HIV-1 Tat B-cell epitope vaccination was ineffectual in preventing viral rebound after ART cessation

Goldstein, Gideon; Damiano, Eve; Donikyan, Mardik; Pasha, Malika; Beckwith, Erik; Chicca, John J

doi:10.4161/hv.21616

Cited by 23 publications

(6 citation statements)

References 29 publications

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“…The only successful phase II vaccine clinical trial against HIV used a recombinant virus triggering envelope proteins (RV144), and demonstrated an efficacy of about 30 % at preventing HIV infection [ 27 ]. Two previous phase II clinical trials were performed with Tat fragments (TUTI-16) [ 28 ] or with recombinant Tat (ISST-02) [ 29 ]. Interestingly, in these two clinical trials as in this one, a dose of 30 µg of Tat yielded the best results [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…Two previous phase II clinical trials were performed with Tat fragments (TUTI-16) [ 28 ] or with recombinant Tat (ISST-02) [ 29 ]. Interestingly, in these two clinical trials as in this one, a dose of 30 µg of Tat yielded the best results [ 28 , 29 ]. Three years after vaccination in the ISST-02 protocol, a significant increase in CD4 cells and a HIV DNA decrease of 0.2 log copies/10 6 PBMC occurred but there was no placebo group to determine if these results were related to the vaccine [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

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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

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…Similarly, Tat-based vaccines that aimed at inducing cellular responses alone failed in demonstrating any therapeutic efficacy [149]. This may also explain the failure of a therapeutic vaccine based on a single, presumably linear, universal Tat B-cell epitope [150].…”

Section: Discussionmentioning

confidence: 99%

Anti-Tat Immunity in HIV-1 Infection: Effects of Naturally Occurring and Vaccine-Induced Antibodies Against Tat on the Course of the Disease

et al. 2019

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HIV-1 Tat is an essential protein in the virus life cycle, which is required for virus gene expression and replication. Most Tat that is produced during infection is released extracellularly and it plays a key role in HIV pathogenesis, including residual disease upon combination antiretroviral therapy (cART). Here, we review epidemiological and experimental evidence showing that antibodies against HIV-1 Tat, infrequently occurring in natural infection, play a protective role against disease progression, and that vaccine targeting Tat can intensify cART. In fact, Tat vaccination of subjects on suppressive cART in Italy and South Africa promoted immune restoration, including CD4+ T-cell increase in low immunological responders, and a reduction of proviral DNA even after six years of cART, when both CD4+ T-cell gain and DNA decay have reached a plateau. Of note, DNA decay was predicted by the neutralization of Tat-mediated entry of Env into dendritic cells by anti-Tat antibodies, which were cross-clade binding and neutralizing. Anti-Tat cellular immunity also contributed to the DNA decay. Based on these data, we propose the Tat therapeutic vaccine as a pathogenesis-driven intervention that effectively intensifies cART and it may lead to a functional cure, providing new perspectives and opportunities also for prevention and virus eradication strategies.

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“…However, given that NTE is moderately conserved and subtype-specific variations are evident in this epitope, it becomes imperative that immune responses to multiple epitopes are elicited to counter the emergence of escape variants. Indeed, a recent Tat-epitope vaccine trial, despite inducing epitope-specific antibodies, had limited success in inhibiting viral rebound following anti-retroviral therapy (ART) cessation [40] . In this regard, it is noteworthy that the HTL-Tat proteins retain several antibody epitopes and upon immunization elicit a strong antibody response to multiple epitopes.…”

Section: Discussionmentioning

confidence: 99%

The Grafting of Universal T-Helper Epitopes Enhances Immunogenicity of HIV-1 Tat Concurrently Improving Its Safety Profile

et al. 2014

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Extracellular Tat (eTat) plays an important role in HIV-1 pathogenesis. The presence of anti-Tat antibodies is negatively correlated with disease progression, hence making Tat a potential vaccine candidate. The cytotoxicity and moderate immunogenicity of Tat however remain impediments for developing Tat-based vaccines. Here, we report a novel strategy to concurrently enhance the immunogenicity and safety profile of Tat. The grafting of universal helper T-lymphocyte (HTL) epitopes, Pan DR Epitope (PADRE) and Pol711 into the cysteine rich domain (CRD) and the basic domain (BD) abolished the transactivation potential of the Tat protein. The HTL-Tat proteins elicited a significantly higher titer of antibodies as compared to the wild-type Tat in BALB/c mice. While the N-terminal epitope remained immunodominant in HTL-Tat immunizations, an additional epitope in exon-2 was recognized with comparable magnitude suggesting a broader immune recognition. Additionally, the HTL-Tat proteins induced cross-reactive antibodies of high avidity that efficiently neutralized exogenous Tat, thus blocking the activation of a Tat-defective provirus. With advantages such as presentation of multiple B-cell epitopes, enhanced antibody response and importantly, transactivation-deficient Tat protein, this approach has potential application for the generation of Tat-based HIV/AIDS vaccines.

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HIV-1 Tat B-cell epitope vaccination was ineffectual in preventing viral rebound after ART cessation

Cited by 23 publications

References 29 publications

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

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

Anti-Tat Immunity in HIV-1 Infection: Effects of Naturally Occurring and Vaccine-Induced Antibodies Against Tat on the Course of the Disease

The Grafting of Universal T-Helper Epitopes Enhances Immunogenicity of HIV-1 Tat Concurrently Improving Its Safety Profile

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