title: Impact of antiretroviral pressure on selection of primary human immunodeficiency virus type 1 envelope sequences in vitro.
abstract: The initiation of drug therapy results in a reduction in the human immunodeficiency virus type 1 (HIV-1) population, which represents a potential genetic bottleneck. The effect of this drug-induced genetic bottleneck on the population dynamics of the envelope (Env) regions has been addressed in several in vivo studies. However, it is difficult to investigate the effect on the env gene of the genetic bottleneck induced not only by entry inhibitors but also by non-entry inhibitors, particularly in vivo. Therefore, this study used an in vitro selection system using unique bulk primary isolates established in the laboratory to observe the effects of the antiretroviral drug-induced bottleneck on the integrase and env genes. Env diversity was decreased significantly in one primary isolate [KP-1, harbouring both CXCR4 (X4)- and CCR5 (R5)-tropic variants] when passaged in the presence or absence of raltegravir (RAL) during in vitro selection. Furthermore, the RAL-selected KP-1 variant had a completely different Env sequence from that in the passage control (particularly evident in the gp120, V1/V2 and V4-loop regions), and a different number of potential N-glycosylation sites. A similar pattern was also observed in other primary isolates when using different classes of drugs. This is the first study to explore the influence of anti-HIV drugs on bottlenecks in bulk primary HIV isolates with highly diverse Env sequences using in vitro selection.
authors.affiliation: AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.|Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Harada
authors.affiliation: AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.|Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Yamaguchi
authors.affiliation: AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.|Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
authors.forename: Samatchaya
authors.initials: S
authors.lastname: Boonchawalit
authors.affiliation: Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, 1-18-1 Kami-youga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yusa
authors.affiliation: Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
authors.forename: Shuzo
authors.initials: S
authors.lastname: Matsushita
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001483:Base Sequence; D003510:Cyclohexanes / Q000494:pharmacology; D004279:DNA, Viral / Q000737:chemistry / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006031:Glycosylation; D015699:HIV Envelope Protein gp120 / Q000235:genetics*; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D000077592:Maraviroc; D008969:Molecular Sequence Data; D010802:Phylogeny; D011760:Pyrrolidinones / Q000494:pharmacology; D000068898:Raltegravir Potassium; D019713:Receptors, CCR5 / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics; D019258:Saquinavir / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D014230:Triazoles / Q000494:pharmacology; D056189:Viral Tropism
chemical_list: D019380:Anti-HIV Agents; D003510:Cyclohexanes; D004279:DNA, Viral; D015699:HIV Envelope Protein gp120; D011760:Pyrrolidinones; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D014230:Triazoles; D019259:Lamivudine; D000068898:Raltegravir Potassium; D019258:Saquinavir; D000077592:Maraviroc