The Tat protein broadens T cell responses directed to the HIV-1 antigens Gag and Env: Implications for the design of new vaccination strategies against AIDS

HIV-1 Tat-Based Vaccines: An Overview and Perspectives in the Field of HIV/AIDS Vaccine Development

“…Similarly, mice vaccinated with Env or with V2-deleted Env in combination with Tat responded to 17 peptides, 12 more than mice vaccinated with the Env proteins alone. The effect was specific as Tat did not affect Th2-type responses to these structural HIV proteins [97,214]. In contrast with these results, using a DNA vaccination approach Agwale and co-worker reported that vaccination with a bi-cistronic gp120-tat DNA diminished IFN-γ CD8+ T cell responses against the immunodominant HIV-1 gp120 Env peptide in mice compared to those induced by vaccination with DNA encoding gp120 alone and that the effect of Tat was abolished by a sequence deletion (aa 31-50) in the cys-core domain of Tat (2).…”

“…This in vitro evidence suggested that Tat may function in vivo as both an antigen and a novel adjuvant with the capacity to increase T cell responses, particularly those that are subdominant. Indeed, it was shown that co-immunization of mice with ovalbumin (OVA) and Tat proteins induces CTL responses against subdominant and cryptic OVA-derived epitopes, which were not detected in mice vaccinated with OVA alone [97]. Similarly, mice vaccinated with the HIV-1 Gag, Env, or V2-deleted Env antigens in combination with the biologically active Tat showed Th-1 type and CTL responses directed to a larger number of T cell epitopes, as compared to mice vaccinated with Gag, Env, or V2-deleted Env proteins alone.…”

“…These combined vaccines should be more efficacious because they may attack the virus on early and late gene products. In these studies, mice vaccinated subcutaneously with the HIV-1 Gag, Env, or V2-deleted Env protein antigens in combination with the biologically active Tat protein developed strong humoral and cellular (Th1-and Th2-type) immune responses against Tat and the co-administered antigen and broadened the Th1-type and CTL responses against Gag or Env antigens [97,214]. In addition, these strategies were safe, immunogenic, and effective in containing SHIV 89.6P replication in cynomolgus macaques [Ensoli et al, manuscript in preparation], and based on these preclinical results, a Tat/V2-deleted Env protein vaccine will soon undergo phase I clinical trial testing in Italy (http://www.hiv1tat-vaccines.info/).…”

“…However, results from the first phase IIb STOC (a screening-test-of-concept efficacy study) STEP trial based on this rationale (HIV vaccine trial based on rAd5-gag/pol/nef) developed by Merck have been largely disappointing as no protection from primary infection and no control on plasma viremia have been Among the early proteins of HIV-1, the Tat protein is considered an interesting target for a combined vaccine approach as it plays a major role in HIV-1 replication and pathogenesis. Furthermore, the biologically active Tat protein displays immunomodulatory activities which can be favorably exploited for the development of novel combined subunit vaccines [95][96][97][98][99]. Hence, the Tat antigen is being tested in combination with other HIV structural and regulatory genes in preclinical models within the European AIDS Vaccine Integrated Project (AVIP) (http://www.avip-eu.org/) and the Mucosal Vaccines for Poverty Related Diseases (MUVAPRED) (http://www.mucosalimmunity.org/muvapred), which represent cooperative international frameworks aimed at developing an effective HIV/AIDS vaccine.…”

Transgenic 4-1BBL-engineered vaccine stimulates potent Gag-specific therapeutic and long-term immunity via increased priming of CD44+CD62Lhigh IL-7R+ CTLs with up- and downregulation of anti- and pro-apoptosis genes

“…51 It has been reported that the HIV-1 early regulatory protein Tat can broaden T-cell responses to HIV-1 envelope proteins. 52,53 To enhance the therapeutic efficacy of the Gag-Texo /4-1BBL vaccine, the construction and the assessment of a Gag-Tat-Texo /4-1BBL vaccine expressing both late HIV-1 Gag and early HIV-1 Tat proteins and the examination of Gag-Texo /4-1BBL vaccinated cells with PD-1 blocked by anti-PD-1 antibody in our transgenic HLA-A2 mouse model are also underway in our laboratory.…”