Clinical pharmacology in HIV cure research – what impact have we seen?

ABSTRACT

Introduction: Combined antiretroviral therapy (cART) has transformed an inexorably fatal disease into a chronic pathology, shifting the focus of research from the control of viral replication to the possibility of HIV cure.

Areas covered: The present review assesses the principal pharmacological strategies that have been tested for an HIV cure starting from the in vitro proof of concept and the potential rationale of their in vivo applicability. We evaluated the possible pharmacological procedures employed during the early-stage HIV infection and the possibility of cART-free remission. We then analyzed the shock and kill approach from the single compounds in vitro mechanism of action, to the in vivo application of single or combined actions. Finally, we briefly considered the novel immunological branch through the discovery and development of broadly neutralizing antibodies in regard to the current and future in vivo therapeutic strategies aiming to verify the clinical applicability of these compounds.

Expert opinion: Despite an incredible effort in HIV research cure, the likelihood of completely eradicating HIV is unreachable within our current knowledge. A better understanding of the mechanism of viral latency and the full characterization of HIV reservoir are crucial for the discovery of new therapeutic targets and novel pharmacological entities.

KEYWORDS:

• HIV
• eradication
• shock and kill
• pharmacology

Article highlights

• In the early phases of HIV infection, the establishment of a reservoir composed by quiescent and long-lasting cells represents the major obstacle to HIV eradication.

• Intervention strategies in acute HIV infection could lead to a significant reduction in the reservoir’s size but inexorably HIV-RNA rebounds in plasma after cART interruption even if the reservoir result unquantifiable.

• Shock and kill strategies have the aim of revert the latency of quiescent cells composing the HIV reservoir and subsequently kill the same cell. Several models have demonstrated how this kind of intervention can be effective in vitro and in animal model, but at the moment no strategy has been demonstrated to be effective in reducing the reservoir size in clinical studies.

• Immunological strategies accounting for the use of check-point inhibitors developed in cancer research seems to be promising. To date, the major concern regards the safety profile for this class of compounds.

• Broadly neutralizing antibodies represent not only an option among strategies for long-term control of HIV viremia and HIV prevention but they could be also part of combined strategies for targeting HIV reservoir as a part of kill interventions.

• Since every single strategy has failed in HIV eradication, the future interventions will have to focus on multitarget combination therapies.

This box summarizes key points contained in the article.

Declaration of interest

S Rusconi has received research grants or personal fees for ECM activities or advisory boards from: ViiV, MSD, BMS, Gilead, and Janssen. 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.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.