Despite decades of insights about how CD8+ T cells and natural killer (NK) cells contribute to natural control of infection, additional hurdles (mutational escape from cellular immunity, sequence diversity, and hard-to-access tissue reservoirs) will need to be overcome to develop a cure. In this review, we highlight recent findings of novel mechanisms of antiviral cellular immunity and discuss current strategies for therapeutic deisgn.

Of note are the apparent converging roles of viral antigen-specific MHC-E-restricted CD8+ T cells and NK cells, interleukin (IL)-15 biologics to boost cytotoxicity, and broadly neutralizing antibodies in their native form or as anitbody fragments to neutralize virus and engage cellular immunity, respectively. Finally, renewed interest in myeloid cells as relevant viral reservoirs is an encouraging sign for designing inclusive therapeutic strategies.

Several studies have shown promise in many preclinical models of disease, including simian immunodeficiency virus (SIV)/SHIV infection in nonhuman primates and HIV infection in humanized mice. However, each model comes with its own limitations and may not fully predict human responses. We eagerly await the results of clinical trails assessing the efficacy of these strategies to achieve reductions in viral reservoirs, delay viral rebound, or ultimately elicit immune based control of infection without combination antiretroviral therapy (cART).