title: Possible therapeutic vaccine strategy against human immunodeficiency virus escape from reverse transcriptase inhibitors studied in HLA-A2 transgenic mice.
abstract: Mutation of human immunodeficiency virus (HIV) leading to escape from anti-HIV drugs is the greatest challenge to the treatment of HIV infection. High-grade resistance to the nucleoside reverse transcriptase (RT) inhibitor lamivudine (also known as 3TC) is associated with a substitution of valine for methionine at position 184 of RT. This amino acid residue is contained within the HLA-A2-restricted epitope VIYQYMDDL (RT-WT). Here, we sought to determine whether a peptide vaccine could be developed using an epitope enhancement strategy that could induce a cytotoxic T-lymphocyte (CTL) response specific for an epitope containing the drug resistance mutation M184V to exert an opposing selective pressure. RT-WT-specific CTLs developed from HLA-A2 transgenic mice did not recognize the M184V mutation of RT-WT (RT-M184V). However, RT-M184V exhibited higher binding affinity for HLA-A2 than RT-WT. Also, both anchor-enhanced RT-WT (RT-2L9V) and RT-2L9V-M184V-specific CTLs recognized RT-M184V and displayed cross-reactivity to RT-WT. Nevertheless, the CTL repertoire elicited by the epitope-enhanced RT-2L9V-M184V appeared more selective for the RT inhibitor-induced M184V mutation. Peptide vaccines based on such strategies may be worth testing for their ability to exert selective pressure against drug-resistant strains and thus delay or prevent the development of HIV with the M184V resistance mutation.
authors.affiliation: Vaccine Branch, Center for Cancer Research, National Cancer Institute, Building 10, Room 6B-04 (MSC#1578), NIH, Bethesda, MD 20892-1578, USA.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Okazaki
authors.forename: Masaki
authors.initials: M
authors.lastname: Terabe
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Catanzaro
authors.forename: C David
authors.initials: CD
authors.lastname: Pendleton
authors.forename: Robert
authors.initials: R
authors.lastname: Yarchoan
authors.forename: Jay A
authors.initials: JA
authors.lastname: Berzofsky
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D024882:Drug Resistance, Viral / Q000235:genetics; D000939:Epitopes / Q000235:genetics; D006678:HIV / Q000187:drug effects* / Q000235:genetics*; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000276:immunology; D015789:HLA-A2 Antigen / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018448:Models, Immunological; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000939:Epitopes; D015789:HLA-A2 Antigen; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase