New insights into pathogenesis point to HIV-1 Tat as a key vaccine target

Abstract

Despite over 30 years of enormous effort and progress in the field, no preventative and/or therapeutic vaccines against human immunodeficiency virus (HIV) are available. Here, we briefly summarize the vaccine strategies and vaccine candidates that in recent years advanced to efficacy trials with mostly unsatisfactory results. Next, we discuss a novel and somewhat contrarian approach based on biological and epidemiological evidence, which led us to choose the HIV protein Tat for the development of preventive and therapeutic HIV vaccines. Toward this goal, we review here the role of Tat in the virus life cycle as well as experimental and epidemiological evidence supporting its key role in the natural history of HIV infection and comorbidities. We then discuss the preclinical and clinical development of a Tat therapeutic vaccine, which, by improving the functionality and homeostasis of the immune system and by reducing the viral reservoir in virologically suppressed vaccinees, helps to establish key determinants for intensification of combination antiretroviral therapy (cART) and a functional cure. Future developments and potential applications of the Tat therapeutic vaccine are also discussed, as well as the rationale for its use in preventative strategies. We hope this contribution will lead to a reconsideration of the current paradigms for the development of HIV/AIDS vaccines, with a focus on targeting of viral proteins with key roles in HIV pathogenesis.

Fig. 1

Roles of extracellular Tat in HIV in virus life cycle and in the latent virus reservoir. A Stochastic oscillations of HIV-1 Tat protein expression (the Tat stochastic switch) determine the fate of HIV infection [40]; B Membrane-bond extracellular Tat induces CTL apoptosis [64]; C Extracellular Tat binds Env to form a HIV entry complex [35] that increases virus infectivity and the HIV basic reproduction number (R₀), thus increasing the chances of infection in tissue compartments with low-drug penetration; at the same time, extracellular Tat induces in naïve CD4+ T cells a non-classical activation pathway rendering these cells susceptible to HIV infection [54]; D Extracellular Tat enhances the expansion and differentiation of naïve CD4+ T cells into effector-memory cells [75], thus increasing the number of cells transitioning from the activated to the resting state, a cell state that favors latent infection [94]; E Extracellular Tat forms chemotactic gradients [46; 48, 49] recruiting monocytes/macrophages and dendritic cells to the site of infection (51), induces the release of pro-inflammatory cytokines [–63] and the maturation of dendritic cells with a Th-1 polarization [52]; F Tat upregulates BCL2 in CD4+ T cells, leading to increased reservoir cell survival [93] while rendering these cells resistant to CTL killing [94]