Mosaic Vaccines Elicit CD8+ T lymphocyte Responses in Monkeys that Confer Enhanced Immune Coverage of Diverse HIV Strains

An effective HIV vaccine must elicit immune responses that recognize genetically diverse viruses. It must generate CD8+ T lymphocytes that control HIV replication and CD4+ T lymphocytes that provide help for the generation and maintenance of both cellular and humoral immune responses against the virus. Creating immunogens that can elicit cellular immune responses against the genetically varied circulating isolates of HIV presents a key challenge for creating an HIV vaccine. Polyvalent mosaic immunogens derived by in silico recombination of natural strains of HIV are designed to induce cellular immune responses that recognize genetically diverse circulating virus isolates. Here we immunized rhesus monkeys by plasmid DNA prime and recombinant vaccinia virus boost with vaccine constructs expressing either consensus or polyvalent mosaic proteins. As compared to consensus immunogens, the mosaic immunogens elicited CD8+ T lymphocyte responses to more epitopes of each viral protein than did the consensus immunogens and to more variant sequences of CD8+ T lymphocyte epitopes. This increased breadth and depth of epitope recognition may contribute both to protection against infection by genetically diverse viruses and to the control of variant viruses that emerge as they mutate away from recognition by cytotoxic T lymphocytes.

[1]  D. Montefiori,et al.  Recombinant poxvirus boosting of DNA-primed rhesus monkeys augments peak but not memory T lymphocyte responses. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Norman L. Letvin,et al.  T-Cell Vaccine Strategies for Human Immunodeficiency Virus, the Virus with a Thousand Faces , 2009, Journal of Virology.

[3]  D. Barouch,et al.  Challenges in the development of an HIV-1 vaccine , 2008, Nature.

[4]  Feng Gao,et al.  Diversity Considerations in HIV-1 Vaccine Selection , 2002, Science.

[5]  James Theiler,et al.  Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants , 2007, Nature Medicine.

[6]  Bette Korber,et al.  Mosaic HIV-1 Vaccines Expand the Breadth and Depth of Cellular Immune Responses in Rhesus Monkeys , 2010, Nature Medicine.

[7]  H. Rammensee,et al.  SYFPEITHI: database for MHC ligands and peptide motifs , 1999, Immunogenetics.

[8]  Donald K Carter,et al.  HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case–cohort analysis , 2008, The Lancet.

[9]  Norman L. Letvin,et al.  Coping with Viral Diversity in HIV Vaccine Design: A Response to Nickle et al , 2008, PLoS Comput. Biol..

[10]  B. Korber,et al.  Expanded Breadth of the T-Cell Response to Mosaic Human Immunodeficiency Virus Type 1 Envelope DNA Vaccination , 2008, Journal of Virology.

[11]  G. Pialoux,et al.  [HIV vaccines]. , 2005, Presse medicale.

[12]  B. Korber,et al.  A centralized gene-based HIV-1 vaccine elicits broad cross-clade cellular immune responses in rhesus monkeys , 2008, Proceedings of the National Academy of Sciences.

[13]  T. Tree,et al.  Reconstruction of a pathway of antigen processing and class II MHC peptide capture , 2007, The EMBO journal.

[14]  S. McCormack,et al.  An HIV-1 clade C DNA prime, NYVAC boost vaccine regimen induces reliable, polyfunctional, and long-lasting T cell responses , 2008, The Journal of experimental medicine.

[15]  L Adorini,et al.  Capacity of intact proteins to bind to MHC class II molecules. , 1989, Journal of immunology.

[16]  N. Letvin.  Progress and obstacles in the development of an AIDS vaccine , 2006, Nature Reviews Immunology.

[17]  Mario Roederer,et al.  Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8+ T cell responses , 2007, The Journal of experimental medicine.

[18]  J. Heeney.  Requirement of diverse T-helper responses elicited by HIV vaccines: induction of highly targeted humoral and CTL responses , 2004, Expert review of vaccines.