Chronic viral infections are characterized by the up-regulation of a set of immunomodulatory receptors. The over-expression of co-inhibitory molecules on T cells leads to a dysfunctional T cell response with an "exhausted" phenotype. Programmed Death-1 (PD-1) is a molecule that exerts an inhibitory signal on the T cell receptor when it binds to the PD-L1 or PD-L2 ligands present on antigen-presenting cells. Also, the expression of these molecules has been associated to the loss of T cell functions as well as clinical markers of the progression of HIV infection. The study of these molecules has gained attention due to reports indicating that blockade of PD-1 pathway could partially reconstitute T cell functions. In fact, this mechanism has been proposed as an alternative treatment for some chronic viral infections such as HIV infection. This review is focused on those mechanisms that might be favouring the over-expression of PD-1 and its ligands during HIV infection and on the possible new approaches that, by reducing its expression, might represent new strategies for the treatment of HIV infection. Knowing the exact mechanism leading to PD-1, PD-L1 and PDL2 expression in physiologic and pathological conditions is essential for the development of successful treatments. Novel molecular mechanisms inhibiting PD-1 activation might have potential therapeutic use not only in HIV infection but also in other diseases.