Impact of human leukocyte antigen-B*51-restricted cytotoxic T-lymphocyte pressure on mutation patterns of nonnucleoside reverse transcriptase inhibitor resistance. 2010

Hiroyuki Gatanaga, and Hirotaka Ode, and Atsuko Hachiya, and Tsunefusa Hayashida, and Hironori Sato, and Masafumi Takiguchi, and Shinichi Oka
AIDS Clinical Center, International Medical Center of Japan, Tokyo, Japan. higatana@imcj.acc.go.jp

OBJECTIVE The objective of this study is to determine the impact of human leukocyte antigen (HLA)-B*51-restricted cytotoxic T-lymphocyte (CTL) pressure on the development of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance. METHODS The prevalence of HIV-1 harboring an escape mutation, I135X, in a major epitope of HLA-B*51-restricted CTL located in reverse transcriptase is increasing worldwide. We analyzed the effects of escape mutations on the emerging mutation patterns of NNRTI resistance. METHODS Monoclonal HIV-1 sequences harboring each of the escape mutations, including I135L (HIV-1I135L), I135V (HIV-1I135V), I135T (HIV-1I135T), and I135R (HIV-1I135R) in reverse transcriptase, and a wild-type monoclonal HIV-1 (HIV-1WT) were cultured in the presence of increasing concentrations of efavirenz. Induced mutations during culture passages of the culture were analyzed. RESULTS E138K emerged during the cultural passages of HIV-1I135V, HIV-1I135T, and HIV-1I135R, but not during the passages of HIV-1WT. The combination of I135T, the most frequent escape mutation, and E138K (HIV-1I135T/E138K) conferred significant resistance to efavirenz, nevirapine, and etravirine. The HIV-1I135L/E138K and HIV-1I135R/E138K were significantly resistant to nevirapine and etravirine, respectively, though each solo of escape mutations and E138K did not confer significant resistance to NNRTI. Computational analysis indicated that I135T and E138K cooperatively extend the gap between the binding site of reverse transcriptase and NNRTI. CONCLUSIONS HLA-B*51-restricted CTL can induce novel mutation patterns of NNRTI resistance by selecting escape mutations. The spread of CTL escape variants may alter the mutation patterns of drug resistance.

UI MeSH Term Description Entries
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D013602 T-Lymphocytes, Cytotoxic Immunized T-lymphocytes which can directly destroy appropriate target cells. These cytotoxic lymphocytes may be generated in vitro in mixed lymphocyte cultures (MLC), in vivo during a graft-versus-host (GVH) reaction, or after immunization with an allograft, tumor cell or virally transformed or chemically modified target cell. The lytic phenomenon is sometimes referred to as cell-mediated lympholysis (CML). These CD8-positive cells are distinct from NATURAL KILLER CELLS and NATURAL KILLER T-CELLS. There are two effector phenotypes: TC1 and TC2. Cell-Mediated Lympholytic Cells,Cytotoxic T Cells,Cytotoxic T Lymphocyte,Cytotoxic T-Lymphocytes,TC1 Cell,TC1 Cells,TC2 Cell,TC2 Cells,Cell Mediated Lympholytic Cells,Cell, Cell-Mediated Lympholytic,Cell, TC1,Cell, TC2,Cell-Mediated Lympholytic Cell,Cytotoxic T Cell,Cytotoxic T Lymphocytes,Cytotoxic T-Lymphocyte,Lymphocyte, Cytotoxic T,Lympholytic Cell, Cell-Mediated,Lympholytic Cells, Cell-Mediated,T Cell, Cytotoxic,T Lymphocyte, Cytotoxic,T Lymphocytes, Cytotoxic,T-Lymphocyte, Cytotoxic
D015235 HLA-B Antigens Class I human histocompatibility (HLA) surface antigens encoded by more than 30 detectable alleles on locus B of the HLA complex, the most polymorphic of all the HLA specificities. Several of these antigens (e.g., HLA-B27, -B7, -B8) are strongly associated with predisposition to rheumatoid and other autoimmune disorders. Like other class I HLA determinants, they are involved in the cellular immune reactivity of cytolytic T lymphocytes. Antigens, HLA-B,HLA-B Antigen,HLA-B,Antigen, HLA-B,Antigens, HLA B,HLA B Antigen,HLA B Antigens
D015497 HIV-1 The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. Human immunodeficiency virus 1,HIV-I,Human Immunodeficiency Virus Type 1,Immunodeficiency Virus Type 1, Human
D015658 HIV Infections Includes the spectrum of human immunodeficiency virus infections that range from asymptomatic seropositivity, thru AIDS-related complex (ARC), to acquired immunodeficiency syndrome (AIDS). HTLV-III Infections,HTLV-III-LAV Infections,T-Lymphotropic Virus Type III Infections, Human,HIV Coinfection,Coinfection, HIV,Coinfections, HIV,HIV Coinfections,HIV Infection,HTLV III Infections,HTLV III LAV Infections,HTLV-III Infection,HTLV-III-LAV Infection,Infection, HIV,Infection, HTLV-III,Infection, HTLV-III-LAV,Infections, HIV,Infections, HTLV-III,Infections, HTLV-III-LAV,T Lymphotropic Virus Type III Infections, Human
D016056 Immunodominant Epitopes Subunits of the antigenic determinant that are most easily recognized by the immune system and thus most influence the specificity of the induced antibody. Antigenic Determinants, Immunodominant,Antigens, Immunodominant,Epitopes, Immunodominant,Immunodominant Determinant,Immunodominant Domain,Immunodominant Epitope,Immunodominant Region,Immunodominant Site,Immunodominant Determinants,Immunodominant Domains,Immunodominant Regions,Immunodominant Sites,Determinant, Immunodominant,Determinants, Immunodominant,Determinants, Immunodominant Antigenic,Domain, Immunodominant,Domains, Immunodominant,Epitope, Immunodominant,Immunodominant Antigenic Determinants,Immunodominant Antigens,Region, Immunodominant,Regions, Immunodominant,Site, Immunodominant,Sites, Immunodominant
D057131 Immune Evasion Methods used by pathogenic organisms to evade a host's immune system. Evasion, Immune,Evasions, Immune,Immune Evasions
D018894 Reverse Transcriptase Inhibitors Inhibitors of reverse transcriptase (RNA-DIRECTED DNA POLYMERASE), an enzyme that synthesizes DNA on an RNA template. Reverse Transcriptase Inhibitor,Inhibitors, Reverse Transcriptase,Inhibitor, Reverse Transcriptase,Transcriptase Inhibitor, Reverse

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