The increased production of monocytes with immunosuppressive transcriptional profiles predicts the development of SIV encephalitis

Abstract

HIV-associated neurocognitive disorders (HAND) remain common despite antiretroviral therapy. We previously demonstrated that increased percentages of newly generated BrdU-labeled (BrdU+) monocytes predict AIDS progression and SIV encephalitis (SIVE) as early as 8 and consistently by 21 days post-infection (DPI) in SIV-infected macaques, but their molecular identity remained unknown. We performed Bulk RNA sequencing of FACS-sorted BrdU+ and BrdU- monocytes from uninfected animals and SIV-infected macaques at 21 DPI and necropsies, including SIVE or not (SIVnoE). BrdU+ monocytes underwent progressive transcriptional remodeling during SIV infection. Early SIVE-predictive monocytes exhibited suppressed interferon, TNF-/NF-{kappa}B, antigen-presentation, and antimicrobial pathways, with increased LILRB4 and PARP2 expression. At terminal disease, SIVE BrdU+ monocytes displayed an immunosuppressive profile, reduced HLA-DR expression, and increased structural variants compared with SIVnoE monocytes. Together, newly generated circulating monocytes in animals progressing to SIVE are an immature and immunosuppressive population that emerges before neuropathology, implicating dysregulated monocytopoiesis and pathogenic monocytes in HAND.