CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

386 EFFECT OF TIM-3 BLOCKADE ON T CD8+ AND NK CELLS IN ART-TREATED HIV-INFECTED PATIENTS Carolina Gutiérrez 1 , Marta Sanz 1 , Nadia Madrid-Elena 1 , Sergio Serrano-Villar 1 , María J Vivancos 1 , Alejandro Vallejo 1 , Francisco J. Hernández-Walias 1 , Santiago Moreno 1 1 Hospital Ramón y Cajal, Madrid, Spain Background: TIM-3 is a large transmembrane inhibitory receptor that is expressed in multiple cells of the immune system, including T-CD8+ cells and NK cells. Galectin-9 that has been described as a potent mediator of HIV transcription and reactivation constitutes one of the most important ligands of TIM-3.The purpose of this study was to analyze the effect of TIM-3 blockade on the specific HIV-1 CTL response of T-CD8+ cells and NK cells from HIV-infected-patients. Methods: We included 10 ART-treated, HIV-1 infected donors fromwhomwe obtained 200 mL of peripheral blood for the isolation of T-CD4+, T-CD8+ and NK cells. We cocultured the isolated T-CD4+ cells with T-CD8+ cells and NK cells in a 1:1 ratio. To evaluate the impact of TIM-3 blockade on the HIV-suppressive capacity of T-CD8+ cells we used a specific antibody against TIM-3. The impact of TIM-3 blockade was determined by measuring p24 levels in the supernatants of the cocultures at day 7 and day 10. To analyze the effect of Galectin-9 (natural ligand of TIM-3), p24 levels were compared in cocultures with or without the addition of exogenous Galectin-9 Results: The 10 patients had plasma HIV RNA <50 copies/mL with a mean T-CD4+ 661 cells/mm 3 and mean T-CD8+ 920 cells/mm 3 . We observed a poor HIV suppressive capacity of T-CD8+ cells with a mean p24 decrease of 0.9 log. However it was significantly improved after TIM-3 blockade (mean 2.4log), mean difference 1.5log (IQR, [0.4–2.20], p=0.007). No differences were observed with the presence of NK cells in the coculture (mean difference with and without blockade, 1.15log [0.49-1.69], p=0.011). The addition of Galectin-9 did not change the effect of TIM-3 blockade (mean difference, 1.25log [0.77- 1.42], p=0.012). Conclusion: We demonstrated that the blockade of TIM-3 improves the CTL response of the T-CD8+ cells of ART-treated HIV-infected patients. No negative effects were observed with the same blockage in NK cells. Galectin-9 addition does not have impact on the response. A combination of Galectin-9/TIM-3 could be evaluated as an effective shock and kill strategy in HIV-eradication. 387 REDUCED MEMORY, FUNCTIONAL CONNECTIVITY IN 41- TO 70-YEAR-OLD HIV+ APOE Ε4 CARRIERS Fan N. Yang 1 , Margarita Bronshteyn 1 , Sarah A. Flowers 1 , Matthew Dawson 2 , Monica M. Diaz 2 , Harvey R. Fernandez 1 , Princy N. Kumar 1 , G. W. Rebeck 1 , Raymond S. Turner 1 , David J. Moore 2 , Ronald J. Ellis 2 , Xiong Jiang 1 1 Georgetown University, Washington, DC, USA, 2 University of California San Diego, La Jolla, CA, USA Background: ApoE ε4 is the strongest genetic risk factor for late onset Alzheimer’s disease. In people with HIV (PWH), the potential impact of ApoE ε4 on brain structure and function remains to be determined. Older PWH ApoE ε4 carriers may experience additional impairment in brain structure and function compared to age-matched PWH non-carriers; however, results are unclear for middle-aged PWH. Moreover, the interactions between ApoE ε4 status and HIV disease severity are largely unknown. Methods: Ninety-nine PWH participated in a cross-sectional study (56.2±6.5yrs, range 41-70yrs, 27 females). A comprehensive 7-domain neuropsychological (NP) test battery was administered and HIV-Associated Neurocognitive Disorders (HAND) diagnoses were assigned according to Frascati criteria. Structural MRI and resting-state functional MRI (functional connectiveity, FC) were collected. All statistical analyses were performed after controlling for demographics, and additional MRI-specific confounding factors were accounted for in the MRI data analysis.

