CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

in PLWH. We use transcriptional TB risk scores to explore risk of TB associated with HIV in a unique acute infection cohort of PLWH with longitudinal sample collection before and after HIV acquisition Methods: We utilized stored whole blood collected in RNAlater from the MERLIN cohort: a longitudinal cohort of transgender women and men who have sex with men. Uninfected participants were followed from 2013-2016 with monthly testing for HIV; 216 participants with acute or recent HIV infection (by serology or RNA) and a documented HIV-negative test within 90 days were enrolled and randomized to begin ART immediately or to defer for 6 months. Participants (~50%) have remained in follow up with viral suppression for 8-10 years after ART initiation. We sequenced RNA from two pre-HIV samples (enrolment and last sample before diagnosis), at the first post-diagnosis timepoint, months 3, 6, 12, 24, and 48 after HIV diagnosis. TB risk scores were calculated at each timepoint using the Risk6 TB signature that we previously developed, consisting of three upregulated and three downregulated genes. The risk scores were computed as follows: geometric mean of log2 (GMlog2) counts of upregulated genes – GMlog2 counts of downregulated genes Results: Prior to HIV infection, there was no difference in TB risk between enrollment and last timepoint before HIV-infection. TB risk increased at diagnosis (p<0.0001), and then decreased by month 3 (p = 0.0008) and month 6 (p<0.0001). At six months after diagnosis, TB risk scores had decreased to enrollment (baseline) levels in both the immediate (treated) and deferred (untreated) arms. Conclusions: TB risk increased soon after HIV acquisition. Our preliminary data suggests that the risk decreases in PLWH who show at least some virologic control, as scores decreased at 6 months even in untreated participants. We previously showed that TB risk scores (derived from interferon inducible genes) are associated with viremia, suggesting viremia contributes to the signature. Thus, decrease in TB risk scores may reflect VL reductions due to treatment or progression to set point in untreated participants. Impact of Cytomegalovirus Infection on the Progression of TB Disease in People With HIV on ART Sivaporn Gatechompol 1 , Sasiwimol Ubolyam 2 , Thitiporn Somjit 2 , Chavachol Setthaudom 1 , Anchalee Avihingsanon 3 , Stephen Kerr 4 , Frank van Leth 5 , Frank Cobelens 6 1 Mahidol University, Bangkok, Thailand, 2 Thai Red Cross AIDS Research Centre, Bangkok, Thailand, 3 HIV-NAT, Thai Red Cross AIDS and Infectious Disease Research Centre, Bangkok, Thailand, 4 Chulalongkorn University, Bangkok, Thailand, 5 Vrije Universiteit Amsterdam, Amsterdam, Netherlands, 6 Amsterdam Institute for Global Health and Development, Amsterdam, Netherlands Background: Emerging evidence suggests that human cytomegalovirus (HCMV) infection is associated with the progression of tuberculosis (TB) disease. This study aimed to evaluate the temporal relationship of HCMV infection on TB progression in people with HIV (PWH). Methods: In a case-control study nested within a Thai HIV cohort, stored plasma samples from PWH who developed active TB after stable ART (cases) were assessed for HCMV infection. For controls, we selected stored samples from PWH in the same cohort who did not develop TB disease, matched in a 1:2 ratio by ART duration. HCMV DNA, HCMV IgM, and IgG were measured at 3 timepoints: (1) 6-24 months before TB diagnosis (pre-TB visit), (2) at TB diagnosis (TB visit), and (3) 6-24 months after TB diagnosis (post-TB visit). HCMV viremia was defined as detectable CMV DNA in plasma. Conditional logistic regression with backwards selection was used to investigate associations with TB disease. Results: A total of 34 TB cases and 68 control PWH were enrolled. The majority (58.8%) were male with median (interquartile range: IQR) time of ART duration of 10.6 (6.5-17.4) years. The age was 42 (34-51.) and 44 (38-52) years for cases and controls, respectively. 100% of participants were HCMV seropositive. At the

