Acquired Immunodeficiency Syndrome: Ueno T

Ueno T, Sakai H. · Laboratory of Gene Analysis, Department of Viral Oncology, Institute for Virus Research, Kyoto University. · Nippon Rinsho. · Pubmed #11968772 No free full text.

Abstract: Human immunodeficiency virus type 1 (HIV-1) has 4 auxiliary genes, vpr, vpu, nef, and vif, which are dispensable for viral replication in vitro. However, many studies with animal model revealed that these genes play important roles on the viral replication and the development of AIDS in vivo through many complicated mechanisms. Although several key factors involved in the function have been identified, further studies are required for the complete understandings of the action mechanisms. The elucidation of the function of the auxiliary genes on molecular bases leads to the discovery of new therapeutic strategies against HIV and the understanding of basic cellular mechanisms. In this review, we summarize new observations mainly about the interactions between auxiliary genes and host cell functions.

Humphrey RW, Wyvill KM, Nguyen BY, Shay LE, Kohler DR, Steinberg SM, Ueno T, Fukasawa T, Shintani M, Hayashi H, Mitsuya H, Yarchoan R. · HIV and AIDS Malignancy Branch, Division of Clinical Sciences, National Cancer Institute, NIH, Bethesda, MD 20892, USA. · Antiviral Res. · Pubmed #10321576 No free full text.

Abstract: The pharmacokinetics, toxicity, and activity of KNI-272, a transition state inhibitor of HIV-1 protease, was assessed in a phase I trial. After an initial phase in which the pharmacokinetics were assessed, 37 patients with AIDS or symptomatic HIV infection and 100-400 CD4 cells/mm3 were entered in an escalating dose study. KNI-272 was administered four times daily for up to 12 weeks. Oral bioavailability ranged from 22 to 55% and was not appreciably different in the fasting and post-prandial state. The dose limiting toxicity was hepatic transaminase elevation; this could be reduced by escalating the dose over 4 weeks. When administered this way, the maximum tolerated oral dose was 40 mg/kg per day. At the highest two tolerated doses (26.4 and 40 mg/kg per day), there was some evidence of an anti-HIV effect with median decreases of 0.2-0.3 log10 copies/ml plasma HIV RNA; these decreases persisted through 7-8 weeks of treatment. There was an upward trend in the CD4 count at the 40 mg/kg per day dose but not at other doses. Additional studies focused on approaches to improve the therapeutic index of KNI-272 may be warranted.

Ueno T, Mitsuishi T, Kimura Y, Kato T, Hasegawa H, Katano H, Sata T, Kurane S, Kawana S. · Department of Dermatology, Nippon Medical School, Tokyo, Japan. · Eur J Dermatol. · Pubmed #17951139 links to  free full text

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Iwatani Y, Kawano K, Ueno T, Tanaka M, Ishimoto A, Ito M, Sakai H. · Department of Microbiology, Yamanashi Medical University, Tamaho-cho, Yamanashi, 409-3898, Japan. · Virology. · Pubmed #11448157 No free full text.

Abstract: The Env protein of human immunodeficiency virus type 1 is assembled into a stable trimer, and oligomerization is required for maintenance of viral infectivity. This property of Env suggests that Env mutants may have a dominant-negative effect on virus infectivity. To investigate this possibility, we established a packaging cell line in which both wild-type and mutant Env proteins could be expressed simultaneously in a single cell. We analyzed the effects of two types of Env mutants: cytoplasmic tail-truncated TM mutants and a mutant defective in gp120/gp41 cleavage. The cytoplasmic tail-truncated proteins were found to be incorporated into virions by forming an oligomer with wild-type TM, but could not inhibit the wild-type function. In contrast, phenotypic mixing of cleavage-defective Env with the wild-type protein caused dramatic inhibition of infectivity, indicating that this mutant has a strong dominant-negative phenotype.