Intradermal injection of a Tat Oyi-based therapeutic HIV vaccine reduces of 1.5 log copies/mL the HIV RNA rebound median and no HIV DNA rebound following cART interruption in a phase I/II randomized controlled clinical trial

Abstract

BackgroundA Tat Oyi vaccine preparation was administered with informed consent to 48 long-term HIV-1 infected volunteers whose viral loads had been suppressed by antiretroviral therapy (cART). These volunteers were randomized in double-blind method into four groups (n = 12) that were injected intradermally with 0, 11, 33, or 99 µg of synthetic Tat Oyi proteins in buffer without adjuvant at times designated by month 0 (M0), M1 and M2, respectively. The volunteers then underwent a structured treatment interruption between M5 and M7.ResultsThe primary outcomes of this phase I/IIa clinical trial were the safety and lowering the extent of HIV RNA rebound after cART interruption. Only one undesirable event possibly due to vaccination was observed. The 33 µg dose was most effective at lowering the extent of HIV RNA and DNA rebound (Mann and Whitney test, p = 0.07 and p = 0.001). Immune responses against Tat were increased at M5 and this correlated with a low HIV RNA rebound at M6 (p = 0.01).ConclusionThis study suggests in vivo that extracellular Tat activates and protects HIV infected cells. The Tat Oyi vaccine in association with cART may provide an efficient means of controlling the HIV-infected cell reservoir.

The effects of HIV-1 regulatory TAT protein expression on brain reward function, response to psychostimulants and delay-dependent memory in mice

“…Taken together, these data indicate that HIV-associated proteins, such as TAT or gp120, may enhance the rewarding properties of methamphetamine, and other drugs of abuse, by impairing dopaminergic function in mesolimbic circuitry. Our findings suggest that the use of TAT vaccines, currently being tested in clinical trials (Loret et al, 2016), if administered early enough may prevent alterations in brain reward function, and decrease the rewarding properties of methamphetamine or other drugs of abuse in the HIV+ population.…”

“…Alternatively, a longer period of TAT protein exposure (via doxycycline containing food or water) may lead to more robust neuropathology and thus impact working memory. If this is the case, TAT vaccines (Loret et al, 2016) may prevent aspects of cognitive decline in HIV+ individuals. Our results suggest that short-term TAT protein exposure is insufficient to induce delay-dependent working memory impairments but sufficient to induce persisting alterations to the rewarding properties of methamphetamine.…”

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.…”

“…A parallel Tat-BH10 trial (ISS T-003, yet to report) is randomized, blinded and includes a placebo arm. The Tat-Oyi trial was a randomized controlled study involving 48 people in four groups followed for 12 months [86]. Interestingly, optimal immune responses were reported when Tat-BH10 and Tat-Oyi were administered intradermally at 30 or 33 µg, respectively, and given 3 times, once monthly and without adjuvant.…”

Development of an Attenuated Tat Protein as a Highly-effective Agent to Specifically Activate HIV-1 Latency

“…28,29,30,31 Because of the specificity and efficiency of Tat to activate HIV-1 transcription and the proven safety of bioactive recombinant Tat protein in several clinical trials for vaccine development, it is possible to develop a mutated Tat protein as a novel HIV-1 latency activator by decreasing its cytotoxicity and immunogenicity. 32,33,34,35,36 In this study, we employed multiple mutations and explored various combinations of mutants and have developed a recombinant mutated Tat protein for the effective activation of HIV-1 latency.…”