CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

318

IL7RA rs10491434 Polymorphism Is Related to Spontaneous HIV Infection Control: A Retrospective Study Daniel Sepúlveda-Crespo 1 , María A. Jiménez-Sousa 1 , Amanda Fernández Rodíguez 1 , María A. Muñoz-Fernández 2 , José L. Jiménez 2 , Jorge del Romero 3 , Sergio Reus Bañuls 4 , Helem Vilchez 5 , Beatriz Mothe 6 , Isidoro Martínez 1 , José M. Benito 7 , Norma Rallón 7 , Salvador Resino 1 1 Institute of Health Carlos III, Madrid, Spain, 2 University Hospital Gregorio Marañon, Madrid, Spain, 3 Centro Sandoval, Madrid, Spain, 4 Hospital General Universitario de Alicante, Alicante, Spain, 5 Hospital Universitario de Son Espases, Palma de Mallorca, Spain, 6 IrsiCaixa Institute for AIDS Research, Badalona, Spain, 7 Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain Background: Interleukin 7 receptor (IL7R) is vital in the adaptive immune response against HIV. We assessed IL7RA polymorphisms (SNPs) in antiretroviral therapy (ART)-naïve HIV patients for their association with spontaneous HIV infection control. Methods: We conducted a retrospective cohort study involving 667 ART naïve patients categorized by HIV progression (ordinal variable): 150 rapid progressors, 334 moderate/typical progressors, 86 long-term nonprogressors elite controllers (LTNPs-EC), and 97 LTNPs-non-EC. We genotyped three IL7RA SNPs using Agena Bioscience's MassARRAY platform. The association between IL7RA SNPs and spontaneous HIV infection control was evaluated using ordinal logistic regression. Results: Individuals carrying the rs10491434 G allele have a higher likelihood of spontaneous HIV infection control (adjusted odds ratio (aOR)=1.33; p=0.023). Moreover, the IL7RA GCT haplotype, consisting of three specific SNPs (rs6897932, rs987106, and rs10491434), demonstrated an association with the control of untreated HIV infection (aOR=1.34; p=0.050). Remarkably, the rs10491434 SNP and the IL7RA GCT haplotype exhibited similar aOR values, suggesting that rs10491434 may be primarily responsible for the observed effect of the haplotype. Conclusion: IL7RA rs10491434 G allele is associated with a higher likelihood of spontaneous HIV infection control, indicating its significant role in the pathogenesis of HIV, possibly influencing infection course and viral replication control. Genetic Variants Associated to HIV Control Are Associated With NK Cell Markers and Response to CMV Suzanne Ruijten 1 , Jessica d. Santos 1 , Albert L. Groenendijk 2 , Marc Blaauw 1 , Louise E. van Eekeren 1 , Wilhelm A. Vos 1 , Nadira Vadaq 1 , Victoria Rios-Vazquez 1 , Leo Joosten 1 , Casper Rokx 2 , Annelies Verbon 2 , Mihai Netea 1 , Vasiliki Matzaraki 1 , Andre J. van der Ven 1 , for 2000HIV 1 Radboud University Medical Center, Nijmegen, Netherlands, 2 Erasmus University Medical Center, Rotterdam, Netherlands Background: Genome-wide association studies (GWAS) have shown that genetic variants in the MHC region are associated with spontaneous HIV-1 control. How these variants affect immune functioning is, however, poorly understood. We used a functional genomics approach in which we integrated GWAS with transcriptomic, plasma proteomic and functional immunological data to understand how genetics contribute to HIV control. Methods: 1380 people living with HIV of European ancestry were included as part of the 2000HIV study (clinicaltrials.gov NTC03994835). To find genetic variants associated to control, a GWAS was performed in 67 HIV controllers (HIC) and 272 matched non-HIV controllers on ART (non-HIC) using a logistic regression model. To unravel how genetics affects phenotype, we performed quantitative trait locus (QTL) mapping with data from the 2000HIV cohort. A linear regression model was used to associate genetic dosages with: 1) cytokine production upon ex vivo PBMC stimulation with various stimuli (cQTLs), 2) levels of 2367 plasma proteins as measured by Olink technology (pQTLs), 3) bulk RNA expression in PBMCs (eQTLs) measured by RNA- sequencing in 1146, 1222 and 1208 individuals, respectively. All genome-wide significant (P < 5∙ 10-8) QTLs were intersected with suggestive GWAS loci. Results: In agreement with previous GWAS, the strongest association with HIV control was identified in the MHC locus (Fig A), where we found 8 independent suggestive SNPs (P < 1 ∙ 10-5, r2 < 0.5). SNP rs2524092-C (P = 2.44 ∙ 10-6, OR = 3.4) was associated with higher GZMA and KLRF1 and lower KIR2DL2, KIR2DL3 and MICA/MICB plasma levels (Fig B), lower HLA-C and higher HLA-H and PSORS1C3 gene expression in PBMCs. Additionally, rs2524092-C is in linkage disequilibrium (r2 = 0.52) with rs9264388-T (P = 1.13 ∙ 10-5, OR = 4.33), which was associated with lower IL-1β and TNF production upon PBMC stimulation with CMV (Fig B).

