Understanding HIV latent reservoirs in tissues is essential for the development of new strategies targeting these sites for eradication. Here, we assessed the size of latent reservoirs and the source of residual viruses in multiple lymphoid tissues of SIV-infected and fully suppressed rhesus macaques of Chinese-origin (cRMs). Eight cRMs were infected with SIVmac251 and treated with tenofovir and emtricitabine daily for 24 weeks initiated 4 weeks post-infection. Four of the eight animals reached sustained full viral suppression with undetectable viremia. The levels of cell-associated SIV DNA varied in peripheral blood mononuclear cells (PBMCs) and multiple lymphoid tissues, but with higher levels in the mesenteric lymph nodes (MesLNs). The levels of cell-associated SIV RNA also varied in different tissues. The higher frequency of viral RNA detection in the MesLNs was also observed by in situ hybridization. Consistently, the infection unit per million cells (IUPM) in the MesLNs was higher than in PBMCs and other tested lymphoid tissues by quantitative viral outgrowth assay (QVOA). Furthermore, env gp120 from tissue SIV RNA was amplified by single genome amplification. Phylogenetic analysis revealed diverse variants from tissues parallel to the viral inoculum in all viral suppressed animals. These results demonstrate that the latency and viral reservoirs in the lymphoid tissues still exist in aviremic macaques under full suppressive therapy. Moreover, the size of viral latent reservoirs differs in various lymphoid tissues with a relatively larger size in the MesLNs.

The central nervous system (CNS) HIV reservoir is an obstacle to achieving an HIV cure. The basal ganglia harbor a higher frequency of SIV than other brain regions in the SIV-infected rhesus macaques of Chinese-origin (chRMs) even on suppressive combination antiretroviral therapy (ART). Since residual HIV/SIV reservoir is associated with inflammation, we characterized the neuroinflammation by gene expression and systemic levels of inflammatory molecules in healthy controls and SIV-infected chRMs with or without ART. CCL2, IL-6, and IFN-γ were significantly reduced in the cerebrospinal fluid (CSF) of animals receiving ART. Moreover, there was a correlation between levels of CCL2 in plasma and CSF, suggesting the potential use of plasma CCL2 as a neuroinflammation biomarker. With higher SIV frequency, the basal ganglia of untreated SIV-infected chRMs showed an upregulation of secreted phosphoprotein 1 (SPP1), which could be an indicator of ongoing neuroinflammation. While ART greatly reduced neuroinflammation in general, proinflammatory genes, such as IL-9, were still significantly upregulated. These results expand our understanding of neuroinflammation and signaling in SIV-infected chRMs on ART, an excellent model to study HIV/SIV persistence in the CNS.

Introduction: Natural hosts of simian immunodeficiency virus (SIV), including sooty mangabeys (SMs), maintain high viremia without progressing to AIDS and AIDS‐associated histopathogenesis. The mechanisms underlying this protection and lack of pathogenesis remain incompletely understood, particularly in relation to monocyte/macrophage activation. Methods: Plasma soluble CD163 (sCD163), monocyte CD163 expression, and monocyte subset phenotypes were quantified in uninfected and naturally SIV‐infected SMs and compared with uninfected and SIV‐infected rhesus macaques (RMs). Flow cytometry and multivariate analyses were used to assess monocyte activation and subset distribution. Results: sCD163 levels and CD163 surface expression were increased in SIV‐infected RMs but not SMs. SIV‐infected SMs exhibited reduced CD14 ⁺ CD16 ⁺ monocyte expansion and lower expression of CD64, MAC387, CD11b, and CCR2 compared with SIV‐infected RMs. Machine learning identified CD14 ⁺ CD16 ⁺ CCR8 ⁺ monocytes as the top discriminator of SIV infection in SMs. Conclusion: These findings indicate a lack of monocyte activation in SMs that correlates with non‐pathogenic infection.