CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

381

Extracellular Vesicles’ miRNAs Correlate With Inflammatory Markers in Tanzanians With HIV Mussa H. Bago 1 , Godfrey Barabona 2 , Doreen Kamori 2 , Lilian Nkinda 2 , Takamasa Ueno 1 1 Kumamoto University, Kumamoto, Japan, 2 Muhimbili University of Health and Allied Sciences, Dar es Salaam, United Republic of Tanzania Background: Although antiretroviral therapy (ART) effectively improves the life expectancy among people living with HIV (PLWH), persistent chronic immune activation and inflammation remain a concern. Recent studies suggest that some miRNA species in extracellular vesicles (EVs) play a role in modulating inflammation. We thus hypothesized that dysregulation of EVs’ miRNAs during HIV infection may be associated with HIV-related inflammation. Methods: We isolated EVs from plasma samples comprising 16 untreated and 12 treated HIV-infected patients and 10 healthy individuals in Tanzania, and the total RNA within the resultant EVs was isolated. The relative abundance of 20 immunomodulatory miRNAs was quantified using RT-qPCR and assessed for association with the serum levels of IL-6, IL-10, sCD14, CRP, baseline CD4+ T cell count, and viral load. Results: We observed a significant decrease in expression levels of six miRNAs, including miR-16-5p, 20a-5p, 142-3p, 146a-5p, 382-5p, and 615-5p (>9-fold, p <0.05) in the HIV-untreated group compared to the healthy control group. Compared to the untreated group, four of the six miRNAs (miR-16-5p, 20a-5p, 146a-3p, and 615-5p) showed a marked increase in the treated group but remained below healthy levels ( p < 0.05), whereas the remaining two (miR 142-3p and 382-5p) showed no restoration. In contrast, expression levels of the remaining 14 miRNAs showed no substantial difference between the groups. Moreover, the expression levels of miR-16-5p and 615-5p significantly correlated inversely with sCD14 and IL-6 ( p <0.05) in the treated group, suggesting a potential link between the dysregulated miRNAs in EVs and inflammation. None of the analyzed miRNAs was associated with plasma viral load, baseline CD4+ T cell count, CRP, or IL-10. Conclusions: Collectively, we identified six miRNAs showing substantial dysregulation in EVs in HIV infection. In particular, expression levels of miR 16-5p and miR-615-5p in EVs correlated with inflammation markers in the treated group. These results suggest the potential usefulness of miR-16-5p and miR-615-5p as surrogate markers of chronic inflammation during antiviral treatment in PLWH. Pro-Inflammatory Markers in Persons Living With HIV, HCV, and/or Drug Use Wei-Wen Hsu 1 , Heidi L. Meeds 1 , Janani Madhuravasal Krishnan 1 , Krishna M. Roskin 1 , Matthew Juhascik 2 , John M. Cafardi 3 , Jennifer L. Brown 4 , Caroline Freiermuth 1 , Michael S. Lyons 5 , Kenneth E. Sherman 6 , Jason T. Blackard 1 1 University of Cincinnati Medical Center, Cincinnati, OH, USA, 2 Montgomery County Coroner's Office, Dayton, OH, USA, 3 The Christ Hospital and the Lindner Research Center, Cincinnati, OH, USA, 4 Purdue University, West Lafayette, IN, USA, 5 The Ohio State University, Columbus, OH, USA, 6 University of Connecticut Health Center, Farmington, CT, USA Background: The US is experiencing a major drug epidemic that is attributed in large part to synthetic opioids such as fentanyl. We previously reported that fentanyl enhanced the replication of several viruses including HIV. Here, we considered how fentanyl use impacted inflammatory markers in persons living with HIV. Methods: Whole blood was collected from adults living with HIV, HCV, and/or opioid use, as well as non-opioid using controls. Plasma samples were screened for commonly abused drugs, pro-inflammatory cytokines/chemokines (IL-6, IL-8, SDF-1a, MIP-1a, MIP-1b, RANTES, TNFa), and the apoptosis marker M30 by Liquid Chromatography Mass Spectrometry, Luminex multiplex cytokine array, and the M30 Apoptosense ELISA, respectively. Median values were compared by HIV or HCV status using the Kruskal-Wallis test. Multiple regression models were used to explore the associations between the log 10 -transformed cytokine/ chemokine/M30 values and other covariates. Results: 37 of 98 (37.8%) individuals had a diagnosis of opioid use disorder (OUD), and 48 (53.9%) had ever injected drugs. Of those ever-having opioids, 95.9% (47/49) had used fentanyl. HIV-positive status indicated higher RANTES levels (363.1 vs. 174.9; p = 0.014) and lower M30 levels (84.4 vs. 114.7; p = 0.009) compared to HIV-negative status. Being HCV positive was linked to higher IL-8 (9.6 vs. 6.3; p = 0.023), MIP-1b (25.7 vs. 18.4; p = 0.029), TNFa (17.3 vs .10.7; p = 0.033), and M30 (105.7 vs. 90.0; p = 0.029) and lower RANTES (210.5 vs. 363.9; p = 0.044), compared to HCV-negative status. After adjusting

