CROI 2024 Abstract eBook

Abstract eBook

Oral Abstracts

Methods: Twenty-two RMs infected with SIVmac251 were initiated on antiretroviral therapy (ART) at 8 weeks post-SIV infection for 9-months. Three groups of animals received cytokine treatments - IL-15/IL-15Ra (n=6), IL-12 (n=5), IL-15/IL-15Ra+IL-12 (n=6) - in two phases (5 doses once a week). The first phase was administered at 6 weeks post SIV (2 weeks prior to ART) and the second phase was during ART at 12 weeks pre- ATI. ART alone (n=5) group served as the control. Animals were monitored longitudinally for immunological and virological parameters. Results: IL-15/IL-15Ra and IL-15/IL-15Ra+IL-12 therapies induced significant expansion of functional SIV- specific CD8 T cells with proliferative capacity (Ki-67) and follicular homing (CXCR5); and CD16+ NK cells in blood and LN. Importantly, IL-15/IL-15Ra therapy resulted in the significant expansion of degranulating CD107a+CD8 T cells pre-ATI (P=0.03). In addition, the blood transcriptomic profile confirmed the induction of cytolytic molecules (granzyme-B, perforin), Jak/Stat signaling pathway in IL-15/IL-15a group, while genes associated with cell cycle arrest, DNA damage (MDM2, DDIT4) were significantly reduced. Post-ATI, virus rebounded in all animals but IL-15/IL-15Ra treated animals showed nearly 3-log lower viremia compared to ART only animals (p=0.004) with 83% of animals below 500 copies/ml at 20 weeks post ATI. This level of viral control was not observed in IL-12 or dual cytokine treated group. SIV-specific CXCR5+ CD8 T cells in blood (p=0.04) and LN (p=0.02) and SIV-specific CD28+ cells in blood (p=0.002 and LN (p=0.03), were associated with control of viremia post ATI. Conclusion: The IL-15/IL-15Ra therapy at the initiation of ART and during ART markedly enhance the magnitude and function of SIV-specific CXCR5+CD8 T cells and CD16+ NK cells and contribute to profound control of viremia post ATI. These studies define IL-15/IL-15Ra as a potentially effective immune therapy for HIV cure strategy.

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A T Cell-Targeting mRNA SIV Vaccine Extends Time to Rebound and Enhances Post-ART Viral Control Robert W Omange 1 , Benjamin Varco-Merth 1 , Omo Fadeyi 1 , William Goodwin 1 , Alejandra Marenco 1 , Derick Duell 1 , Jeremy Smedley 1 , Michael Axthelm 1 , Brandon Keele 2 , Jeffrey Lifson 2 , Janina Gergen 3 , Susanne Rauch 3 , Benjamin Petsch 3 , Louis Picker 1 , Afam A. Okoye 1 1 Oregon Health and Sciences University, Portland, OR, USA, 2 AIDS and Cancer Virus Program, Frederick, MD, USA, 3 CureVac SE, Tuebingen, Germany Background: Natural CD8+ T cell responses are ineffective at intercepting rebounding reservoirs after antiretroviral therapy (ART) release until after systemic viral replication and spread. Here, we evaluated whether a nucleoside unmodified mRNA vaccine (RNActive®) expressing full length SIV Gag and formulated in lipid nanoparticles (LNP) can be used to enhance Gag-specific CD8+ T cells in SIVmac239-infected rhesus macaques (RM) on ART. We hypothesized that vaccination during ART followed by a boost just prior to ART interruption (ATI) will enhance the immune intercept of reactivating SIV infections and facilitate post-ART viral control. Methods: 16 RMs were infected with 5000IU of SIVmac239M and started on ART 9 days post-infection. Following viral suppression, RM were divided into 2 balanced groups that received 5 intramuscular injections at 100μg each of the SIV-Gag (n=8) or control mRNA/LNP vectors (n=8) at 59-, 62-, 65-, 79- and 106-weeks post- infection (wpi). SIV-specific T cell responses were assessed by intracellular cytokine stimulation assay. Two weeks after the last immunization, at 108wpi, ART was stopped to assess the impact of vaccine-induced immune responses on post-ART viral replication using RT-PCR. Results: SIV-Gag mRNA/LNP increased Gag-specific CD8+ T cells in multiple tissues, particularly the bronchoalveolar lavage (BAL), which saw responses peak to 25% (mean ± 4.4% SEM) of CD8+ T cells. Indeed, overall frequencies of Gag-specific CD8+ T cells in BAL were higher in SIV-Gag mRNA/LNP vaccinated RM relative to controls after 47 weeks (AUC, p=0.0002). A boost SIV-Gag mRNA/ LNP at 16 days prior to ATI significantly increased frequencies of Gag-specific CD8+ T cells in blood (p=0.0002), BAL (p=0.0002), lymph node (p=0.0003), bone marrow (p=0.0002), spleen (p=0.0002), rectum (p=0.02) and liver (0.0002) relative to controls. Upon ART cessation, time to viral rebound was delayed in RM that received the SIV-Gag mRNA/LNP (median 20 vs. 11.5 days, p=0.0005) (Figure 1A). Additionally, SIV-Gag mRNA/LNP RM had lower post-ART peak viremia (p=0.002) and lower viral burden up to 5 weeks after rebound (AUC, p=0.002) (Figure 1B). Conclusion: Collectively, these data suggest that a T cell-targeted vaccination strategy that systemically increases the frequencies of SIV-specific CD8+ T cells immediately prior to ATI can restrict early viral spread and facilitate enhanced post-ART viral control.

Oral Abstracts

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IL-15/IL-15RA Cytokine Therapy Enhances Control of Viral Rebound in SIV-Infected Macaques Sakthivel Govindaraj 1 , Hemalatha Babu 1 , Syed Ali 2 , Sheikh A. Rahman 1 , Susan P. Ribeiro 1 , Jeffrey A.Tomalka 1 , Ashish A. Sharma 1 , Rafick P. Sekaly 1 , Francois J. Villinger 2 , Rama R. Amara 1 , Vijayakumar Velu 1 1 Emory University, Atlanta, GA, USA, 2 University of Louisiana at Lafayette, Lafayette, LA, USA Background: Immunotherapeutic cytokines can enhance immune responses against chronic infections. Cytokines such as IL-15 and IL-12 expand CD8 T and NK cells and increase their cytotoxicity. Importantly IL- 15 can enhance follicular homing of CD8 T cells, and IL-15 + IL-12 enhances follicular homing of NK cells during chronic SIV infection. Here we tested the therapeutic effects of IL-15 and IL-12 when administered alone or in combination during chronic SIV infection in rhesus macaques (RMs).

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High Rates of Viral Suppression in Pregnancy Drop Postpartum in South African Women on TLD Elaine J Abrams 1 , Jennifer Jao 2 , Elton Mukonda 3 , Hlengiwe Madlala 3 , Phindi Zwane 3 , Jack Hu 3 , Allison Zerbe 1 , Justine Legbedze 2 , Landon Myer 3 1 ICAP at Columbia University, New York, NY, USA, 2 Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA, 3 University of Cape Town, Cape Town, South Africa Background: The global transition to 1st-line antiretroviral treatment (ART) with tenofovir+lamivudine+dolutegravir (TLD) has shown high rates of viral suppression (VS) in adults and children but little is known about pregnant and postpartum women.

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CROI 2024