CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

Methods: Eight infant rhesus macaques (3 male, 5 female) were orally infected with SIVmac251 at 4 weeks of age, initiated on ART 4 weeks after infection, and underwent ATI after 60 weeks of ART. Plasma samples were collected at pre/early ART and late ART for cytokine/chemokine quantification using multiplex assay and untargeted metabolomics by high performance liquid chromatography and mass spectrometry. SIV reservoir was evaluated at late ART, and viral load was quantified post-ATI to determine area under the curve (AUC) of rebound. Results: Longitudinal metabolite modulation was driven by lipid and amino acid pathways, with pre/early ART segregating from later timepoints. Cytokines clustered into two groups, with similar timepoint delineation. At pre/early ART, IL-15 and fatty acids were negatively associated while non-essential amino acids were positively associated with late ART levels of SIV DNA in CD4+ T cells. Comparing cytokines and metabolites at late ART with SIV DNA at late ART, we found a negative correlation with ITAC and a positive correlation with modified amino acids. Branched-chain amino acids (BCAAs) at late ART were positively associated with viral rebound AUC post-ATI, while a negative association was found between viral rebound AUC and interferons, interferon-induced cytokines/chemokines and IL-7 measured at late ART. Conclusions: Cytokine modulation of CD4+ T cells and NK/CD8+ T cell effector function may explain the observed associations with reservoir size and viral rebound. While less studied, metabolites also influence immune cells; for example, the non-essential amino acids glycine/serine are associated with T cell proliferation and BCAAs similarly support proliferation of activated T cells. These effects may cause both reservoir expansion and fuel viremia off ART. Validation of a direct role of these pathways and immune modulators in seeding and maintenance of the SIV reservoir could lead to new approaches for HIV cure. Immunometabolic Reprogramming by Caloric Restriction Leads to Protection From SIV in Rhesus Macaques Naveen Suresh Babu 1 , Chrysostomos Perdios 2 , Anna T. Brown 2 , Celeste Coleman 2 , Carolina Allers 2 , Matilda Mostrom 2 , Lara Doyle-Meyers 2 , Ricki Colman 3 , Anne Le 4 , Pratik Khare 4 , Clovis Palmer 2 , Joseph C. Mudd 1 1 Tulane University, Metairie, LA, USA, 2 Tulane National Primate Research Center, Covington, LA, USA, 3 University of Wisconsin–Madison, Madison, WI, USA, 4 Gigantest, Inc, Baltimore, MD, USA Background: Nutrient metabolism influences HIV-1 replication, immunity, and chronic inflammation but is difficult to target therapeutically. We hypothesized that regulating metabolism via caloric restriction (CR), a safe, anti-aging modality with anti-inflammatory effects could improve SIV disease outcome in rhesus macaques (RMs). Methods: Healthy, non-obese, adult male and female RMs (n=6) were experimentally restricted to consume 30% fewer daily calories than ad-libitum (AL) intake. After 3 months of CR, animals were infected with SIVmac239, left untreated for 28 days, and given ART for 11 months while maintaining CR. Animals were compared to age, gender, and weight-matched AL-fed RMs (n=10). Immune phenotypic profiling by flow, plasma SIV load, and -omic classification of soluble proteins/metabolites in plasma were assessed during acute SIV (14 dpi) and 11 months of ART. Results: CR was safe, well tolerated, and led to modest reduction in weight and fat/lean mass ratio. CR animals exhibited near log fold reductions in acute phase viremia (AUC) when compared to that of the AL-fed cohort (-0.8log, Fig. A). Viremic control in CR was characterized by more robust memory CD8 T cell proliferative response in lymphoid (p=0.008) and gut tissues (p=0.03). At 11 months of ART, CR animals had lower immune cell infiltration (Fig. B) and reduced levels of HLA-DR+ CD4 (p=0.0013) and CD8 (p=0.008) memory T cells in the colon. This was also associated with lower sCD14 (p=0.0002) and several TNF-related proteins (p=0.002). Of the 376 acute SIV metabolites, LASSO regression revealed a set of 3: Spermidine, ADP, and Glucose-1-phosphate (breakdown product of glycogen and galactose stores) that inversely predicted lower plasma SIV AUC. Indeed, ex vivo glycolytic flux and mTORC1 activity was higher in PBMCs (p=0.009) and memory CD8 T cells of CR animals during acute SIV (p=0.03). During ART, LASSO suggested a central role for glutamine metabolism, with 2-oxoglutarate (TCA intermediate promoting gut enterocyte proliferation), and cysteinylglycine (glutathione-derived antioxidant), as predictive markers of colonic reconstitution. Conclusions: The data highlight that diet, in regulation of caloric content, can have a significant therapeutic impact on SIV disease outcomes. Pharmacologically reducing caloric intake by mimicking satiety with glucagon like peptide-1 agonists, which are currently taken by 16 million US adults,

warrants further investigation in the context of virologic control and residual inflammation in HIV-1. The figure, table, or graphic for this abstract has been removed. A New Mouse Model of HIV in Pregnancy: The EcoHIV Pregnancy Model Michelle M. Ranjbar 1 , Ingrid Hsieh 1 , Maud Collomb 2 , Shreya Dhumé 2 , Lena Serghides 2 1 University of Toronto, Toronto, Canada, 2 University Health Network, Toronto, Canada Background: Children who are born HIV-exposed but uninfected (HEU) are the fastest growing HIV-affected population, numbering at over 16 million children globally.There is a large gap in our understanding of how in utero exposure to HIV and antiretrovirals influence the development and long-term health of these children. A mouse HIV pregnancy model would greatly facilitate such research. EcoHIV is a chimeric ecotropic HIV virus that has been modified to express the envelope coding region from the murine leukemia virus gp80 instead of gp120 to allow HIV infection in mouse immune cells. EcoHIV infection parallels several major characteristics of HIV in humans including susceptibility to antiretrovirals, induction of anti-viral immune responses, and elevation of inflammatory markers. EcoHIV has not been used in the context of pregnancy before. Here we present a new EcoHIV infection model in a mouse pregnancy model. Methods: 7-week-old C57BL/6 mice were intraperitoneally injected with 2.5x10 6 pg EcoHIV virus or mock infected with 500uL PBS, and were mated 1 week post infection. Pregnant dams were euthanized on gestational day (GD) 14.5 or 18.5 (N=5/group). Tissue and blood were collected to detect infection through HIV gag expression by qPCR. Fetal and placenta weights, fetal viability and number of resorptions were recorded. mRNA expression of neuroinflammatory markers were assessed in fetal brains (N=24/group) by qPCR. Mann-Whitney test was used for statistical comparisons. Results: Injection with EcoHIV resulted in 100% maternal infection, confirmed by HIV gag detection in spleen tissue of all dams. No infection was detected in EcoHIV exposed fetuses. EcoHIV infection was associated with significantly lower fetal weights (Figure), lower placenta efficiency, and lower viability rates. TNFa mRNA levels were increased, and mRNA levels of synapsin 1 (SYN1) and synaptophysin (SYP), which are markers of neuronal health, were decreased in brains of EcoHIV exposed fetuses compared to controls (Figure). Conclusions: The EcoHIV pregnancy model represents the first mouse pregnancy model that includes HIV. In utero EcoHIV exposure was associated with fetal growth restriction and placental insufficiency even in the absence of fetal infection, paralleling clinical findings. Neuroinflammation and neuronal toxicity in EcoHIV exposed uninfected fetuses, may represent a mechanism contributing to neurodevelopmental deficits seen in children who are HEU.

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CROI 2025