The HIV-1 Tat Protein Induces the Activation of CD8+ T Cells and Affects In Vivo the Magnitude and Kinetics of Antiviral Responses

Abstract

T cells are functionally compromised during HIV infection despite their increased activation and proliferation. Although T cell hyperactivation is one of the best predictive markers for disease progression, its causes are poorly understood. Anti-tat natural immunity as well as anti-tat antibodies induced by Tat immunization protect from progression to AIDS and reverse signs of immune activation in HIV-infected patients suggesting a role of Tat in T cell dysfunctionality. The Tat protein of HIV-1 is known to induce, in vitro, the activation of CD4+ T lymphocytes, but its role on CD8+ T cells and how these effects modulate, in vivo, the immune response to pathogens are not known. To characterize the role of Tat in T cell hyperactivation and dysfunction, we examined the effect of Tat on CD8+ T cell responses and antiviral immunity in different ex vivo and in vivo models of antigenic stimulation, including HSV infection. We demonstrate for the first time that the presence of Tat during priming of CD8+ T cells favors the activation of antigen-specific CTLs. Effector CD8+ T cells generated in the presence of Tat undergo an enhanced and prolonged expansion that turns to a partial dysfunctionality at the peak of the response, and worsens HSV acute infection. Moreover, Tat favors the development of effector memory CD8+ T cells and a transient loss of B cells, two hallmarks of the chronic immune activation observed in HIV-infected patients. Our data provide evidence that Tat affects CD8+ T cell responses to co-pathogens and suggest that Tat may contribute to the CD8+ T cell hyperactivation observed in HIV-infected individuals.

Balance of cellular and humoral immunity determines the level of protection by HIV vaccines in rhesus macaque models of HIV infection

“…We hypothesized that the inactivated Tat toxoid would improve the protection offered by rhFLSC by inducing antibodies that would neutralize extracellular Tat and reduce the T-cell hyperactivation and dysfunction that exacerbates viral expansion that is induced by native extracellular Tat (35). Combinations of envelope and inactivated mutants of Tat have been reported to protect against homologous SHIV infection in cynomolgus macaques (36,37). Notably, Tat toxoid physically associated with rhFLSC in solution (Fig.…”

HIV-1 Tat affects the programming and functionality of human CD8+ T cells by modulating the expression of T-box transcription factors

“…Moreover, it has been demonstrated that anti-Tat immunity is important for disease control and restoration of immune functions [25,26], suggesting that Tat may contribute to immune activation. In accordance with this hypothesis, we have recently shown in murine models that Tat favors the activation and the expansion of antigen-specific cytotoxic T lymphocytes (CTLs) and modulates antiviral responses causing dysfunctions similar to those observed in HIV-infected individuals [22,27].…”

“…These transcription factors are regulated by or regulate interferon (IFN)-g and interleukin (IL)-2 signaling [34][35][36]. As we have shown in murine models that Tat enhances T-cell receptor stimulation favoring IFN-g production [27], and several works describe that Tat increases IL-2 release in CD4 þ T cells [13,15], we sought to determine whether Tat may favor the activation of human CD8 þ T cells affecting the expression of these transcription factors. We demonstrate here for the first time that CD8 þ T cells activated in the presence of Tat enhance their effector functions and display an increased expression of those transcription factors important for T-cell programming.…”

Effects of different routes of administration on the immunogenicity of the Tat protein and a Tat-derived peptide

“…Serum and mucosal samples were collected at day 42 and tested for the presence of anti-Tat antibodies. 30,31 Anti-Tat IgG were present in sera of all animals ( Fig.2A) with titers comparable among groups (Fig. 2B).…”