infection susceptibility are not fully understood. We therefore sought to characterize unconventional T cell phenotypes in 25 HIV-exposed seroconverted (HESC) individuals prior to seroconversion and compare them to HIV-exposed seronegative (HESN) individuals. Methods: RV217 is a prospective natural-history study which recruited individuals at high risk for HIV acquisition. PBMC from the RV217 cohort were used to investigate T cell phenotypes in 25 HESC individuals prior to seroconversion. Each HESC study participant was matched for age, gender, and risk behavior with 3 HESN individuals for comparative analysis. A multicolor flow cytometry panel was developed to investigate mucosal associated invariant T (MAIT), invariant natural killer T (iNKT), gamma delta T, and CD4+ T cell phenotypes prior to HIV seroconversion. Results: Our analysis showed increased frequency of total α 4β7 expressing CD4+ memory T cells in HESC individuals (% α 4β7+, p=0.0755; % α 4β7 high , p=0.0030) compared to HESN individuals. Additionally, our study shows increased frequency of α 4β7 expressing iNKT cells in HESC individuals compared to HESN individuals ((% α 4β7+, p=0.0039). To further characterize α 4β7 expressing iNKT cells, we analyzed α 4β7 expression in major iNKT cell subsets: CD4+ iNKT cells, CD8+ iNKT cells and CD4-CD8- (DN) iNKT cells. Our results reveal that α 4β7 expression in HESC individuals is increased in CD4+ iNKT cells (p=0.0342) and not CD8+ iNKT (p=0.5424) or DN iNKT cells (p=0.7334) compared to HESN individuals. No differences were found in MAIT and gamma delta T cells. Conclusion: Our study supports the existing role of α 4β7 high CD4+ memory T cells in HIV susceptibility and identifies a potential role for gut homing α 4β7+ CD4+ iNKT cells in HIV susceptibility in the context of individuals at high risk for HIV acquisition. Mobility of Transmitted/Founder HIV-1 Variants in Human Cervicovaginal Mucus Matrona M Akiso 1 , Marianne Mureithi 1 , Sarah Joseph 2 , Ann M. Carias 3 , Omu Anzala 1 , Thomas Hope 3 1 University of Nairobi, Nairobi, Kenya, 2 Imperial College London, London, UK, 3 Northwestern University, Chicago, IL, USA Background: HIV-1 needs to traverse the mucus barrier overlaying the mucosal epithelia for infection of the target cells to occur. A single or a limited number of HIV-1 variant(s), known as Transmitted/founder (T/F) HIV- 1, are typically responsible for successive infections, overcoming the mucosal barriers, including the protective mucus layer. Factors affecting cervicovaginal mucus physical and chemical properties may influence its barrier function. How this influences the mobility of T/F HIV-1 variants in the mucus is yet to be determined. Our study sought to unravel how factors affecting the cervicovaginal mucus properties, such as serum levels of reproductive hormones, cervicovaginal pH, microbiome, immunoglobulin content and cytokines, may influence the mobility of T/F HIV-1 variants in cervicovaginal mucus. Methods: A cross-sectional evaluation was conducted to assess the mobility of three T/F HIV-1 clades in cervicovaginal mucus from at least 80 adult women, both HIV-1 infected and uninfected, aged between 18 and 45 years in Nairobi, Kenya. Spearmen correlation was used to correlate the mobility data to the cervicovaginal mucus pH, serum estradiol and progesterone levels and age. A t-test and ANOVA were used for comparing viral mobility between different HIV-1 infection statuses, bacterial vaginosis statuses, and viral clades, respectively. Results: Our results show a significant impediment to the mobility of T/F HIV-1 variants in the cervicovaginal mucus. We observed significant variabilities in the mobility of the different T/F HIV-1 clades in the cervicovaginal mucus. Clade B lab adopted strain (R9 Bal) and T/F HIV-1 variant (CH040) had the lowest mobility compared to clade C (CAP045) and the CRF_AE (92TH023). The mobility of the CRF_AE (92TH023) negatively correlated to the mucus pH and viscosity. Interestingly, we observed significant positive mobility correlations among some viral clades. Conclusion: Our study results demonstrate that cervicovaginal mucus impedes the mobility of T/F HIV-1 variants, which varies among clades. These results also show that cervicovaginal microenvironment may influence the mucus barrier function. This study is crucial for gaining insights into the biological traits of T/F HIV-1 variants, enabling them to bypass the mucosal immune bottleneck. By understanding these early interaction events, we can facilitate the development of preventive strategies and treatments that enhance mucosal barrier function, thus reducing the transmission of HIV-1.

Poster Abstracts

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CROI 2024