It is disclosed herein that heterologous antigens such as viral and bacterial expressed by cytomegalovirus vectors induce a T cell immunodominance profile that is fundamentally different from that induced by all other known vectors. While this approach was not designed to prevent infection, it proved to be highly successful in animals models of HIV/AIDS with about 50% of CMV/SIV vector-vaccinated rhesus macaques (RM) challenged with highly pathogenic SIV manifesting immediate, stringent and durable virologic control (Hansen, 2011 infra).ĭuring the course of these studies, it was observed that CMV/SIV vectors did not elicit the typical, immunodominant CD8+ T cell responses towards SIV peptides presented by the well characterized Mamu-A1*001:01 (A*01) MHC-I protein suggesting that CMV vectors induce new T cell epitopes targeted by these effective responses and that these novel responses contributed to vaccine efficacy. Although the AIDS vaccine field has endeavored to develop strategies capable of eliciting HIV/SIV-specific CD8 + T cell responses targeting “vulnerable” epitopes across diverse MHC-I haplotypes (by either increasing recognition breadth or the focusing of responses to conserved sequences), this effort has not, to date, yielded strategies capable of substantially modifying CD8 + T cell immunodominance hierarchies, nor achieved the goal of establishing protective CD8 + T cell responses in the majority of individuals.Īn HIV/AIDS vaccine strategy using a recombinant Cytomegalovirus (CMV) expressing an HIV protein has been created as a persistent vector to generate and maintain HIV-specific effector memory T cell responses that would intercept HIV infection prior to the viral amplification needed for efficient immune evasion (Picker, 2012 supra). While vaccination against these viruses can greatly augment the magnitude of CD8 + T cell responses after infection, these larger responses target many of the same immunodominant epitopes as infection of unvaccinated subjects, and therefore are still subject to immune escape (Picker, 2012 supra Barouch D H et al, J Vi(2003) Mudd P A et al, Nature 491, 129 (2012) all of which are incorporated by reference herein).
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Indeed, CD8 + T cell responses in the majority of subjects infected with these viruses fail to target epitopes containing conserved, functionally critical viral sequences, and do not effectively control viral replication (McMichael A J et al, Nat Rev Immunol 10, 11 (2010) incorporated by reference herein). The massive replication of these viruses, combined with their high rate of mutation and functional plasticity, allows escape from most CD8 + T cell responses (Picker U et al, Ann Rev Med 63, 95 (2012), incorporated by reference herein). However, this is not the case for agents with efficient immune evasion capabilities like the human immunodeficiency virus (HIV) and its simian counterpart SIV. For the vast majority of pathogens, CD8 + T cell responses targeting such immunodominant epitopes are able to both recognize pathogen-infected cells and mount effective anti-pathogen effector and memory responses. Despite the complexity of the process, pathogen-specific CD8 + T cell responses mounted by individuals with shared MHC-I alleles tend to recognize an overlapping set of so-called immunodominant epitopes (Yewdell et al 2006 supra Irvine et al, 2006 supra, Goulder P J and Watkins D I, Nat Rev Immunol 8, 619 (2008) incorporated by reference herein).
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Although pathogens can potentially generate many thousands of different peptides of the appropriate length for CD8 + T cell recognition, requirements for proteolytic processing, peptide transport, binding to available MHC-I allomorphs and TCR repertoire matching, as well as poorly understood immunoregulatory mechanisms, winnow down these candidates to a relative handful of peptide epitopes that actually serve as targets for the CD8 + T cells that comprise anti-pathogen effector and memory responses (Yewdell J W et al, Immunity 25, 533 (2006) Irvine K et al, Expert Rev Clin Immunol 2, 135 (2006) Assarsson E et al, J Immunol 178, 7890 (2007). CD8 + T cells detect intracellular pathogens by T cell receptor (TCR)-mediated recognition of short pathogen-derived peptides selected and transported to the cell surface by class I MHC proteins (MHC-I) and an exquisite system of intracellular peptide sampling and transport (Neefjies M L et al, Nat Rev Immunol 11, 823 (2011) incorporated by reference herein).