Pronounced acute immunosuppression in vivo mediated by HIV Tat challenge

Abstract

HIV infection is accompanied by an early immune dysfunction limiting host control of virus and likely contributing to difficulties in achieving a successful vaccine against HIV. We report here that the HIV Tat protein is strongly immunosuppressive, both immediately after immunization of mice with soluble protein (sTat), and in seroconverting humans, and propose that Tat-induced suppression cripples immune surveillance to HIV infection. We show that macrophages are sensitive to sTat stimulation at concentrations 1,000-fold lower (500 pM) than T cells, and this stimulation is accompanied by the immunosuppressive induction of Fas ligand on the macrophage. T cell proliferative defects induced by sTat in vitro can be completely (at lower concentrations of sTat) or partially (at higher concentrations) reversed by antagonists to Fas͞Fas ligand interaction. We further report a method to preserve immunogenicity while inactivating Tat immunosuppression through oxidation, which advances the use of oxidized Tat as a component of an anti-HIV vaccine. These observations define additional methods to study the immunosuppressive functions of sTat that now may be rapidly applied to primary isolates from individuals with differing clinical courses. Our findings have immediate relevance for vaccine development, by describing and supporting a strategy that includes inactivated sTat in a multicomponent, anti-HIV vaccine.

HIV-1 Tat Suppresses gp120-Specific T Cell Response in IL-10-Dependent Manner

“…Thus, our finding that Tat induces production of IL-10, a cytokine with known immunosuppressive activity (46), could be a crucial player in the immune response to the virus. Tat-mediated immunosuppression has also been observed by a few other groups (18,19), but we did not observe any suppression of the Ab response as reported by Cohen et al (19) due to the presence of Tat. However, we have observed the Ab switch from IgG2a to IgG1 in the presence of Tat.…”

“…Several studies indicate that Abs to Tat play a host-protective role in HIV-1 infection and thus have been also considered as a target for the development of novel AIDS therapy (45). Although Tat has been found to be a successful candidate, few reports imply that Tat acts as an immunosuppressor for the coimmunized viral Ags (18,19). The mechanism by which Tat mediates its immunosuppression remains to be elucidated.…”

“…Due to its important role in virus life cycle and relatively well-conserved sequence in various isolates, Tat has been used as an immunogen both alone or as a part of multicomponent vaccines. Although results from several studies strongly indicate Tat as a potential vaccine candidate, some studies show an immunosuppressive role of Tat, particularly against the coimmunogens, in the host (18,19). In addition, studies from patients have indicated an increase in IL-10 production from infected cells (20) and Tat has been implicated in such IL-10 induction (21,22).…”

HIV‐1 Tat Triggers TGF‐β Production and NK Cell Apoptosis that is Prevented by Pertussis Toxin B

“…The transactivating effect of HIV-1 Tat is mediated by the multimolecular complex AP-1; interestingly, the same pathway is activated by TGF-b, which acts mainly upregulating the Jun family of AP-1 transcription factors (Gibellini et al 1997;Cohen et al 1999). In addition, TGF-b has been reported to induce apoptosis of different cell types through AP-1-dependent activation of SHIP which, in turn, determines the dephosphorylation of Akt, a phosphoinositol-3 kinase (PI-3K)-dependent enzyme that induces the transcription of the antiapoptotic proteins Bcl-2 and Bcl-x (Yamamura et al 2000;ValderramaCarvajal et al 2002).…”

Immunoprevalence of the CD4+ T‐cell response to HIV Tat and Vpr proteins is provided by clustered and disperse epitopes, respectively

“…Besides its transactivating activity, Tat exerts a wide range of activities. It diminishes T-cell function and provokes immunosuppression [5]. It enhances DC maturation [6] and exhibits an adjuvant activity [7].…”