Despite eliciting an early antiviral T cell response, HIV-specific T cells are unable to prevent disease progression, partly because of their loss of effector functions, known as T cell exhaustion. Restoring this T cell functionality represents a critical step for regaining immunological control of HIV-1 replication, and may be fundamental for the development of a functional cure for HIV. In this context, the use of animal models is invaluable for evaluating the efficacy and mechanisms of novel therapeutics aimed at reinvigorating T cell functions.
Although nonhuman primates continue to be a mainstay for studying HIV pathogenesis and therapies, recent advances in humanized mouse models have improved their ability to recapitulate the features of cell exhaustion during HIV infection. Targeting coinhibitory receptors in HIV-infected and simian immunodeficiency virus (SIV)-infected animals has resulted in viral load reductions, presumably by reinvigorating the effector functions of T cells. Additionally, studies combining programmed death-1 (PD-1) blockade with suppressive antiretroviral therapy provide further support to the use of coinhibitory receptor blockades in restoring T cell function by delaying viral load rebound upon antiretroviral therapy interruption. Future in-vivo studies should build on recent in-vitro data, supporting the simultaneous targeting of multiple regulators of cell exhaustion.
In this review, we describe the most recent advances in the use of animal models for the study of cell exhaustion following HIV/SIV infection. These findings suggest that the use of animal models is increasingly critical in translating immunotherapeutics into clinical practice.
aEmory Vaccine Center
bYerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
Correspondence to Dr Mirko Paiardini, Division of Microbiology and Immunology, Yerkes National Primate Research Center, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 929 Gatewood Rd, Atlanta, GA 30329, USA. Tel: +1 404 727 9840; fax: +1 404 727 7768; e-mail: firstname.lastname@example.org