DNA Vaccine-Induced Long-Lasting Cytotoxic T Cells Targeting Conserved Elements of Human Immunodeficiency Virus Gag Are Boosted Upon DNA or Recombinant Modified Vaccinia Ankara Vaccination.

Xintao Hu,Eric G Ramírez-Salazar,Linda S Wyatt,James I Mullins,Niranjan Y Sardesai,George N Pavlakis,Barbara K Felber,Yanhui Cai,Antonio Valentin,Viraj Kulkarni,Bernard Moss,Kate E Broderick,Patricia L Earl,Margherita Rosati,Frances Dayton

doi:10.1089/hum.2018.065

Abstract

DNA-based vaccines able to induce efficient cytotoxic T-cell responses targeting conserved elements (CE) of human immunodeficiency virus type 1 (HIV-1) Gag have been developed. These CE were selected by stringent conservation, the ability to induce T-cell responses with broad human leukocyte antigen coverage, and the association between recognition of CE epitopes and viral control in HIV-infected individuals. Based on homology to HIV, a simian immunodeficiency virus p27gag CE DNA vaccine has also been developed. This study reports on the durability of the CE-specific T-cell responses induced by HIV and simian immunodeficiency virus CE DNA-based prime/boost vaccine regimens in rhesus macaques, and shows that the initially primed CE-specific T-cell responses were efficiently boosted by a single CE DNA vaccination after the long rest period (up to 2 years). In another cohort of animals, the study shows that a single inoculation with non-replicating recombinant Modified Vaccinia Ankara (rMVA62B) also potently boosted CE-specific responses after around 1.5 years of rest. Both CE DNA and rMVA62B booster vaccinations increased the magnitude and cytotoxicity of the CE-specific responses while maintaining the breadth of CE recognition. Env produced by rMVA62B did not negatively interfere with the recall of the Gag CE responses. rMVA62B could be beneficial to further boosting the immune response to Gag in humans. Vaccine regimens that employ CE DNA as a priming immunogen hold promise for application in HIV prevention and therapy.

Highlights

VIRAL DIVERSITY AND IMMUNE DOMINANCE are two major obstacles for the development of an effective human immunodeficiency virus (HIV) vaccine
The present study shows that the T-cell responses induced by the DNA-based conserved elements (CE) vaccine regimens targeting CE within Gag are long-lasting and that they are effectively recalled upon a single booster vaccination using CE DNA, indicating the DNA vaccine regimen induced durable memory responses in macaques
The key immunogens in the vaccine regimens described in this work are DNA plasmids encoding CE within human immunodeficiency virus type 1 (HIV-1) p24Gag and the homologous simian immunodeficiency virus (SIV) p27Gag, termed HIV p24CE and SIV p27CE, respectively (Fig. 1A), described elsewhere.[16,23,35]

Summary

Introduction

VIRAL DIVERSITY AND IMMUNE DOMINANCE are two major obstacles for the development of an effective human immunodeficiency virus (HIV) vaccine. To address these problems, different approaches have been implemented in the field of vaccine development, including the use of consensus and conserved sequences, center-of-tree (COT) sequences, mosaic immunogens, use of ancestral sequences, or generation of chimeric molecules combining known epitopes.[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22] The authors’ approach has been to generate immunogens encod-. Ing highly conserved sequences within HIV-1 p24Gag, and the vaccine comprised seven regions covering 54% of the HIV-1 p24Gag protein.[12,13,14,15,16,17,23] The focus was on Gag because it has been shown that T-cell responses targeting epitopes within Gag are beneficial to control viral replication in HIV-1-infected individuals.[12,13,24,25,26,27,28,29] the simian immunodeficiency virus (SIV)/ macaque model showed that Gag-specific T-cell responses inversely correlate with both peak viral load and chronic viremia, suggesting a protective mechanism of these responses in controlling viremia.[30,31,32,33,34]

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