CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

536

Impact of Gender-Affirming Hormone Therapy on HIV Reservoirs and Inflammation in Transgender Women Elizabeth Hastie 1 , Antoine Chaillon 1 , Alan Wells 1 , Christophe Vanpouille 2 , Christy Anderson 1 , Magali Porrachia 1 , Kyra Forsyth 1 , Vanessa Gomez-Moreno 1 , Megha S. Srivatsa 1 , Jill Blumenthal 1 , Marvin Hanashiro 1 , Eileen P. Scully 3 , Jordan E. Lake 4 , Jonathan Karn 5 , Sara Gianella 1 1 University of California San Diego, La Jolla, CA, USA, 2 National Institute of Child Health and Human Development, Bethesda, MD, USA, 3 The Johns Hopkins University School of Medicine, Baltimore, MD, USA, 4 University of Texas at Houston, Houston, TX, USA, 5 Case Western Reserve University, Cleveland, OH, USA Background: Transgender women (TW) are at increased risk for HIV but are underrepresented in research. We investigated how the initiation of gender affirming hormone therapy (GAHT) impacts HIV reservoir (size and activity) and inflammation. Methods: TW with HIV starting estradiol-based GAHT were recruited at two clinics in San Diego, CA and Houston, TX. Participants were on antiretroviral therapy (ART) and had suppressed HIV-1 RNA during the study. Blood and plasma were collected prior to starting GAHT and longitudinally 2, 4, 6, 9, 12, and 18 months post GAHT initiation. Historical samples from cisgender men with HIV were matched by age, CD4+ T cell count, duration of HIV, and time on ART. At each timepoint, we measured estradiol and testosterone by ELISA, cell-associated HIV RNA (unspliced and multiple spliced) and HIV DNA (total and 2-LTR) by ddPCR, and 41 cytokine/chemokines by Luminex. We used a linear mixed effects model with HIV reservoir values as outcomes, and time, group, and their interaction as predictors along with a random intercept. Partial least squares-discriminant analysis (PLS-DA) was used to predict gender groups using cytokine/chemokines. Error rates were estimated using k-fold cross-validation. Results: A total of 22 TW were enrolled. Nine were lost to follow-up including one suicide, one homicide, and two imprisonments. A total of 77 samples from TW and 79 samples from cisgender controls were analyzed. Compared to cisgender controls, TG women had higher overall estradiol (145.83 vs 45.62 pg/mL, p<0.001), and lower testosterone concentrations (226 vs. 436 ng/dL, p<0.001) with a sharp decrease after baseline. Overall, TW had higher HIV DNA levels (both total and 2LTR). We observed a significant interaction between time and gender group for 2-LTR but not for total HIV DNA (Panel A). There was no difference in unstimulated cellular HIV RNA between groups. Using our cytokine/chemokines dataset, we accurately predicted gender group in the PLS-DA model with an error rate of 10% (Panel B). Conclusion: TW had increased HIV DNA with faster decline in 2-LTR circle after initiating GAHT compared to cisgender men, supporting estradiol's inhibition of residual HIV replication. TW had unique immune signatures, which might impact HIV disease outcomes and comorbidities. Our study underscores the challenges associated with recruiting and studying this unique population, emphasizing the need for trauma-informed care and tailored research efforts.

combo treated group pre-ATI (APOBECs, SAMDH, ISGs) that was persistent till the end of the follow up (6 months post-ATI). Monocytes, CD8 and CD4 T cells presented significantly higher protein-expression of pIRF3 and pIRF7. Use of multi-ome platform that allows simultaneous single cell assessment of transcription and epigenetic profiles showed that the enhanced expression of antiviral ISGs was concomitant with the increased chromatin accessibility of the IRF3, IRF7 and Stat1 transcription factors known to confer refractoriness to viral infections by inducing Interferon antiviral genes. Moreover, pre-ATI, the accessibility of the Tbet locus and its target genes such as granzyme B, perforin and IFNg, in CD4 and CD8 T cells from combo treated animals was observed. This poised antiviral environment was associated with viral rebound control. Conclusion: The combo therapy triggers an epigenetic reprogramming of innate and adaptive immune cells highlighted by poised intrinsic antiviral machinery and poised effector molecules of T cell function that together synergize to block the de novo CD4 T cell infection post-ATI and viral dissemination. The figure, table, or graphic for this abstract has been removed. Disrupting SIV Reservoir Seeding by Targeting Stemness Pathways in Rhesus Macaques Inna Ruiz-Salinas 1 , Riri R. Hamid 1 , Nils Schoof 1 , Alice Lin 1 , Jordan Goldy 1 , Guido Silvestri 2 , Ann Chahroudi 1 , Maud Mavigner 1 1 Emory University, Atlanta, GA, USA, 2 Emory National Primate Research Center, Atlanta, GA, USA Background: Latently HIV-infected CD4+ T cells persist indefinitely through proliferation. We previously showed that inhibition of proliferation and induction of differentiation of the long-lived, self-renewing central (CM) and stem cell memory (SCM) CD4+ T cells can be achieved in ART-treated SIV infected rhesus macaques (RMs) through modulation of the Wnt pathway. Here, we evaluated a combined approach targeting Wnt and Notch pathways during acute SIV infection of RMs to disrupt viral reservoir establishment. Methods: Five RMs were infected i.v. with SIVmac239 before receiving 8 weeks of treatment with the Wnt inhibitor PRI-724 administered subcutaneously daily at 18-20 mg/kg in combination with the Notch inhibitor LY3039478 administered orally at 2.5 mg/kg three times per week. ART was initiated 8 weeks post-infection (wpi) and PBMC were collected longitudinally on ART to FACS sort subpopulations of naïve, SCM, CM, transitional memory (TM) and effector memory (EM) CD4+ T cells. Levels of cell-associated total SIVgag DNA and unintegrated 2-LTR circles were measured by multiplex qPCR in sorted cells. A group of 7 RMs infected with SIVmac239 and treated with ART alone served as controls. Results: The combined treatment PRI-724+LY3039478 demonstrated an acceptable safety profile and did not alter plasma viral load dynamics in SIV-infected RMs. After ART initiation, the decay in the SIV 2-LTR circles, that are diluted with proliferation, was greater in the CM (p=0.005 at 12wpi) and TM (p=0.018 at 12wpi, p=0.003 at 20wpi) CD4+ T cells from the PRI 724+LY3039478-treated RMs as compared to controls. The ratio of SIVgag/2 LTR was higher in all subsets of memory CD4+ T cells from the treated RMs versus controls at 8 (p<0.035) and 12wpi (p<0.073). Interestingly, a reduced contribution of CM to the total SIV reservoir in CD4+ T cells was observed in the treated RMs as compared to controls at both 8 and 12wpi (p=0.010 for both). This reduction was attributed to lower levels of SIVgag DNA in CM CD4+ T cells at 12wpi (p=0.048) and decreased frequencies of CM cells within the CD4+ T cell pool at 8 and 12wpi (p=0.004 and 0.018) in PRI-724+LY3039478-treated RMs versus controls. Conclusion: This proof-of-concept study suggests that the combined pharmacological modulation of Wnt and Notch pathways during acute SIV infection of RMs impacts viral reservoir seeding by transiently reducing the relative contribution of the CM cells to the peripheral CD4+ T cell compartment and to the pool of the infected CD4+ T cells.

535

Poster Abstracts

CROI 2024 143