HIV therapeutic vaccines aimed at intensifying combination antiretroviral therapy

ABSTRACT

Introduction: Although successful at suppressing HIV replication, combination antiretroviral therapy (cART) only partially restores immune functions and fails to reduce the latent HIV reservoir, thus requiring novel interventions for its intensification.

Areas covered: Here are reviewed therapeutic vaccine candidates that are being developed to this goal. Among them, the Tat vaccine has been shown to promote immune restoration, including CD4+ T-cell recovery in low immunological responders, and to reduce the virus reservoirs well beyond what achieved with long-term suppressive cART.

Expert opinion: The authors propose the Tat vaccine as a promising vaccine candidate for cART intensification toward HIV reservoirs depletion, functional cure, and eradication strategies, suggesting that targeting a key protein in the virus life cycle is pivotal to success.

KEYWORDS:

• HIV-1 therapeutic vaccine
• immunotherapy
• cART intensification
• HIV-1 Tat
• clinical trials
• proviral DNA
• immune system restoration
• anti-Tat antibodies
• functional cure
• HIV reservoir

Article highlights

• cART has several shortcomings since it does not: i) completely silence virus gene expression, ii) block replenishment of viral reservoirs, iii) eliminate low level chronic inflammation, iv) fully restore T- and B-cell number and function, v) reverse immune dysregulation, and vi) prevent selection of resistant strains.

• Therapeutic HIV vaccine in conjunction with antiretroviral therapy may represent a relevant, cost-effective approach to increase the effectiveness of cART by: i) accelerating time-to-response to therapy, ii) blocking or reducing virus transmission, iii) solving unmet needs of ART (immune activation, immune defects, proviral DNA), iv) allowing drug simplification or virus control despite low adherence to therapy.

• The Tat vaccine intensifies cART as indicated by: i) CD4+ T-cell increase beyond cART alone (particularly in poor immunological responders), ii) increased peripheral blood proviral DNA decay, iii) reduction of immune activation/dysregulation, iv) increased number and function of CD4+ and CD8+ T cells, B, NK cells and memory subsets (increase of central memory and decrease of effector memory T cells)

• The Tat vaccine has the potential to intensify cART efficacy by: i) reducing the rate of treatment failure, ii) reducing the prevalence of AIDS and non-AIDS co-morbidities, iii) restoring the immune response that may lead to greater efficacy of routine immunizations and containment of co-infections, and iv) allowing periodic drug-free time.

Acknowledgments

The authors like to thank: A Arancio, M Campagna, V Francavilla, G Paniccia, MR Pavone-Cossut (National HIV/AIDS Research Center) for laboratory support; F Cammisa (National HIV/AIDS Research Center) for support to study management and editorial assistance; S De Menna, F Fedeli and S Tobelli (National HIV/AIDS Research Center) for administrative support; P Arciero (National HIV/AIDS Research Center) for technical support; GB Cozzone (VAXXIT, Rome, Italy) for helpful discussion.

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

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received travel grants from Gilead, Merck, Gilead, Bristol and Pfizer; payment for lectures from Merck, Gilead, Bristol and Abbvie; consulting fees from Angelini SpA. and research funding from Gilead. All other peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was funded by the Italian Ministry of Health (Special Program “Development of a vaccine against HIV/AIDS, based on the biologically active recombinant HIV-1 Tat protein”).