Therapeutic conserved elements (CE) DNA vaccine induces strong T-cell responses against highly conserved viral sequences during simian-human immunodeficiency virus infection

ABSTRACT

HIV-specific T-cell responses play a key role in controlling HIV infection, and therapeutic vaccines for HIV that aim to improve viral control will likely need to improve on the T-cell responses induced by infection. However, in the setting of chronic infection, an effective therapeutic vaccine must overcome the enormous viral genetic diversity and the presence of pre-existing T-cell responses that are biased toward immunodominant T-cell epitopes that can readily mutate to evade host immunity and thus potentially provide inferior protection. To address these issues, we investigated a novel, epidermally administered DNA vaccine expressing SIV capsid (p27^Gag) homologues of highly conserved elements (CE) of the HIV proteome in macaques experiencing chronic but controlled SHIV infection. We assessed the ability to boost or induce de novo T-cell responses against the conserved but immunologically subdominant CE epitopes. Two groups of animals were immunized with either the CE DNA vaccine or a full-length SIV p57^gag DNA vaccine. Prior to vaccination, CE responses were similar in both groups. The full-length p57^gag DNA vaccine, which contains the CE, increased overall Gag-specific responses but did not increase CE responses in any animals (0/4). In contrast, the CE DNA vaccine increased CE responses in all (4/4) vaccinated macaques. In SIV infected but unvaccinated macaques, those that developed stronger CE-specific responses during acute infection exhibited lower viral loads. We conclude that CE DNA vaccination can re-direct the immunodominance hierarchy towards CE in the setting of attenuated chronic infection and that induction of these responses by therapeutic vaccination may improve immune control of HIV.

KEYWORDS:

• HIV
• SIV
• SHIV
• therapeutic vaccination
• conserved elements vaccine
• DNA vaccines
• gag

Abbreviations

ART	=	antiretroviral therapy
CE	=	conserved elements
FL	=	full-length
LT	=	heat labile E. coli enterotoxin

Disclosure of potential conflicts of interest

The authors claim no conflict of interest.

Funding

This work was supported by National Cancer Institute (NCI) and the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health under award numbers [T32CA080416 to Paul Munson]; [N01AI60006-7 (M Agy, PI)] and [R01 AI104679 (Fuller/Mullins, MPI)].

Acknowledgments

The authors would like to thank all veterinary and research support staff of the Washington National Primate Research Center with special thanks to Drew May, Solomon Wangari, Dr. Jennifer Lane, Dr. Cassie Moats, Dr. Jeremy Smedley, and Dr. Robert Murnane. We also wish to thank Dr. Nancy Miller of the Division of AIDS, National Institutes of Health. Gag peptides were kindly provided by the NIH AIDS Research and Reference Reagent Program. Additionally, we acknowledge the MHC Genotyping Service at the University of Miami, which is supported by the NIH grant 5R24RR016038 awarded to Dr. David Watkins, for providing the MHC data in this manuscript. This manuscript is dedicated to the late Dr. Michael Agy who was the PI of the Simian Vaccine Evaluation Unit grant that, in part, funded this project.

Previous presentation of data

Portions of this manuscript have not been previously published.