CROI 2025 Abstract eBook

Abstract eBook

Oral Abstracts

144

T-Cell Responses Induced by GS-1966+GS-1144 Vaccines in Virally Suppressed People With HIV Susie S. Y. Huang 1 , Anne-Maud Ferreira 1 , Constance A. Benson 2 , Cynthia Brinson 3 , Moti Ramgopal 4 , Anthony Mills 5 , Edwin DeJesus 6 , Karin Jooss 7 , Christiaan R. de Vries 1 , Devi Sengupta 1 , Pamela M. Odorizzi 1 1 Gilead Sciences, Inc, Foster City, CA, USA, 2 University of California San Diego Medical Center, La Jolla, CA, USA, 3 Central Texas Clinical Research, Austin, TX, USA, 4 Midway Immunology and Research Center, Fort Pierce, FL, USA, 5 Men's Health Foundation, Los Angeles, CA, USA, 6 Orlando Immunology Center, Orlando, FL, USA, 7 Gritstone bio, Inc, Emeryville, CA, USA Background: Vaccination to enhance HIV-specific T-cell immunity may be important for HIV cure strategies. GS-1966+GS-1144 is a novel heterologous vaccine regimen comprising GS-1966 (chimpanzee adenovirus vector) and GS-1144 (self-amplifying mRNA-lipid nanoparticle), both encoding a novel conserved HIV-1 immunogen that spans Gag, Pol, and Nef. This regimen was safe and well tolerated in a phase 1b study in virologically suppressed people with HIV on antiretroviral therapy (ART). To better understand the impact of GS-1966+GS-1144 on antigen-specific T-cell quality, we assessed changes in breadth, T-cell phenotype, and polyfunctionality. Methods: The study included 3 cohorts randomized 2:1 to receive GS 1966+GS-1144 or placebo. Two doses of GS-1966+GS-1144 were evaluated. Cohorts 1 (low dose) and 2 (high dose) received a monovalent HIV-1 immunogen; cohort 3 (high dose) received a bivalent version. Participants maintained ART. T-cell breadth was evaluated by interferon-γ ELISpot assay using 16 peptide mini pools covering vaccine epitopes. Polyfunctionality was assessed by intracellular cytokine staining and cells were analyzed via LSR flow cytometer and CellEngine software. Antigen-specific polyfunctionality was evaluated for each participant at days 1 and 183 using COMPASS. Results: Although no significant increase in breadth of the vaccine-specific T-cell response was observed over time or between cohorts, the median number of mini-pool responses was numerically highest for cohort 3 at day 183 (median of 3 for cohort 3 compared with 1.5, 1.0, and 2.0 for placebo, cohort 1, and cohort 2, respectively). GS-1966+GS-1144 induced a CD8+ T-cell dominant response; vaccine-specific CD4+ T cells were also detected. No changes in the frequency of effector memory subsets were observed. COMPASS analysis revealed an increase in polyfunctionality of Gag-specific CD4+ T cells in cohorts 2 and 3, and in Gag specific CD8+ T cells in cohort 3 at day 183 compared with baseline. Conclusions: Breadth of the vaccine-specific T-cell response was not significantly different over time or between cohorts. Significant differences in Gag-specific T-cell polyfunctionality were noted for both CD4+ and CD8+ T-cell responses in cohort 3, suggesting that GS-1966+GS-1144 is able to induce highly functional T-cell responses to a key vaccine region. These results expand our understanding of T-cell response quality induced by GS-1966+GS-1144, a novel vaccine regimen for HIV cure. Lymph Node HIV-Specific CD8 T Cells of HIV Controllers Harbour a Specific Transcriptomic Signature Erica Lana 1 , Mathilde Foglierini-Perez 1 , Philippe Guillaume 2 , Riddhima Banga 1 , Francesco Procopio 1 , Matthias Cavassini 3 , Sébastien Déglise 1 , Alexandre Harari 2 , Giuseppe Pantaleo 1 , Matthieu Perreau 1 , Andrea Mastrangelo 1 1 Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, 2 University of Lausanne, Lausanne, Switzerland, 3 Lausanne University Hospital, Lausanne, Switzerland Background: Depletion studies in non-human primates demonstrated the crucial role of CD8 T cells in controlling SIV replication. However, the precise mechanisms underlying the control of HIV replication remain elusive. Lymph nodes (LN) are a primary site of HIV replication, and studying the CD8 T cell response at this level may provide additional insights. Methods: We performed an in-depth characterization of HIV-specific CD8 T cells of matched blood and LN samples from 5 chronic HIV infected individuals (CHI) and 4 HIV controllers by scRNA-seq and scTCR-Seq. In addition, longitudinal blood samples collected from 3 HIV controllers were also evaluated over-time (median interval years=11). Results: A total of 63’881 and 32’922 HIV-specific CD8 T cells were sequenced from blood and LN, respectively. Consistently with previous studies, HIV-specific CD8 T cells showing canonical cytotoxic functions (granzyme B, perforin) were rare ex vivo in LN of both CHI and controllers. However, blood and, to a greater extent, LN HIV-specific CD8 T cells of controllers were enriched ( p <2 -16 ) in cells characterized by stemness markers (i.e. TCF7 , IL7R , BACH2 ). This population, The figure, table, or graphic for this abstract has been removed.

