Cardiac morbidity in HIV infection is associated with checkpoint inhibitor LAG-3 on CD4 T cells

• Published in: PloS one 2018-10, Vol.13 (10), p.e0206256
• Main Authors: Pallikkuth, Suresh, Pahwa, Rajendra, Kausalya, Bagavathi, Saravanan, Shanmugam, Pan, Li, Vignesh, R, Iqbal, Syed, Solomon, Sunil S, Murugavel, Kailapuri G, Poongulali, Selvamuthu, Kumarasamy, Nagalingeswaran, Pahwa, Savita
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Adult; AIDS; Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; Antigens, CD - metabolism; Antiretroviral therapy; Apoptosis; Biology and Life Sciences; Cardiovascular Diseases - complications; Cardiovascular Diseases - epidemiology; Cardiovascular Diseases - pathology; Cardiovascular Diseases - physiopathology; CD223 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Chronic infection; Education; Elasticity; Female; Gene Expression Regulation - drug effects; Heart - drug effects; Heart - physiopathology; HIV; HIV Infections - complications; HIV Infections - drug therapy; HIV Infections - immunology; HIV Infections - metabolism; Homeostasis; Human immunodeficiency virus; Humans; Immune checkpoint; Immune system; Immunoglobulins; Immunology; Immunotherapy; Infections; Inflammation; Inhibitors; Kinases; Lymphocytes; Lymphocytes T; Male; Medicine; Medicine and Health Sciences; Middle Aged; Morbidity; PD-1 protein; Physical Sciences; Programmed Cell Death 1 Receptor - metabolism; Proteins; Receptors; Regulation; Stiffness; Vascular Stiffness - drug effects; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0206256

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.