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Microbial translocation is a significant contributor to chronic inflammation in people living with HIV (PLWH) and is associated with increased mortality and morbidity in individuals treated for long periods with antiretrovirals. The use of therapeutics to treat microbial translocation has yielded mixed effects, in part, because the species and mechanisms contributing to translocation in HIV remain incompletely characterized. To characterize translocating bacteria, we cultured translocators from chronically SIV-infected rhesus macaques. Proteomic profiling of these bacteria identified cytosine-specific methyltransferases as a common feature and therefore, a potential driver of translocation. Treatment of translocating bacteria with the cytosine methyltransferase inhibitor decitabine significantly impaired growth for several species in vitro. In rhesus macaques, oral treatment with decitabine led to some transient decreases in translocator taxa in the gut microbiome. These data provide mechanistic insight into bacterial translocation in lentiviral infection and explore a novel therapeutic intervention that may improve the prognosis of PLWH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Experimental simian immunodeficiency virus (SIV) infection of Asian macaques is an excellent model for HIV disease progression and therapeutic development. Recent coformulations of nucleoside analogs and an integrase inhibitor have been used for parenteral antiretroviral (ARV) administration in SIV-infected macaques, successfully resulting in undetectable plasma SIV RNA. In a cohort of SIVmac239-infected macaques, we recently observed that administration of coformulated ARVs resulted in an unexpected increase in plasma levels of soluble CD14 (sCD14), associated with stimulation of myeloid cells. We hypothesized that the coformulation solubilizing agent Kleptose (2-hydroxypropyl-β-cyclodextrin [HPβCD]) may induce inflammation with myeloid cell activation and the release of sCD14. Herein, we stimulated peripheral blood mononuclear cells (PBMCs) from healthy macaques with HPβCD from different commercial sources and evaluated inflammatory cytokine production in vitro . Treatment of PBMCs resulted in increased sCD14 release and myeloid cell interleukin-1β (IL-1β) production-with stimulation varying significantly by HPβCD source-and destabilized lymphocyte CCR5 surface expression. We further treated healthy macaques with Kleptose alone. In vivo , we observed modestly increased myeloid cell activation in response to Kleptose treatment without significant perturbation of the immunological transcriptome or epigenome. Our results demonstrate a need for vehicle-only controls and highlight immunological perturbations that can occur when using HPβCD in pharmaceutical coformulations. IMPORTANCE SIV infection of nonhuman primates is the principal model system for assessing HIV disease progression and therapeutic development. HPβCD has recently been incorporated as a solubilizing agent in coformulations of ARVs in SIV-infected nonhuman primates. Although HPβCD has historically been considered inert, recent findings suggest that HPβCD may contribute to inflammation. Herein, we investigate the contribution of HPβCD to healthy macaque inflammation in vitro and in vivo. We observe that HPβCD causes an induction of sCD14 and IL-1β from myeloid cells in vitro and demonstrate that HPβCD stimulatory capacity varies by commercial source. In vivo , we observe modest myeloid cell activation in blood and bronchoalveolar lavage specimens absent systemic immune activation. From our findings, it is unclear whether HPβCD stimulation may improve or diminish immune reconstitution in ARV-treated lentiviral infections. Our results demonstrate a need for vehicle-only controls and highlight immunological perturbations that can occur when using HPβCD in pharmaceutical coformulations., Competing Interests: The authors declare no conflict of interest.

The lumen of the gastrointestinal (GI) tract contains an incredibly diverse and extensive collection of microorganisms that can directly stimulate the immune system. There are significant data to demonstrate that the spatial localization of the microbiome can impact viral disease pathogenesis. Here we discuss recent studies that have investigated causes and consequences of GI tract pathologies in HIV, SIV, and SARS-CoV-2 infections with HIV and SIV initiating GI pathology from the basal side and SARS-CoV-2 from the luminal side. Both these infections result in alterations of the intestinal barrier, leading to microbial translocation, persistent inflammation, and T-cell immune activation. GI tract damage is one of the major contributors to multisystem inflammatory syndrome in SARS-CoV-2-infected individuals and to the incomplete immune restoration in HIV-infected subjects, even in those with robust viral control with antiretroviral therapy. While the causes of GI tract pathologies differ between these virus families, therapeutic interventions to reduce microbial translocation-induced inflammation and improve the integrity of the GI tract may improve the prognoses of infected individuals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pandrea, Brooks, Desai, Tare, Brenchley and Apetrei.)

Defective gastrointestinal barrier function and, in turn, microbial translocation have been identified as significant contributors to persistent inflammation in antiretroviral (ARV)-treated people living with HIV. Metabolic supplementation of short-chain fatty acids (SCFAs), generally produced by the commensal microbiome, may improve these outcomes. Butyrate is a SCFA that is essential for the development and maintenance of intestinal immunity and has a known role in supporting epithelial integrity. Herein we assessed whether supplementation with the dietary supplement sodium butyrate would improve immune reconstitution and reduce inflammation in ARV-treated, simian immunodeficiency virus (SIV)-infected rhesus macaques. We demonstrate that butyrate supplementation does not significantly improve immune reconstitution, with no differences observed in systemic CD4+ T-cell frequencies, T-cell functionality or immune activation, microbial translocation, or transcriptional regulation. Our findings demonstrate that oral administration of sodium butyrate is insufficient to reduce persistent inflammation and microbial translocation in ARV-treated, SIV-infected macaques, suggesting that this therapeutic may not reduce co-morbidities and co-mortalities in treated people living with HIV., (© 2022. The Author(s).)