HIV-Tat immunization induces cross-clade neutralizing antibodies and CD4+ T cell increases in antiretroviral-treated South African volunteers: a randomized phase II clinical trial

Abstract

Background Although combined antiretroviral therapy (cART) has saved millions of lives, it is incapable of full immune reconstitution and virus eradication. The transactivator of transcription (Tat) protein is a key human immunodeficiency virus (HIV) virulence factor required for virus replication and transmission. Tat is expressed and released extracellularly by infected cells also under cART and in this form induces immune dysregulation, and promotes virus reactivation, entry and spreading. Of note, anti-Tat antibodies are rare in natural infection and, when present, correlate with asymptomatic state and reduced disease progression. This suggested that induction of anti-Tat antibodies represents a pathogenesis-driven intervention to block progression and to intensify cART. Indeed Tat-based vaccination was safe, immunogenic and capable of immune restoration in an open-label, randomized phase II clinical trial conducted in 168 cART-treated volunteers in Italy. To assess whether B-clade Tat immunization would be effective also in patients with different genetic background and infecting virus, a phase II trial was conducted in South Africa.MethodsThe ISS T-003 was a 48-week randomised, double-blinded, placebo-controlled trial to evaluate immunogenicity (primary endpoint) and safety (secondary endpoint) of B-clade Tat (30 μg) given intradermally, three times at 4-week intervals, in 200 HIV-infected adults on effective cART (randomised 1:1) with CD4+ T-cell counts ≥200 cells/µL. Study outcomes also included cross-clade anti-Tat antibodies, neutralization, CD4+ T-cell counts and therapy compliance.ResultsImmunization was safe and well-tolerated and induced durable, high titers anti-Tat B-clade antibodies in 97 % vaccinees. Anti-Tat antibodies were cross-clade (all vaccinees tested) and neutralized Tat-mediated entry of oligomeric B-clade and C-clade envelope in dendritic cells (24 participants tested). Anti-Tat antibody titers correlated positively with neutralization. Tat vaccination increased CD4+ T-cell numbers (all participants tested), particularly when baseline levels were still low after years of therapy, and this had a positive correlation with HIV neutralization. Finally, in cART non-compliant patients (24 participants), vaccination contained viral load rebound and maintained CD4+ T-cell numbers over study entry levels as compared to placebo.ConclusionsThe data indicate that Tat vaccination can restore the immune system and induces cross-clade neutralizing anti-Tat antibodies in patients with different genetic backgrounds and infecting viruses, supporting the conduct of phase III studies in South Africa.Trial registration ClinicalTrials.gov NCT01513135, 01/23/2012Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0261-1) contains supplementary material, which is available to authorized users.

Mucosal vaccination with a live recombinant rhinovirus followed by intradermal DNA administration elicits potent and protective HIV-specific immune responses

“…High titre Tat-specific serum IgG appears to correlate with control of HIV infection in humans1133 and SIV in macaques3435. Therefore, we compared the titres of Tat-specific IgG generated after vaccination with wt-HRV-A1/pVAX, rHRV-DNA or 3X pVAX-Gag-Tat.…”

“…In addition to robust CMI, rHRV-DNA induced higher Tat-specific serum IgG and mucosal sIgA titres than wtHRV-A1/pVax or 3X pVAX-Gag-Tat vaccination (Fig. 4A), additional markers which appear to correlate with control of HIV in humans1133 and SIV in animals3443. Although we did not assess functionality of the Tat-specific antibodies in terms of anti-Tat neutralization, a previous study conducted in our laboratory indicated that intradermal vaccination with pVAX-sTat-IMX313, one of the vaccines used in the regimens of this study, elicited antibodies with Tat neutralization activity that correlated with control of EcoHIV25.…”

Tat-Based Therapies as an Adjuvant for an HIV-1 Functional Cure

“…Likewise, Tat-BH10 vaccine responders produced antibodies that recognize Tat for HIV subtypes A, B, C and D. These antibodies may be therapeutic. Tat-BH10 responders had increased levels of CD4 + cells compared to baseline, as well as reduced viral loads in plasma and proviral DNA load in PBMCs [79,83]; and Tat-Oyi vaccine responders had reduced viral rebound following cessation of cART [86]. The evidence suggests that restoration of cell mediated immunity contributed to decreased proviral load.…”

“…Both types of Tat vaccine were tested in non-human primate (SHIV) models, producing conflicting results regarding efficacy [80,81,87,[151][152][153]. Here we recap recent small-scale phase l/lla vaccination clinical trials with Tat-BH10 or Tat-Oyi [78,79,82,86,154,155] (Table 1). In these trials, HIV-infected participants were treated with cART, which controlled viremia.…”

Immunotherapeutic strategies for sexually transmitted viral infections: HIV, HSV and HPV

“…Combined treatment of Tat Oyi vaccine and cART has found to increase CD4+ T-cell numbers. Phase III studies that has been conducted in South Africa (Trial registration ClinicalTrials.gov NCT01513135) unfolded that Tat vaccination induces cross-clade neutralizing anti-Tat antibodies in patients with different infecting viruses and belonging to different genetic backgrounds [84].…”