CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

Results: Among 350 study participants, despite similar ages, females and PLWH had more NHV than males and controls, respectively (Table 1). By univariate analysis, a lower CD4:CD8 ratio was associated with male sex, HIV+ status, and having 2-3 or 4-6 vs. 0-1 NHV. The CD8 + ,CD28 + :CD28 - ratio decreased with increasing number NHV, and was lower among PLWH. For both CD4 and CD8 T cells the naive:effector ratio decreased with increasing number of NHV. Living with HIV, being male, and having CMV were all independently associated with a decreased CD4:CD8 ratio when controlling for age, ethnicity, smoking, and the six other NHVs (all β >0.22, p<0.001) . In a similar model for the CD8 + ,CD28 + :CD28 - ratio, HIV, CMV and HSV2 were independently associated with a decreased ratio (all β >0.21, p<0.01), but male sex was not (p=0.055). Finally, male sex and CMV were independently associated with lower naive:effector ratio in CD4 and CD8 T cells. In contrast, HSV1 was associated to a decrease in naive CD4 T cells, while HSV2 was associated with a decrease in naive CD8 T cells (all β >0.11, p<0.01). Conclusions: Our findings suggest that NHV, including those that are typically asymptomatic such as CMV, HSV1 and HSV2, likely contribute to immune aging. Paradoxically, despite harbouring more NHV, female participants showed healthier immune cell profiles for all markers studied, a sex effect similar in size to that seen for HIV or CMV. Sex Differences in Cytokine Responses and Genetic Regulation Thereof in People Living With HIV Suzanne D. E. Ruijten 1 , Nadira Vadaq 1 , Albert L. Groenendijk 2 , Louise E. van Eekeren 1 , Wilhelm A. Vos 3 , Marc J. T. Blaauw 4 , Mihai G. Netea 1 , Andre van der Ven 1 , Jéssica dos Santos 1 , Vasiliki Matzaraki 1 , for the 2000HIV Human Functional Genomics Partnership Program 1 Radboud University Medical Center, Nijmegen, Netherlands, 2 Erasmus University Medical Center, Rotterdam, Netherlands, 3 OLVG, Amsterdam, Netherlands, 4 Elisabeth-TweeSteden Ziekenhuis, Tilburg, Netherlands Background: Females living with HIV have improved viral control but increased immune activation compared to males. Some of these differences appear before puberty, suggesting a role of genetics, but this remains poorly understood. In this study, we assessed the effect of biological sex on circulating cytokine levels and cytokine production upon PBMC stimulation, and the genetic regulation of the latter. Methods: The 2000HIV study (NTC03994835) included 1895 virally suppressed PLHIV, split into a discovery (1309 males, 233 females) and validation cohort (281 males, 52 females). Plasma levels of 54 cytokines were measured using Olink technology. PBMCs were stimulated with a range of stimuli to assess cytokine production across 77 cytokine-stimuli pairs. Associations with sex were assessed using (rank-based) linear regression. We investigated sex-specific genetic regulation of cytokine responses through sex-stratified cytokine QTL (cytQTL) mapping in individuals from European ancestry (discovery: 861M & 97F, validation: 221M & 26F). Suggestive cytQTLs were tested for sex-specific effects using a student’s t -test, and sex-specific QTLs (ssQTLs) were tested for association with other phenotypic traits using the OpenTargets database. Results: Females showed significantly (FDR dis < 0.05 & P val < 0.05) higher plasma levels of GM-CSF, G-CSF, and CCL22 and significantly lower levels of IL-18, IL-17C, CCL4, IL-16 and IL-22. Cytokine production upon PBMC stimulation was similar between sexes, except for significantly (FDR dis < 0.05 & P val < 0.05) increased IL-22 production upon stimulation with S. pneumoniae in females. cytQTL mapping identified 40 independent suggestive (P dis < 1E-5 & P val < 0.05) cytQTLs in males and 20 in females, of which 22 were sex specific (P < 8.3E-4). Notably, we identified two SNPs regulating IL-22 responses to C. albicans conidia and E. coli , in females but not in males. Finally, we found that ssQTLs are linked with phenotypic traits related to autoimmune diseases, blood cell composition, and sex hormone levels. Conclusions: In our study, the effect of sex seems more pronounced on plasma cytokine levels compared to cytokine production upon PBMC stimulation. Yet, sex differences in HIV immunopathogenesis may be driven by differences in cytokine signalling, such as IL-22, which regulates host defences at mucosal sites. We showed sex-specific genetic regulation of cytokine responses in PLHIV, which could be used to stratify PLHIV in immunological intervention studies.