representing up to 63% of HIV-specific CD8 T cells in controllers, expressed the receptor GPR183 (EBI2), responsible for cell positioning at the T:B border in LN, and the effector molecule granzyme K. Interestingly, follicular-homing CXCR5+ HIV specific CD8 T cells in LN of controllers were also enriched in stem-like markers such as IL7R and CCR7 ( p <10 -18 ), while LN CXCR5+ HIV specific CD8 T cells of CHI expressed more exhaustion markers ( TIGIT , CD160 , p <10 -5 ). Finally, TCR repertoire analysis revealed that HIV-specific CD8 T cells of CHI were more oligoclonal (blood, p =0.03; LN, p =0.25), suggesting the selection and/or elimination of some clonotypes during chronic infection. Of note, longitudinal analyses revealed that the clonotypic distribution of HIV-specific T cells may evolve in controllers, with expansion of subdominant clonotypes associated with transcriptomic traces of recent TCR engagement. Conclusions: This study suggests that LN HIV-specific CD8 T cells in controllers harbor a distinct “stem-like” transcriptomic profile, possibly underlying an enhanced proliferative potential, associated with an optimal positioning in the LN microenvironment. Interestingly, both the transcriptomic profile and the TCR repertoire of HIV-specific CD8 T cells of HIV controllers can evolve with time, suggesting a dynamic adaptation of the immune response. HIV-Specific CD8+ T Cell Stemness Predicts Post-Intervention Control of Viremia Zahra Kiani 1 , Mpho Olatotse 1 , Jonathan Urbach 1 , Mathias Lichterfeld 1 , Jesper D. Gunst 2 , Ole S. Søgaard 3 , Marina Caskey 4 , Michel Nussenzweig 4 , Bruce Walker 1 , David R. Collins 1 1 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 2 Aarhus University Hospital, Aarhus, Denmark, 3 Aarhus University, Aarhus, Denmark, 4 The Rockefeller University, New York, NY, USA Background: Durable post-intervention control of viremia (PIC) occurs in a subset of people with HIV (PWH) after broadly-neutralizing antibody (bNAb) therapy and analytical treatment interruption (ATI). While prior studies support a role for CD8+ T cells in PIC, precise determinants remain unclear. We hypothesized that CD8+ T cell stemness against autologous proviral epitopes may determine PIC. Methods: We obtained longitudinal peripheral blood before and 6-12 weeks following ATI, prior to viral rebound, from post-intervention controllers (PICs, n =7) and non-controllers (PINCs, n =5) from the MCA-906, MCA-965, TITAN, and eCLEAR trials, in which participants received infusions of bNAbs 3BNC117 and/ or 10-1074 and underwent ATI. We mapped HLA-optimal HIV epitope-specific CD8+ T cell responses by interferon (IFN)-γ ELIspot using peptides matching participants’ autologous proviruses. We measured the proliferative capacities of detected responses by CFSE dilution and assessed HIV-specific CD8+ T cell phenotypes via flow cytometry. Results: HIV-specific CD8+ T cells were significantly more proliferative at baseline in PICs than PINCs ( p <0.001) despite similar epitope-specific breadth and IFN-γ production between groups and over time. HIV-specific CD8+ T cell proliferative capacities increased modestly after bNAb infusion in both PICs ( p <0.01) and PINCs ( p <0.05). Ex vivo HIV epitope-specific CD8+ T cells in PICs were enriched for a CD45RA+CD62L+ stem cell-like memory (TSCM) phenotype both at baseline ( p <0.05) and after bNAb therapy ( p <0.01), which was associated with proliferative capacity (Spearman ρ =0.67, p =0.001). In contrast, PINCs were enriched for a CD45RA–CD62L– effector-memory phenotype ( p <0.01). T SCM frequency increased after bNAb infusion in PICs ( p <0.01) without significant changes in ex vivo frequency or markers of activation, proliferation, or cytotoxicity. Conclusions: The proliferative capacity and stem cell-like memory phenotype of pre-existing CD8+ T cell responses targeting autologous HIV epitopes were associated with subsequent PIC. Although PIC was not associated with the emergence of new responses or the in vivo activation or expansion of memory responses, modest increases in proliferative capacity and T SCM frequency after bNAb therapy were consistent with a potential vaccinal effect. These results identify functional determinants of PIC that may guide the development of effective immunotherapies to elicit durable ART-free control of viremia in a larger proportion of PWH.

Oral Abstracts

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CROI 2025