HIV-1 therapeutic vaccines in clinical development to intensify or replace antiretroviral therapy: the promising results of the Tat vaccine

ABSTRACT

Introduction

Upon the introduction of the combination antiretroviral therapy (cART), HIV infection has become a chronic disease. However, cART is unable to eradicate the virus and fails to restore the CD4 counts in about 30% of the treated individuals. Furthermore, treatment is life-long, and it does not protect from morbidities typically observed in the elderly. Therapeutic vaccines represent the most cost-effective intervention to intensify or replace cART.

Areas covered

Here, we briefly discuss the obstacles to the development and evaluation of the efficacy of therapeutic vaccines and review recent approaches evaluated in clinical trials.

Expert opinion

Although vaccines were generally safe and immunogenic, evidence of efficacy was negligible or marginal in most trials. A notable exception is the therapeutic Tat vaccine approach showing promising results of cART intensification, with CD4 T-cell increase and proviral load reduction beyond those afforded by cART alone. Rationale and evidence in support of choosing Tat as the vaccine target are thoroughly discussed.

KEYWORDS:

• Therapeutic HIV vaccine
• cART intensification
• analytical treatment interruption
• HIV remission
• HIV latent reservoir
• HIV proviral load
• immune restoration
• HIV Tat
• Tat vaccine
• anti-Tat antibodies

Article highlights

• The SARS-CoV-2 pandemic has shown how difficult is to ensure medical assistance and treatment to people with chronic diseases. For HIV/AIDS, this translates into a higher occurrence of treatment failure, HIV-associated comorbidities, and drug resistance, hampering the ending of the HIV pandemic

• Therapeutic vaccines are the most cost-effective interventions to address these issues

• So far, results have been disappointing or marginally promising, despite the enormous advancements in the knowledge of HIV biology and structure and host immune response have been readily applied to the vaccine field

• A growing body of evidence indicates that in virologically suppressed individuals HIV hides in very peculiar niches, very hard to attack, likely the result of the selective pressure exerted by cART and the partially reconstituted immune surveillance

• Thus, at present cART intensification or simplification are the more attainable goals for a therapeutic vaccine, possibly leading to off-cART virus control (remission)

• Targeting HIV proteins that are critical in the early phases of the virus life cycle should help achieve virus control and virus reservoir reduction

• Approaches aimed at harnessing and training innate immunity should also be considered, as HIV has proved extremely effective at evading adaptive immunity

• Association of a vaccine with novel forms of interventions aimed to block virus spreading and to attack HIV reservoir are needed, as the results obtained so far have been unsatisfactory.

• The unprecedented response to the SARS-CoV-2 pandemic, including governments support, public funding, and sharing of risks and benefits, has led to the parallel conduction of phase I, II, and III trials, accelerating incredibly the evaluation of new vaccine strategies, a strategy which has been pivotal for the development of successful SARS-CoV-2 vaccines. This represents a valuable model to adopt in the HIV field, where the pathogen to fight is much tougher than SARS-CoV-2, and therefore requires more aggressive initiatives

• Head-to-head comparison of the most promising approaches is needed, with efficacy evaluated according to a consensus protocol

Acknowledgments

The authors like to thank F. Cammisa (National HIV/AIDS Research Center) for support to study management and editorial assistance; O. Picconi (National HIV/AIDS Research Center) for submission assistance; S. De Menna, F. Fedeli, and S. Tobelli (National HIV/AIDS Research Center) for administrative support; and P. Arciero, F. Costa, and P. Cocco (National HIV/AIDS Research Center, ISS, Rome, Italy) for technical support.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14760584.2022.2089119

Additional information

Funding

This study was funded by the Italian Ministry of Health, Special Project on the Development of a Vaccine against HIV based on the Tat protein, the Italian Ministry of Health, grant number F-2011-02348970 and RF-2016-02364744 (B.E.), and Ricerca Corrente 2020 (B.E.).