Improving combination antiretroviral therapy by targeting HIV-1 gene transcription

ABSTRACT

Introduction: Combination Antiretroviral Therapy (cART) has not allowed the cure of HIV. The main obstacle to HIV eradication is the existence of quiescent reservoirs. Several other limitations of cART have been described, such as strict life-long treatment and high costs, restricting it to Western countries, as well as the development of multidrug resistance. Given these limitations and the impetus to find a cure, the development of new treatments is necessary.

Areas covered: In this review, we discuss the current status of several efficient molecules able to suppress HIV gene transcription, including NF-kB and Tat inhibitors. We also assess the potential of new proteins belonging to the intriguing DING family, which have been reported to have potential anti-HIV-1 activity by inhibiting HIV gene transcription.

Expert opinion: Targeting HIV-1 gene transcription is an alternative approach, which could overcome cART-related issues, such as the emergence of multidrug resistance. Improving cART will rely on the identification and characterization of new actors inhibiting HIV-1 transcription. Combining such efforts with the use of new technologies, the development of new models for preclinical studies, and improvement in drug delivery will considerably reduce drug toxicity and thus increase patient adherence.

KEYWORDS:

• cART
• HIV transcription
• Tat
• NF-KB
• DING

Article highlights

• Adding to cART drugs which block the production including the virus transcription could be a significant improvement since this could prevent cART-related side effects like multidrug resistance.

• Intensifying cART with transcriptional inhibitors will help to reduce the size of latent reservoirs, to reduce the prevalence of HAND and to prevent brain injuries in strategies aiming to reactivate and eliminate the brain reservoirs.

• NF-kB and Tat are the two main targets for the improvement of cART. These targets control HIV progression by activating transcription.

• Most of the potential transcriptional inhibitors still await preclinical and clinical trials.

• Improvement of cART relies on identification of new targets, development of adequate animal models and introduction of new technologies.

• In the next 10 years, new drugs and methods to increase bioavailability and bio-distribution may allow at least a functional cure including strategies aiming at the reduction of the pool of latent reservoirs.

This box summarizes key points contained in the article.

Acknowledgments

We are grateful to Andras and Andrea Janossy for a careful and critical reading of the manuscript.

Declaration of interest

This work was supported by grants from the Agence Nationale de Recherches sur le SIDA (ANRS) to O Rohr, C Schwartz, and V Le Douce, from the Sidaction, Ligue contre le cancer to O Rohr and C Schwartz, and from Institut Universitaire de France to O Rohr. Additional funding was received from the Marie Skłodowska-Curie Research and Innovation Staff Exchange (MSCA-RISE; EU4HIVCURE; call for proposal: H2020-MSCA-RISE; project reference: 691119). The authors have no other 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 apart from those disclosed.