DNA levels between the pre-ART time point and one year post ART initiation (CA-DNA reduction). We performed a supervised multivariate regression using the least absolute shrinkage and selection operator (LASSO). This approach selected the expression of perforin, CD38, 2B4, TIGIT, and CD96 on NK cells and the T cell response to “nef, tat, rev” peptide pools as the best explanatory variables for the prediction of CA-DNA reduction (see Table). Conclusion: Here we show that specific NK cell marker expression levels and T cell responses can be used as explanatory variables in the regression analysis of the decline in HIV DNA levels following ART initiation. These observations suggest that specific NK cell features may drive an enhanced response to infected cells in the context of treatment initiation. Harnessing this potential may lead to the development of novel therapeutic strategies aimed at a functional cure for HIV.

Poster Abstracts

385 HIV-1 RESERVOIR SIZE CORRELATES TO PD-1 EXPRESSION IN MEN, BUT NOT WOMEN, IN UGANDA Katherine Yu 1 , Jessica L. Prodger 1 , Eileen P. Scully 2 , Adam Capoferri 2 , Steven J. Reynolds 3 , Jingo Kasule 4 , Taddeo Kityamuweesi 4 , Paul Buule 4 , David Serwadda 5 , Yun-Hee Choi 1 , Andrew D. Redd 6 , Thomas Quinn 6 1 Western University, London, ON, Canada, 2 Johns Hopkins University School of Medicine, Baltimore, MD, USA, 3 NIAID, Bethesda, MD, USA, 4 Rakai Health Sciences Program, Kalisizo, Uganda, 5 Makerere University, Kampala, Uganda, 6 NIH, Bethesda, MD, USA Background: There is evidence to suggest that HIV-1 latency varies by sex; women have been reported to have fewer CD4 T cells containing HIV-1 provirus, lower levels of residual viral activity in resting CD4 T cells (rCD4), and lower T cell activation. Immunologic characteristics that correlate with latent reservoir size have been used to inform cure strategies, but these studies have been performed in predominantly male cohorts. We sought to determine if immune correlates of reservoir size differed by biological sex. Methods: Blood samples were collected from HIV-1+, ART-suppressed (<40 copies/ml for >1 year) adults living in Rakai, Uganda (n=42 females, n=20 males). The frequency of rCD4 containing replication competent provirus was estimated by quantitative viral outgrowth assay (QVOA). 14 soluble immune biomarkers were measured in plasma using custommultiplexed immunosorbent assays (MesoScale Discovery) and T cell memory subsets, activation and exhaustion markers, and effector T cell function were quantified by flow cytometry. Regression analysis was used to identify immune characteristics associated with reservoir size according to biological sex. Results: Women and men were similar in terms of age, HIV-1 subtype distribution (A, D and recombinants), nadir CD4, pre-ART viral load and duration of viral suppression on ART. Compared to men, women had significantly higher serum concentration of D-dimer (272.8 vs. 130.1 ng/ml, p<0.01) and there was a trend (p<0.1) towards a lower proportion of IL2+ CD8 T cells (1.85 vs. 4.31%) and effector memory CD4 T cells (1.88 vs. 3.44%). Consistent with prior reports, among men reservoir size correlated positively with PD-1 expression on CD4 T cells (r = 0.04, p<0.05). However, this association was not observed in women. Among women, reservoir size correlated positively with CD8 and CD4 T cell effector function (IL2 and TNFa production, all p<0.05). Conclusion: These data identify distinct immunologic correlates of the replication competent HIV-1 reservoir in men and women. Whether these measures are biomarkers or imply differential immune control/response to the reservoir is unknown. This is important to consider as interventions target immune checkpoint molecules, such as PD-1, for latency reversal and immune stimulation. Globally, females make up more than half of all individuals infected with HIV-1, and cure studies must be adequately powered to examine efficacy in both sexes.

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