(MAIT), invariant natural killer T-cells (iNKT), and Vδ2+ T-cells which mediate gut barrier defence and mucosal inflammation. To investigate whether the distinct clinical courses of HIV subtypes are associated with altered frequency and function of unconventional lymphocytes, we assessed mitochondrial and exhaustion profiles of these populations in HIV-1, HIV-2, and healthy controls (HC). Methods: PBMCs from people with HIV-1 (n=6) people with HIV-2 (n=6) and HC (n=6) were analysed by 26 colour flow cytometry. In addition to conventional T-cell lineage markers, iNKT, MAIT, and Vδ2+ subsets were assessed for frequency and expression of exhaustion markers (PD1, TIGIT) and mitochondrial function (MTG, TMRM). Results: Both HIV-1 and HIV-2 cohorts were virally suppressed (VL<50 c/mL) and on ART (clinical demographics summarised in Table 1). iNKT frequency did not differ between cohorts (p=0.6). HIV-1 was associated with increased MAIT cell frequency (p=<0.03) and expression of TIGIT (p=<0.02) relative to HIV-2, although mitochondrial profile of MAIT cells was comparable between HIV cohorts (p=0.4). Circulating Vδ2+ frequency was higher (p=<0.03) in HIV-1 than in HIV-2, but mitochondrial activity was markedly higher (p=<0.03) in HIV-2 relative to HIV-1 and HC. Conclusions: Preliminary analysis suggests that MAIT and Vδ2+ T-cell frequencies are higher in HIV-1 than in HIV-2, but there is a higher proportion of functional mitochondria in MAIT cells in HIV-2. These data suggest that the innate lymphocyte pool is differentially impacted by HIV subtypes, which may influence gut reservoir size and clinical course of infection. Future work will focus on gut homing potential and add additional markers of mitochondrial function including mtDNA copy number, ROS generation, and cellular respiration.

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Poster Abstracts

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Non-HIV Chronic/Latent Viruses and Immune Aging: Sex Effects Comparable to Those of HIV and CMV Renying (Loulou) Cai 1 , Nancy Yi Yang 1 , Mel Krajden 2 , Amber Campbell 3 , Melanie Murray 3 , Helene Cote 1 , for the Children and Women Antiretrovirals and Markers of Aging (CARMA) Study, CTN 277 1 University of British Columbia, Vancouver, Canada, 2 BC Centre for Disease Control, Vancouver, Canada, 3 BC Children's & Women's Health Centre, Vancouver, Canada Background: Non-HIV chronic/latent Viruses (NHV) such as CMV, EBV, HHV-8, HSV-1, HSV-2, HCV, and HBV are associated with markers of aging and/or age related diseases and play a role in the accelerated cellular aging in people living with HIV (PLWH). We investigated association(s) between sex, HIV status, and NHVs, and selected markers of immune aging, in a cohort of PLWH and controls. Methods: CARMA cohort participants (2-76y), balanced for sex, HIV status, and age were analyzed (Table 1). Seropositivity for the NHV were ELISA based or self-reported (HIV, HCV, HBV). The CD4:CD8, CD8 proliferation competent:senescent (CD8 + ,CD28 + :CD28 - ) and the naïve:effector CD4 and CD8 T cell ratios were determined via flow cytometry. Associations between number of NHV (0-1, 2-3, 4-6), HIV status, sex, and age were assessed using Mann Whitney, Kruskal-Wallis, and Spearman’s tests. Multivariable linear regression determined independent associations (β= effect size) between the markers of aging, NHV, and sex, controlling for age and other potential confounders.

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CROI 2025