HTLV-1 infection is a life-long retroviral infection. Chronic viral antigenic stimulation induces persistent infection which results in a clinically asymptomatic carrier state. Only a minor proportion of infected individuals develop adult T cell leukemia/lymphoma (ATLL) or HTLV-1-associated myelopathy/tropical spastic myelopathy (HAM/TSP). This is dependent on a balance of host and genetic factors. CD8+ cytotoxic T lymphocyte function is important in the immune response against viral infection; however, the contribution of CD160 receptor associated with CD8+ T lymphocytes is unclear. Thus, we sought to decipher its role on CTL function in HTLV-1 infection. Here, we report high frequencies of CD160 on CD8+ T cells, with significantly higher levels on HTLV-1 specific CD8+ T cells. Intercepting the CD160 pathway via blockade of the receptor or its ligand, herpes virus entry mediator (HVEM) resulted in improved perforin production and CD107a degranulation of HTLV-1 specific CD8+ T cells. Analysis of the CD160-expressing CD8+ cells demonstrated a unique subset associated with a highly differentiated effector memory based on CD45RA and CCR7 co-expression, increased expression of inhibitory molecules, 2B4 and PD1. Altogether, these results suggest a role for CD160/HVEM pathway in regulating immune response against HTLV-1 infection which may prove promising in the development of immune therapies for the treatment of HTLV-1 infection and other associated disorders. (C) 2014 Elsevier Inc. All rights reserved.