CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

438

Phenotype of Gamma-Delta T-Cells in Acute HIV-1 Infection Predict Neutralization Breadth Gina L Griffith 1 , Matthew Creegan 2 , Kawthar Machmach Leggat 2 , Margaret Constanzo 2 , Isabella Swafford 2 , Ningbo Jian 2 , Leigh-Anne Eller 2 , Merlin L. Robb 2 , Samantha M. Townsley 2 , Shelly J. Krebs 1 , Julie Ake 1 , Dominic Paquin-Proulx 2 , for the RV217 Study Group 1 Walter Reed Army Institute of Research, Silver Spring, MD, USA, 2 Henry M Jackson Foundation, Bethesda, MD, USA Background: New HIV vaccine approaches are focused on eliciting broadly neutralizing antibodies (bNABs). Leveraging the U.S. Military HIV Research Program's (MHRP) therapy naïve RV217 cohort comprised of study participants monitored for HIV acquisition and progression, we have previously shown that B cell engagement and activation within the first 14-43 days of viremia are predictive of bNAB development. We therefore hypothesized that innate immune cells might provide signals to B cells during acute HIV-1 (AHI) infection resulting in neutralization breadth years later. This study characterized early innate immune responses in RV217 participants previously investigated for bNAB development. Methods: Flow cytometry was performed on PBMC samples from 22 RV217 study participants previously studied for neutralization breadth development. Four timepoints per participant were utilized: pre-infection, days 14-25 post infection (peak viral load), days 30-60 post infection (viral set point), and >365 days post-infection (chronic infection). Data was analyzed utilizing global heat map analysis, univariate summary of marker analysis, longitudinal analysis of markers of interest, logistic regression analysis, cumulative incidence curves analysis, and area under receiver operating characteristic curve analysis. Results: Flow cytometry analysis showed significant differences in gamma delta (γδ) T cell surface marker expression in participants that developed neutralization breadth and those that did not. Levels of CD16 on γδ1 T cells were found to be significantly higher in broad neutralizers at set point viral load while levels of CD57 on γδ2 T cells were found to be significantly higher in broad neutralizers at both pre-infection and set point viral load. CD16 and CD57 are two markers associated with effector functions suggesting that more differentiated γδ T cells may contribute to the development of bNabs. Further analysis of these results revealed that these specific markers are significantly associated with the probability of bNAb development and are predictive of neutralization breadth accuracy at almost 80%. Our results identify CD16+ γδ1 T cells and CD57+ γδ2 T as potential key populations involved in the neutralization breadth development. Conclusion: γδ T cells may play an important role in bNAB development during AHI and these results could inform HIV vaccine design. NK Cells During Acute HIV Infection Are Associated With Slow Disease Progression in Subtype A Aljawharah Alrubayyi 1 , Amin S. Hassan 2 , Jonathan Hare 3 , Anthony Hsieh 1 , Jill Gilmour 3 , Matt A. Price 4 , William Kilembe 5 , Etienne Karita 5 , Eugene Ruzagira 6 , Joakim Esbjörnsson 7 , Eduard J. Sanders 1 , Dimitra Peppa 8 , Sarah Rowland-Jones 1 1 University of Oxford, Oxford, United Kingdom, 2 Kenya Medical Research Institute, Kilifi, Kenya, 3 Imperial College London, London, United Kingdom, 4 International AIDS Vaccine Initiative, New York, NY, 5 Rwanda Zambia HIV Research Group, Kigali, Rwanda, 6 Uganda Virus Research Insitute, Entebbe, Uganda, 7 Lund University, Lund, Sweden, 8 University College London, London, United Kingdom Background: Understanding immune responses linked with viral control during early HIV-1 infection is critical to develop new prophylactic and therapeutic strategies. HIV-1 subtypes impact disease outcomes, but their association with diverse immune responses during acute HIV-1 infection (AHI) is unclear. Natural killer (NK) cells contribute to HIV-1 control and may influence the pathogenesis of AHI. Using longitudinal samples collected during and after peak HIV-1 viral load (VL) in a prospective unique cohort of ART-naïve individuals, we studied evolving NK cell responses in patients with different HIV-1 subtypes in relation to disease progression Methods: Participants with subtype A (n=28) and non-A subtype (n=17 subtype C and n=7 subtype D) were recruited from Kenya, Rwanda, Zambia, and Uganda between 2006-2011 under "IAVI Protocol C". Samples were collected at two weeks (median=18 days), 1-month (median= 32 days), and 3-month (median=91 days) post-HIV-1 infection. Multiparameter flow cytometry was used for phenotypic characterisation. ADCC responses were determined against Raji cells. Soluble markers were evaluated using multiplexed assays Results: AHI induced expansion of NK cell subset with adaptive/memory features, as early as two weeks post- infection, increasing in magnitude after

