Prediction of differential Gag versus Env responses to a mosaic HIV-1 vaccine regimen by HLA class I alleles

Author:

Nelson George W.1ORCID,van Duijn Janine2ORCID,Yuki Yuko1,Pau Maria G.2,Tomaka Frank3,Lavreys Ludo4,DeRosa Steven C.56,McElrath M. Juliana567,Kirk Gregory D.8,Michael Nelson L.9,Haas David W.10,Deeks Steven G.11,Wolinsky Steven12,Walker Bruce13,Barouch Dan H.131415ORCID,Stieh Daniel2,Carrington Mary13ORCID

Affiliation:

1. Basic Science Program Frederick National Laboratory for Cancer Research, National Cancer Institute and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA

2. Janssen Vaccines & Prevention, Leiden, the Netherlands

3. Janssen Research and Development, Titusville, New Jersey, USA

4. Janssen Infectious Diseases BV, Beerse, Belgium

5. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA

6. Division of Vaccine and Infectious Disease, Fred Hutchinson Cancer Center, Seattle, Washington, USA

7. Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA

8. Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA

9. US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA

10. Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

11. Department of Medicine, University of California, San Francisco, California, USA

12. Division of Infectious Diseases, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

13. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA

14. Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

15. Harvard Medical School, Boston, Massachusetts, USA

Abstract

ABSTRACT HLA class I variation has the strongest effect genome-wide on outcome after HIV infection, and as such, an understanding of the impact of HLA polymorphism on response to HIV vaccination may inform vaccine design. We sought HLA associations with HIV-directed immunogenicity in the phase 1/2a APPROACH vaccine trial, which tested vaccine regimens containing mosaic inserts in Ad26 and MVA vectors, with or without a trimeric gp140 protein. While there were no HLA allelic associations with the overall cellular immune response to the vaccine assessed by ELISpot (Gag, Pol, and Env combined), significant associations with differential response to Gag compared to Env antigens were observed. Notably, HLA class I alleles known to associate with disease susceptibility in HIV natural history cohorts are associated with stronger Env-directed responses, whereas protective alleles are associated with stronger Gag-directed responses. Mean viral loads determined for each HLA allele in untreated individuals correlated negatively with the strength of the Gag response minus the Env response in Black vaccinees based on both ELISpot and CD8 + T cell ICS responses. As the association of T cell responses to conserved Gag epitopes with lower viral load in untreated individuals is well established, our data raise the possibility that the Ad26.Mos.HIV vaccine may induce more effective cellular responses in those with HLA alleles that confer improved virologic control in untreated HIV infection. IMPORTANCE No vaccine tested to date has shown sufficient efficacy against HIV infection. A vaccine that induces robust responses in one individual may fail to do so in another individual due to variation in HLA class I genes, loci central to the immune response. Extensive data have shown the strong effect of HLA variation on outcome after HIV infection, but very little is known about the effect of such variation on HIV vaccine success. Here, we identify a link between the effect of HLA variation on HIV disease outcome and immune responses to an HIV vaccine. HLA variants associated with better HIV control after infection also induce stronger responses against the HIV Gag protein relative to the Env protein after vaccination. Given the virologic control conferred by responses to Gag in natural history of HIV infection, these data suggest that HLA alleles conferring protection after HIV infection may also support a more effective cellular response to HIV vaccination.

Funder

Frederick National Laboratory for Cancer Research

Publisher

American Society for Microbiology

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