pre-TB visit, we observed no significant differences in the proportion of HCMV viremia (21% vs 18%, p=0.719), HCMV IgM geometric mean concentration (GMC) (0.13 (95%CI 0.10-0.16) vs 0.12 (95%CI 0.10-0.13), p=0.402) and HCMV IgG GMC (225.6 (95%CI 210.2-242.1) vs 206.6 (95%CI 190.2-224.6), p=0.179) among TB cases and controls. We found the proportion of HCMV viremia was higher among TB cases at TB visit (35% vs 14%, p= 0.028) and post-TB visit (32% vs 5%, p=0.006) compared to controls. The HCMV IgM GMC at the TB visit was higher in the TB group than control (0.17 (95%CI 0.12-0.23) vs 0.12 (95%CI 0.10-0.14) AU/ml, geometric mean ratio (GMR)=1.38 (95%CI 1.01-1.87, p=0.039). In an adjusted model, the odds of TB in those with middle and high tertile HCMV IgG at the TB visit was 5.45 times higher (p=0.044) compared to the lowest tertile (Table). Conclusions: We found no evidence suggesting HCMV viremia and HCMV serology were associated with the progression of TB disease in 6-24 months. At the time of TB diagnosis, HCMV IgG levels show an association with TB disease, possibly reflecting HCMV reactivation due to TB disease or another, common cause.

Poster Abstracts

955

Immune Profiles Can Differentiate Mycobacterial and KSHV Inflammatory Syndromes in Advanced HIV

Silvia Lucena Lage 1 , Joseph Rocco 1 , Ramya Ramaswami 2 , Kathryn Lurain 2 , Maura Manion 1 , Brian P. Epling 1 , Elizabeth Laidlaw 1 , Logan Cook 1 , Frances Galindo 1 , Denise Whitby 3 , Andrea Lisco 1 , Robert Yarchoan 2 , Irini Sereti 1 1 National Institute of Allergy and Infectious Diseases, Baltimore, MD, USA, 2 National Institutes of Health, Bethesda, MD, USA, 3 AIDS and Cancer Virus Program, Frederick, MD, USA Background: Mycobacterial immune reconstitution inflammatory syndrome (myco-IRIS) and Kaposi sarcoma herpesvirus (KSHV) associated diseases (KAD) remain common in people with advanced HIV in resource-constrained settings. These syndromes can be difficult to differentiate clinically, and optimal treatments remain unknown, highlighting the importance of determining their pathogenesis. We have previously shown greater IFNγ production in myco-IRIS whereas IL18 levels are more prominent in KAD. To expand on these findings, we performed high-dimensional flow cytometry on peripheral blood samples from people with myco-IRIS or KAD to determine key cell subsets and signaling pathways involved in their pathogenesis. Methods: Samples were obtained from people with HIV (PWH) and active myco-IRIS or KAD (Kaposi sarcoma multicentric Castleman disease, KSHV inflammatory cytokine syndrome). All participants were enrolled in a NIH-IRB approved protocol and were on antiretroviral therapy (ART). A 29-marker flow panel including monocyte and T-cell/NK-cell markers of differentiation, activation, and function was run on all samples at diagnosis. Wilcoxon test, unsupervised clustering, and differential abundance analyses were performed. Results: Overall, 22-PWH were included (median age 39-years [IQR: 29-46]) with 17-cisgender men (77%). Thirteen-PWH had myco-IRIS (tuberculosis, n=4; nontuberculous, n=9), and 9 had KAD (7 [78%] with concomitant Kaposi sarcoma). Patients with myco-IRIS had a greater percentage of activated (CD38 hi HLADR+) CD8 T-cells with greater EOMES+ positivity compared to KAD (p<0.01). Activated CD4 T-cells were similar between the groups, however KAD had greater caspase-1 activation in monocytes (p<0.05) vs myco-IRIS. Unsupervised clustering analysis identified two uniquely expanded activated T-cell populations (Figure-1: CD4s [violet cluster] and CD8s [dark green cluster]) in myco-IRIS compared to KAD with increased cell cycling (Ki-67 hi ), IL18R+ expression, and mTOR signaling (pS6+) (p<0.01). Patients with KAD had a significant expansion of classical/intermediate monocyte populations (gold clusters) with increased CD163+ and HLADR+ expression as well as greater caspase-1 activation (p<0.01) (Figure-1).

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