PC-6 Cardiac morbidity in HIV is associated with checkpoint inhibitor LAG-3

Abstract

Background: Cardiovascular disease (CVD) is a major contributor to mortality and morbidity in HIV infection. The impact of viral suppression with combination antiretroviral therapy and underlying pathophysiologic mechanisms are under investigation. Elevated expression of certain checkpoint inhibitor (CPI) molecules (eg, PD-1, TIGIT, LAG3, TIM3) on T cells is associated with dampened immunity. Recent evidence for expression of receptors for CPI at the tissue level with selective enrichment of LAG3 receptors in the heart point to a control mechanism for organ immune homeostasis (Rev Immunity 44, 2016). This study was aimed at defining the relationship of CPI molecules on immune cells and CVD in HIV infection in a low resource setting. Methods: Study participants were recruited in YRG CARE, a tertiary care HIV service provider in Chennai, India. ART naive viremic (Gp1, n = 102) and ART experienced aviremic (Gp2, n = 172) were compared to healthy volunteers (Gp3, n = 64) in a cross-sectional analysis of cardiac function and immunologic markers including CPI molecules on CD4 and CD8 T cells. Results: In Gp1 findings of CVD were significant (Mann-Whitney’ U test) for lower cardiac ejection time, stroke volume, stroke volume index, cardiac output and small arterial elasticity with higher systemic vascular resistance compared to Gp2 and Gp3 respectively. Large arterial elasticity was lower in comparison to Gp2. Immune activation and inflammatory cytokines were maximally altered in Gp1. Frequencies of CPI molecules showed differences among the groups, with higher frequencies of CD4+ T cells expressing LAG3 and PD1 in Gp1 compared to GPs 2 and 3, while TIGIT and TIM3 did not differ significantly among the groups (LAG3 Gp1: 4.9 ± 3.4; Gp2: 2.5 ± 1.5; Gp3: 2.4 ± 1.3; PD1 Gp1: 6.2 ± 7.3; Gp2: 1.5 ± 2.5; Gp3: 0.9 ± 1.6; TIGIT Gp1: 34.2 ± 14.9; Gp2: 33.5 ± 11.8; Gp3: 30.1 ± 7.8 and Tim3 Gp1: 1.7 ± 2.7; Gp2: 1.3 ± 1; Gp3: 1.3 ± 0.9). Frequencies of CD4+ T cells positive for LAG3, PD1, and for dual expression of LAG3 plus PD1 were inversely correlated with cardiac ejection time, cardiac output, cardiac index, stroke volume, stroke volume index and systemic vascular resistance in Gp1 and with large artery elasticity, and except for PD1, also with small artery elasticity in Gp2. Conclusions: In ART naive HIV subjects continuous antigenic stimulation of the immune system results in upregulation of multiple CPI molecules in association with immune activation. Our finding of the association of LAG3 and PD1 expressing CD4 cells in cardiac morbidity points to a dominant role of these pathways in regulating cardiac health, given that LAG3 receptors are enriched at the tissue level in the heart. Investigations to understand the immune mechanisms involved could provide insight into potential role of LAG3 immunotherapy (which is in early clinical trials in cancer) in prevention or treatment of cardiac dysfunction in HIV.