Early ART reduces viral seeding and innate immunity in liver and lungs of SIV-infected macaques

Abstract

Identifying immune cells and anatomical tissues that contribute to the establishment of viral reservoirs is of central importance in HIV-1 cure research. Herein, we used rhesus macaques (RMs) infected with SIVmac251 to analyze viral seeding in the liver and lungs of either untreated or early antiretroviral therapy–treated (ART-treated) RMs. Consistent with viral replication and sensing, transcriptomic analyses showed higher levels of inflammation, pyroptosis, and chemokine genes as well as of interferon-stimulating gene (ISG) transcripts, in the absence of ART. Our results highlighted the infiltration of monocyte-derived macrophages (HLA-DR + CD11b + CD14 + CD16 + ) in inflamed liver and lung tissues associated with the expression of CD183 and CX3CR1 but also with markers of tissue-resident macrophages (CD206 + and LYVE + ). Sorting of myeloid cell subsets demonstrated that CD14 + CD206 – , CD14 + CD206 + , and CD14 – CD206 + cell populations were infected, in the liver and lungs, in SIVmac251-infected RMs. Of importance, early ART drastically reduced viral seeding consistent with the absence of ISG detection but also of genes related to inflammation and tissue damage. Viral DNA was only detected in CD206 + HLA-DR + CD11b + cells in ART-treated RMs. The observation of pulmonary and hepatic viral rebound after ART interruption reinforces the importance of early ART implementation to limit viral seeding and inflammatory reactions.

Lipid metabolic reprogramming of hepatic CD4 + T cells during SIV infection

“…We also noticed that hepatic CD4 + T cells also overexpressed CX3CR1 and CXCR3 transcripts, suggesting the recruitment of this population in inflamed tissues ( 42 , 43 ) and consistent with higher levels of CXCL10 transcripts (the ligand of CXCR3) observed in the liver of SIV-infected RMs ( 96 ). Interestingly, CXCL10 was reported to be associated with liver fibrosis in individuals co-infected with HIV and Epstein–Barr virus (EBV) ( 97 ).…”

Retinoic Acid Boosts HIV-1 Replication in MacrophagesviaCCR5/SAMHD1-Dependent and mTOR-Modulated Mechanisms

“…In addition to macrophage permissiveness to HIV-1 infection in vivo and in vitro, studies in ART-treated PLWH provided evidence that macrophages isolated from liver 33 brain 34,35 , broncho alveolar lavage [36][37][38] , duodenum 39 , testis 40 , and most recently urethra 41 carry HIV-1. Similarly, studies performed in humanized mice models, especially in myeloid only models 42,43 , as well as SIV infection model [44][45][46] pointed to macrophages as important sites of viral infection/persistence. Finally, by their intrinsic resistance to apoptosis and CD8 + T-cell-and NK cell-mediated killing [47][48][49] , HIV-infected macrophages escape from immunological pressure.…”