Progress Towards a Therapeutic HIV DNA Vaccine

ABSTRACT

Introduction

Antiretroviral therapy (ART) reduces HIV replication to undetectable levels and prevents AIDS but cannot cure the infection and discontinuing ART results in viral rebound. Therefore, a primary goal of HIV therapeutic vaccine research is to induce potent HIV-specific immunity that could control viremia without ART, a so-called “functional cure” that eliminates the need for lifelong ART. DNA vaccines have several features that make them an attractive modality for an HIV therapeutic vaccine: they are easy to manufacture, induce T-cell and antibody responses without anti-vector immunity, and do not involve ex vivo manipulations of patient cells.

Areas covered

This review covers the progress in developing therapeutic HIV DNA vaccines, emphasizing delivery innovations to enhance vaccine immunogenicity. A central theme is a transition from needle injection delivery to the muscle toward using more sophisticated devices to target the skin and/or increasing transfection efficiency.

Expert opinion

There are multiple barriers to an effective therapeutic HIV DNA vaccine. While variables such as delivery, adjuvants, and immunogen design have been extensively explored, combining DNA vaccines with complementary approaches is underdeveloped. Complementary approaches include co-administration with latency reversal agents, immune checkpoint blockade, and targeting conserved fitness-constrained portions of the virus.

KEYWORDS:

• Delivery
• DNA vaccine
• HIV
• SIV
• therapeutic

Declaration of interest

The author had a paid consultancy with ExcepGen regarding the use of DNA vaccines. This consultation did not affect the conceptualization of the manuscript, the content, or the decision to publish. 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.

Reviewer disclosures

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

Author contributions

P Munson conceptualized, wrote, developed the figures and tables, and revised the manuscript.

Article highlights

• In theory, DNA vaccines represent an attractive modality for therapeutic HIV vaccines due to their ability to elicit T-cellular and antibody responses without anti-vector immunity; however, they are blunted by their modest immunogenicity in humans.

• Improvements in DNA vaccine immunogenicity have primarily focused on devices and routes that improve access to immune cells in the skin (e.g. Biojector/gene gun) or increase transfection efficiency (e.g. electroporation).

• Improvements in the quality of the immune response, such as mucosal homing or a Th1 bias, have focused on selecting DNA-based adjuvants (e.g. IL-12 or RALDH2).

• Improving therapeutic HIV DNA vaccines will likely require combinatorial approaches such as co-administration with latency reversal agents, immune checkpoint blockade ($\alpha$-PD-1/ $\alpha$-CTLA-4), and advanced immunogen design.