CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

viral suppression than HIV-uninfected individuals, consistent with a defect in maturation and proliferation of these cells in vivo. These results may offer a mechanistic explanation for the relatively poor ability of whole blood telomere length to predict morbidity and mortality in the setting of treated HIV infection.

1 Yale University, New Haven, CT, USA, 2 Uniformed Services University of the Health Sciences, Bethesda, MD, USA, 3 Henry M Jackson Foundation, Bethesda, MD, USA, 4 Brooke Army Medical Center, San Antonio, TX, USA, 5 Naval Medical Center San Diego, San Diego, CA, USA, 6 Naval Medical Center Portsmouth, Portsmouth, VA, USA, 7 Madigan Army Medical Center, Takoma, WA, USA Background: After controlling for traditional risk factors and viral suppression, people living with HIV (PLWH) have increased incidence of some cancers. Perturbations of the immune system persist despite virologic control on ART. This study explores the role of T cell subsets on incidence of HIV-associated cancer among ART-treated virally suppressed patients. Methods: The United States Military HIV Natural History Study (NHS) is a well- characterized longitudinal cohort of Department of Defense beneficiaries. The NHS repository was used to identify cell samples from 25 cases and 87 controls. Cases had lung cancer, lymphoma, and HPV-associated cancers diagnosed after durable HIV-suppression. Cases and controls were matched for CD4+ T cell count, duration of HIV infection and viral suppression, and sample availability. Cryopreserved PBMCs from cases were obtained at least 6 months prior to cancer diagnosis. Using flow cytometry, PBMCs were measured for expression of markers of maturation (CD27,CD28,CCR7,CD45RA), inhibitory receptors (PD-1,LAG-3,TIGIT,2B4,CD160), immune activation (CD38,HLADR,Ki-67) and transcription factors (T-bet and Eomesodermin). Mann-Whitney U test was performed for comparison between groups. Results: Cases and controls were well-matched (Table 1). All patients were virally suppressed. Expression of individual immune inhibitory receptors on total CD8+ T cells were not significantly different between the groups, though there was a trend towards higher PD-1 expression in cases compared to controls (25.8%vs21.8 %,p=0.067). The frequency of CD8+ T cells co-expressing three inhibitory receptors (PD-1+CD160+2B4+) was significantly higher among compared to control patients (11.3% vs 7.8%,p=0.03). In addition, among cases, expression of the transcription factor T-bet was higher on effector memory CD8+ T cells in cases compared to controls (24.1%vs15.6%,p=0.0001). There was no difference in the frequency of naïve/memory subsets (using CD27,CD28,CD45RA,CCR7) or activation (CD38+HLADR+) among CD8+ T cells between the two groups. Conclusion: Co-expression of inhibitory markers has been associated with significant impairment of antigen-specific responses in both HIV infection and the tumor microenvironment. Our study shows that in a well-controlled sample set, the co-expression of multiple T cell inhibitory markers (PD-1,CD160+ 2B4+), is associated with a subsequent diagnosis of cancer, supporting the importance of studying the role persistent immune dysfunction on cancer incidence among PLWH.

315 IMPACT OF INTEGRASE INHIBITORS ON CD8 T-CELL FUNCTION AND ACTIVITY Enrico Richter 1 , Marek Korencak 1 , Lea Bornemann 2 , Marc Schuster 2 , Matthias Gunzer 2 , Stefan Esser 3 , Hendrik Streeck 1 1 Institute for HIV Research, Essen, Germany, 2 University of Duisburg-Essen, Essen, Germany, 3 University Hospital Essen, Essen, Germany Background: HIV-specific CD8 T cells play a crucial role in controlling HIV replication. Although they have efficient effector function, CD8 T cells fail to clear HIV infection even in the presence of ART. Here we describe how ART can impact CD8 T cell effector function and therefore interfere -among other factors- with clearance of HIV infected cells. Methods: PBMCs from HIV+ (n=44) and healthy (n=32) individuals were analyzed via flow cytometry to determine phenotype and functional properties of HIV-specific CD8 T cells in the presence of ART drugs and performed ex vivo proliferation assays of PBMCs from treated HIV+ individuals. We used a viral inhibition assay to determine CD8 T cells clear HIV infected cells and analyzed metabolic profiles using extracellular flux analyzer. Results: We assessed CD8 T cell functions in HIV+ ART-treated individuals ex vivo and observed a reduction in cellular function compared to CD8 T cells of HIV+ treatment naïve individuals (p<0.01). We next assessed the proliferation index ex vivo and found a reduction in CD8 T cells of individuals treated with INSTI-based ART regimen (2.43±0.36) compared to both PI (2.79±0.35;p<0.05) and NNRTI (2.92±0.28;p<0.01) based regimens. As we saw a significant impact of INSTI-based regimens on CD8 T cell function, we cultured CD8 T cells with individual ART drugs and determined the impact on CD8 T cell function of each drug individually. CD8 T cells had reduced functional properties with significantly lower expression of IFNγ (p<0.01), IL-2 (p<0.01) as well as TNFα (p<0.01) after treatment with INSTI, but not with other ART drugs. Due to the observed decrease in cytokine expression we decided to examine the killing ability of HIV-specific CD8 T cells in presence of individual ART regimens. Previously INSTI-treated CD8 T cells demonstrated reduced viral inhibitory activity against HIV-infected CD4 T cells compared to PI or NNRTI treated cells. We used a live cell imaging assay to determine the migratory capacity of CD8 T cells treated with different ART regimens. DLG-treated cells showed less migration activity after SDF1α stimulation compared to NRTI regimens (p=0.07). Next, we investigated the respiration of CD8 T cells treated with individual ART regimens and observed a significant reduction (p<0.05) in INSTI- treated cells compared to NRTI-treated cells. Conclusion: Our data shows that the choice of ART can have a significant impact on CD8 T cell effector function. This may have important implications for HIV eradication strategies. 316 CD8 T-CELL INHIBITORY RECEPTOR EXPRESSION IS ASSOCIATED WITH CANCER AMONG PLWH ON ART Omkar Chaudhary 1 , Diane Trotta 1 , Xiuping Chu 2 , Chip Bradley 2 , Xun Wang 3 , Jason Okulicz 4 , Ryan Maves 5 , Karl Kronmann 6 , Christina Schofield 7 , Brian K. Agan 2 , Anuradha Ganesan 3 , Brinda Emu 1

Poster Abstracts

317 IMPACT OF ART ON T-CELL REPERTOIRES OF HIV-INFECTED ADULTS WITH AND WITHOUT CANCER Abrahams Omoding 1 , Andrea Towlerton 2 , David Coffey 2 , Warren Phipps 2 , Edus H. Warren 2 1 Uganda Cancer Institute, Kampala, Uganda, 2 Fred Hutchinson Cancer Research Center, Seattle, WA, USA Background: Response to treatment of HIV-associated malignancies is likely influenced by the restoration of the T-cell repertoire and immune function after initiation of antiretroviral therapy (ART). To understand the impact of immune reconstitution on HIV-associated lymphoma outcomes, we compared the T-cell repertoire in 2 cohorts of HIV-infected adults initiating ART - one without cancer and one with pathologically confirmed diffuse large B cell lymphoma (DLBCL).

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