Recent findings point to a role of Checkpoint Inhibitor (CPI) receptors at the tissue level in immune homeostasis. Here we investigated the role of CPI molecules on immune cells in relation to cardiac function. Participants recruited in Chennai, India consisted of HIV+ ART naive viremic (Gp1 n = 102), HIV+ on ART, virologically suppressed (Gp2, n = 172) and HIV negative healthy controls (Gp3, n = 64). A cross-sectional analysis of cardiac function, arterial resistance and immunologic assessment of CPI expressing T cells was performed. Data indicate that ART naive exhibited cardiac function impairment and greater arterial stiffness than the other groups. Frequencies of CD4+ T cells expressing LAG-3 and PD1 were higher in ART naïve while TIGIT and TIM3 were similar among the patient groups. LAG-3+, PD1+ and dual LAG-3+PD1+ CD4 T cells were inversely correlated with cardiac function and arterial elasticity and directly with arterial stiffness in ART naïve participants and with arterial elasticity in virally suppressed group on ART. We conclude that HIV induced upregulation of LAG-3 singly or in combination with PD1 in immune cells may regulate cardiac health and warrant mechanistic investigations. The implications of these findings have bearing for the potential utility of anti-LAG-3 immunotherapy for cardiac dysfunction in chronic HIV infection.

We have analyzed reverse transcriptase (RT) region of HIV-1 pol gene from 97 HIV-infected children who were identified as failing first-line therapy that included first-generation non-nucleoside RT inhibitors (Nevirapine and Efavirenz) for at least 6 months. We found that 54% and 65% of the children had genotypically predicted resistance to second-generation non-nucleoside RT inhibitors drugs Etravirine (ETR) and Rilpivirine, respectively. These cross-resistance mutations may compromise future NNRTI-based regimens, especially in resource-limited settings. To complement these investigations, we also analyzed the sequences in Stanford database, Monogram weighted score, and DUET weighted score algorithms for ETR susceptibility and found almost perfect agreement between the three algorithms in predicting ETR susceptibility from genotypic data.

We identified high resistance and high inter-compartmental resistance discordance in Indian women, which might lead to unrecognized resistance transmission and re-emergence compromising treatment outcomes, particularly relevant to countries like India, where sexual HIV transmission is predominant.

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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.