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Journal of Virology, November 2006, p. 10645-10651, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.01351-05

Possible Therapeutic Vaccine Strategy against Human Immunodeficiency Virus Escape from Reverse Transcriptase Inhibitors Studied in HLA-A2 Transgenic Mice{triangledown}

Takahiro Okazaki,1,{dagger} Masaki Terabe,1 Andrew T. Catanzaro,2,{ddagger} C. David Pendleton,1 Robert Yarchoan,2 and Jay A. Berzofsky1*

Vaccine Branch,1 HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-15782

Received 29 June 2005/ Accepted 8 August 2006

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.

* Corresponding author. Mailing address: Vaccine Branch, Center for Cancer Research, National Cancer Institute, Building 10, Room 6B-04 (MSC#1578), NIH, Bethesda, MD 20892-1578. Phone: (301) 496-6874. Fax: (301) 480-0681. E-mail: berzofsk{at}helix.nih.gov.

{triangledown} Published ahead of print on 18 August 2006.

{dagger} Present address: Division of Rheumatology and Allergy, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 216-8511, Japan.

{ddagger} Present address: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.

Journal of Virology, November 2006, p. 10645-10651, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.01351-05






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