CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

Conclusions: In this pilot study, we identified transcriptional changes in GALT-resident immune cells of individuals with well-controlled HIV infection on ART following the infusion of 3BNC117-LS and 10-1074-LS bNAbs. These changes suggest that bNAb exposure may modulate TNF/NF-kB and IFN signalling in CD4+ and CD8+ T cells - pathways that have been linked to immune cell susceptibility to HIV infection, innate and adaptive immune response to HIV and reactivation of latent infection. Identification of an Autoantibody Against FCHSD2 in Adipose Tissue of PLWH With Diabetes Laventa Obare 1 , Samuel Bailin 1 , Xiuqi Zhang 1 , Kisyua Nthenge 1 , Mona Mashayekhi 1 , Curtis L. Gabriel 1 , Simon A. Mallal 1 , John Koethe 1 , Wyatt J. McDonnell 2 , Celestine Wanjalla 1 1 Vanderbilt University Medical Center, Nashville, TN, USA, 2 Infinimmune, Alameda, CA, USA Background: Cardiovascular disease (CVD) risk is 1.5- to 2-fold higher in people living with HIV (PLWH). The heightened risk persists despite suppression of plasma viremia and control of traditional risk factors, partly due to chronic inflammation. Subcutaneous adipose tissue (SAT) regulates metabolic health, but inflammation and insulin resistance can shift its secretome to a pro inflammatory, pro-atherogenic state. FCHSD2 is an adapter protein involved in insulin secretion and has been implicated in the pathogenesis of diabetes. B cells have been associated with cardiometabolic disease and are present in SAT. Methods: B cell subsets in the SAT were characterized using single-cell RNA sequencing (CITE-seq) and B cell receptor (BCR) sequencing in a cohort of 91 PLWH and people without HIV (PWoH) with similar traditional CVD risk profiles. Plasmablasts, naïve cells, and memory B cells were compared across metabolic subgroups (diabetic and non-diabetic). The top ten clonal BCRs from PLWH were expressed as recombinant antibodies and tested for reactivity against CMV using ELISA and reactivity against human proteins using a human protein microarray with over 21,000+ unique human proteins (CDI Labs). We verified the specificity of a clonal antibody against FCHSD2 using transient transfection of 293K cells with plasmids expressing FCHSD2 (Figure A). Results: SAT of diabetic PLWH and PWoH had significantly higher plasmablasts and fewer naïve B cells than non-diabetic PLWH (p<0.01). B cells from PWoH with diabetes had higher expression of genes with regulatory functions, including LGALS1 , SPP1 , and LNMA . In contrast, B cells from PLWH with and without diabetes expressed higher CD69 , CD40 , and CXCR4 (all, p<0.0001), consistent with an activated immune response. One of the ten clones was reactive against CMV. Another clone, identified initially as an IgA, was reactive against FCHSD2 (EC50 12.69 ng/ml). Out of 41 PLWH, ten had high titers of anti FCHSD2 antibodies in plasma, six of which had diabetes (Figure B). Notably, the anti-FCHSD2 clone has undergone somatic hypermutation, resulting in an IgH sequence identity of 93.13% and an IgL sequence identity of 93.55 compared to its original germline sequence. Conclusions: HIV infection and co-infections are associated with changes in B cells which have implications for cardiometabolic disease. Anti-FCHSD2 autoantibodies highlight a novel autoimmune mechanism in PLWH that links immune dysregulation and metabolic dysfunction, which has implications for CVD. Detection of Anti-Interferon Alpha/Omega Neutralizing Autoantibodies in PLWH Alessandra D'Auria 1 , Federica Frasca 1 , Matteo Fracella 1 , Roberta Campagna 1 , Luca Maddaloni 1 , Ginevra Bugani 1 , Letizia Santinelli 1 , Ivano Mezzaroma 1 , Caterina Fimiani 2 , Claudio Maria Mastroianni 1 , Guido Antonelli 1 , Ombretta Turriziani 1 , Gabriella d'Ettorre 1 , Carolina Scagnolari 1 1 Sapienza University of Rome, Rome, Italy, 2 Policlinico Umberto I, Rome, Italy Background: Anti-type I interferon (IFN-I) neutralizing autoantibodies (NABs) have been associated with an increased risk of life-threatening viral infections, including SARS-CoV-2, influenza virus and more recently West Nile virus. Given the detrimental role of IFN-I in HIV-1 infection, it is imperative to investigate anti-IFN NABs and associated IFN pathway modulation in people living with HIV (PLWH). Therefore, we investigated the prevalence of anti-IFN-I NABs in a cohort of PLWH, and examined their specificity, fluctuation over time, biological significance and clinical implications. Methods: Blood samples were collected from 280 virologically suppressed ART treated PLWH at the Policlinico Umberto I, hospital of Sapienza in Rome, Italy. The figure, table, or graphic for this abstract has been removed.

Serum samples were tested for the detection of NABs against IFN-α, -β and -ω using an antiviral bioassay. Longitudinal measurements of NABs over a 1-year period were carried out in serum samples from those patients with anti-IFN-I NABs. Expression levels of the IFN induced antiretroviral restriction factors, APOBEC 3G/3F and ISG15, were measured by RT/real time PCR in PBMC from NAB-positive and age- and sex-matched NAB-negative PLWH (n=16). Results: Anti-IFN-I NABs was detected in 3.9% of PLWH (11/280). The range of NAB levels against IFN-α was very wide (53-530000 tenfold reduction units [TRU/mL]). We found that 45% (5/11) of sera containing anti-IFN-I NABs were able to neutralize IFN-ω but not IFN-β. All NABs-positive PLWH were male, with a median age of 65 years (range 30-78) and median nadir CD4+ T cell counts (cells/µl) and CD4+ T cell counts of 190 and 500, respectively. Four PLWH had been hospitalized for severe SARS-CoV-2 infection (two requiring mechanical ventilation and one with a fatal outcome); two individuals had Kaposi's sarcoma and one had AIDS dementia complex with oropharyngeal candidiasis. Reduced levels of APOBEC3G/3F and ISG15 mRNA were observed in PBMC from anti-IFN NABs positive PLWH compared to negative PLWH (p<0.05). Longitudinal evaluation of anti-IFN NABs showed persistence of anti-IFN NABs, with titer fluctuation over time, in 27% (3/11) of PLWH. Conclusions: These results indicate that anti-IFN-α/ω NABs can be detected in the serum of PLWH, reduce the expression of IFN induced retroviral restriction factors and persist in some patients in association with worsening disease, suggesting that assessment of anti-IFN -I NABs could be considered as a novel candidate disease determinant in PLWH. Age Inversely Correlates With T-Cell Response to MVA.HIVconsvX Vaccination in PWH on ART Cynthia L. Gay 1 , Yinyan Xu 1 , Ann Marie Weideman 1 , Joann Kuruc 1 , Fiona Shaw 1 , Shayla Conrad 1 , Alexis Sponaugle 1 , Carolina Kapper 1 , Greg Laird 2 , Joshua C. Cyktor 3 , Joseph J. Eron 1 , David M. Margolis 1 , Michael Hudgens 1 , Tomáš Hanke 4 , Nilu Goonetilleke 1 1 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 2 Accelevir Diagnostics, Baltimore, MD, USA, 3 University of Pittsburgh, Pittsburgh, PA, USA, 4 University of Oxford, Oxford, UK Background: Durable antiretroviral therapy (ART)-free remission from HIV will likely require a robust and targeted T cell response to limit viral reactivation. Methods: We report a double-blind, randomized trial in people with HIV (PWH) suppressed on ART. Participants, 21-60 years (median 41 years), received modified vaccinia Ankara (MVA)-vectored vaccines, MVA.tHIVconsv3 (M3), MVA.tHIVconsv4 (M4), alone or in combination (n=7/group) or saline placebo (n=3). M3 and M4 contain different HIVconsvX immunogens that each span the same regions in HIV Gag and Pol but differ at ~8% of amino acids. T cell immunogenicity was measured by ex vivo ELISpot and CD8 T cell virus inhibition assays. T cell phenotyping was performed using mass cytometry and HIV reservoir measured using single copy assay (SCA) and integrated proviral DNA assays (IPDA). Results: Vaccination (all regimens) was well tolerated, significantly increased the magnitude and breadth of the HIV-specific T cell response, redirected T cells to conserved HIV regions for up to 10 weeks post vaccination and increased the ability of CD8 T cells to detect and clear participants’ autologous reservoir virus. T cell magnitude, breadth or shift in immunodominance were not statistically separable between vaccine regimens. Vaccination did not impact total memory CD4 T cell activation, low-level viremia or integrated HIV DNA. HIV-specific T cell responses to vaccination increased up to 24-fold over baseline (average >3-fold) with the contribution of new T cells to the total vaccine-specific response ranging from 0-80% (average 11%). Across timepoints, linear regression found that age was a significant negative predictor of fold T cell response to vaccination (Figure1). Slope analysis predicted a 0.05 decrease in log2 fold change in T cell magnitude to HIVconsvX immunogens for every additional year of age suggesting the fold-change in magnitude to MVA.HIVconsvX vaccination would approximately halve over a 20-year period. Detection of new T cell responses following vaccination similarly inversely correlated with age. Conversely, years on ART correlated positively with the fold-change in T cell magnitude to vaccination. Conclusions: MVA.HIVconsvX vaccines were safe and consistently immunogenic in PWH on ART. However, the strength of the T cell response to vaccination exhibited an inverse and linear association with age. Novel approaches are needed to improve HIV immunity in middle- to older-aged PWH.

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