resolution of peak VL. This adaptive NK cell signature was delineated by lower expression of the signaling molecule FcεRγ and higher expression of the activating receptors NKG2C and CD2. The kinetics of NK cell responses differed based on the infecting HIV-1 subtype, with patients with subtype A exhibiting a higher magnitude of adaptive NK cells than those with non-A subtype infection (p=0.036). A stronger innate immune response induced by subtype A, including IL-15 (p=0.021) and IL-12 (p=0.009), correlated with the enrichment of adaptive NK cells. This early increase in adaptive NK cells was associated with enhanced ADCC (p=0.002) and correlated with higher levels of CD8+ T-cell activation during AHI (r=0.621, p=0.015).Notably higher frequencies of adaptive NK cells during the first month of infection were associated with future viral control in patients who maintained a persistently undetectable or low viral load (<10,000 copies/ml) up to six years post-infection Conclusion: These data provide insights into the beneficial role of adaptive NK cells during AHI, revealing previously unappreciated diversity of NK cell responses to different HIV-1 subtypes, thereby informing strategies toward NK-cell-directed therapies. PWH on ART and Tyrosine Kinase Inhibitors Show High Cytotoxic Activity Against HIV- 1–Infected Cells Clara Sánchez Menéndez 1 , Guiomar Casado Fernández 1 , Lorena Vigón 1 , Mario Manzanares 1 , Elena Mateos 1 , Juan Ambrosioni 2 , Vicente Estrada 3 , Miguel Cervero Jiménez 4 , Valle Gómez 5 , Christoph Wyen 6 , Christian Hoffmann 7 , Montserrat Torres 8 , Verónica Briz 8 , Vicente Planelles 9 , Mayte Coiras 8 1 Institute of Health Carlos III, Majadahonda, Spain, 2 Hospital Clinic of Barcelona, Barcelona, Spain, 3 Hospital Universitario Clínico San Carlos, Madrid, Spain, 4 Hospital Universitario Severo Ochoa, Madrid, Spain, 5 Hospital Universitario de La Princesa, Madrid, Spain, 6 Cologne University Hospital, Cologne, Germany, 7 ICH Study Center, Hamburg, Germany, 8 Institute of Health Carlos III, Madrid, Spain, 9 University of Utah, Salt Lake City, UT, USA Background: We evaluated if PWH with chronic myeloid leukemia (CML) on antiretrovirals (ART) and tyrosine kinase inhibitors (TKI) had cell populations with high antiviral capacity that may explain the reduced reservoir size observed in these individuals. Methods: Blood samples were obtained from 6 PWH with CML on ART and TKI (n=3 imatinib; n=3 dasatinib) and 18 PWH on ART recruited as controls. Cell immunophenotyping was performed by flow cytometry. Cytotoxic activity was determined using NK-specific target cells K562 and HIV-1-infected TZM-bl. Cytokine release was measured after stimulation with HIV-1 peptide pool. Statistical analysis was performed with Mann-Whitney or unpaired t-test. Results: 1)Most participants were male (100% PWH on ART+TKI and 73% of controls). Median age was 53 (IQR 42-51) and 54 years-old (IQR 47-62), respectively. Age at HIV+ diagnosis was 39 (IQR 32-45) and 31 years-old (IQR 25-36); age at CML diagnosis was 47 years-old (42-63). Time with HIV-1 infection was 22 (IQR 15-30) and 23 years (15-30). Nadir CD4 and CD4 count was 97 (IQR 63-382) and 370 cells/μl (186-843) in PWH on ART+TKI and 292 (IQR 176-385) and 983 cells/μl (IQR 798-1174) in controls. CD4/CD8 was 0.6 (IQR 0.3-1.5) and 1.0 (IQR 0.7-1.5), respectively. PWH on ART+TKI showed CML molecular response of 5.0 log (IQR 4.1-5.1) and they were on imatinib or dasatinib for median 3.3 years (IQR 1.7-9.6). All participants were on standard ART. 2)PBMCs from PWH on ART+TKI showed higher cytotoxicity against NK-specific (p=0.0050) and HIV 1-infected target cells (p=0.0205) than controls. 3)PWH on ART+TKI had higher levels of NK cells (p=0.0179) with higher expression of maturation/memory marker CD57. 4)PWH on ART+TKI showed increased levels of CD8 (p=0.0325) with higher degranulation capacity (CD107a+; p=0.0084) and increased release of GZB (p=0.0002). No changes were observed in the release of IFNγ. 5)CD8 from PWH on ART+TKI released lower levels of TNFα (p=0.0469), which is essential in HIV-1-associated chronic inflammation. 6)No differences were found in the expression of immunosenescence/exhaustion markers in CD4 and CD8 except for KLRG1 that was increased in PWH on ART+TKI (p=0.0176 and p<0.0001, respectively). Conclusion: PWH on ART+TKI show low HIV-1 reservoir size, which may be partly related to higher levels of cytotoxic cells with antiviral activity. These cell populations may have been stimulated by the presence of cancerous cells, so these results have to be confirmed in clinical trials with PWH without CML.

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Poster Abstracts

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CROI 2024 110