for other covariates, IL-8 was associated with both HIV status and HCV status, SDF-1a with ever having injected drugs, and MIP-1b with HCV status. There were no significant associations between the number of drugs of abuse detected and cytokine/chemokine/M30 levels after controlling for covariates. Conclusions: Drugs of abuse may alter the immune system and viral pathogenesis in several ways. Enhanced pro-inflammatory cytokine and chemokine production represent potential mechanisms by which opioids impact viral infection. Future research that antagonize these processes may provide new therapeutic interventions that reduce morbidity/mortality among persons with HIV and HIV/HCV co-infected with OUD. The Systemic Inflammatory Profile Differs According to the Mechanism of HIV Control Norma Rallón 1 , Alejandra Manquillo 1 , Clara Restrepo 1 , Sara Nistal 2 , Aws Al Hayani 3 , Alfonso Cabello 3 , Irene Carrillo 3 , Laura Prieto-Pérez 3 , Miguel Górgolas 3 , Juan C. López 4 , Ana Muñoz 5 , Vicente Estrada 5 , Jose M. Benito 1 1 Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain, 2 Hospital Universitario Rey Juan Carlos, Madrid, Spain, 3 Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain, 4 Hospital General Universitario Gregorio Marañón, Madrid, Spain, 5 Hospital Universitario Clínico San Carlos, Madrid, Spain Background: Elite controllers (EC) are an exceptional group of people living with HIV (PLWH) able to control HIV replication without antiretroviral therapy and have been proposed as a model of functional HIV cure. However, significant evidence suggests that despite viral control, EC subjects may have altered levels of activation and systemic inflammation. We have characterized the systemic inflammation profile in EC compared to non-controllers PLWH with ART mediated control of viral replication. Methods: 30 participants were included: 10 EC, 10 non-controllers PLWH on ART (ART), and 10 uninfected controls (UC) as reference. Plasmatic levels of markers of inflammation (sTNFR1, sTNF2, hsCRP), endothelial activation (sICAM1, sVCAM1), monocyte activation (sCD14), intestinal barrier permeability (FABP2) and coagulopathy (d-Dimer, PAI-1), were assessed using enzyme-linked immunosorbent assay (ELISA). Inter-group differences were tested by non parametric tests (Kruskall-Wallis; Mann-Whitney) and a discriminant analysis was employed to ascertain the markers involved in discriminating between pairs of study. Results: EC and ART groups were matched for CD4 counts, years since diagnosis, route of acquisition and gender. The profile of alterations (taking UC group as reference) of the markers analyzed was different in EC and ART. ART group presented increased levels of sVCAM1 (714[564-890] vs. 474[332-741] ng/mL in ART and UC; p=0.086), whereas EC group presented increased levels of sCD14 (1210[990-1944] vs. 965[574-1140] ng/mL in EC and UC; p=0.054). Moreover, sVCAM was increased in ART group compared to EC group (714[564-890] vs. 560[377-636] ng/mL; p=0.041). The discriminant models were able to separate between EC and UC groups (proportion of individuals correctly classified by the model was 70% and 80% for EC and UC respectively; sCD14 was the only variable in the model); and between EC and ART groups (proportion of individuals correctly classified by the model was 70% and 70% for EC and ART respectively; sVCAM was the only variable in the model). Conclusions: Our results show the existence of a chronic inflammatory status in PLWH in spite of controlled viral replication. Interestingly the profile of inflammation differs according to the mechanism of HIV control and points to monocyte activation as a main driver in PLWH EC. Further studies are warranted to test the effect of differential biomarkers levels on the profile of morbidities observed in PLWH with different mechanisms of viral suppression. Host Transcriptional Signatures Associated With Distinct Inflammatory Bioprofiles in People With HIV Dana Alalwan 1 , Alejandro Abner Garcia Leon 1 , Willard Tinago 1 , Padraig McGettrick 1 , Aoife Cotter 1 , Eoin R. Feeney 1 , Jane A. O'Halloran 1 , Eoghan de Barra 2 , Obada Yousif 3 , Mary Horgan 1 , Corinna Sadlier 4 , Alan Landay 5 , Gabriel Gonzalez 6 , Mallon W. G. Paddy 1 1 University College Dublin, Dublin, Ireland, 2 Royal College of Surgeons in Ireland, Dublin, Ireland, 3 Wexford General Hospital, Wexford, Ireland, 4 Cork University Hospital, Cork, Ireland, 5 University of Texas Medical Branch, Galveston, TX, USA, 6 Hokkaido University, Sapporo, Japan Background: Some people with HIV (PWH) exhibit high levels of inflammation despite effective treatment. In two independent cohorts of treated PWH, we previously demonstrated that PWH fall into three distinct inflammatory clusters: cluster 1 defined by lower inflammation, cluster 2 by high innate immune activation, gut microbial translocation, vascular inflammation, and

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CROI 2025