflammation, as indicated by changes in IL-18 and 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 VR 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 and 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 VR 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.
|Authors:||Rabezanahary H, Clain J, Racine G, Andreani G, Benmadid-Laktout G, Borde C, Mammano F, Mesplèdes T, Ancuta P, Zghidi-Abouzid O, Estaquier J,|
|Journal:||J. Virol.; 2020 Sep 09 . doi:10.1128/JVI.01478-20|
|PubMed:||PMID: 32907978 (Go to PubMed)|