Acquired Immunodeficiency Syndrome: Yoshimura K

Tamiya S, Mardy S, Kavlick MF, Yoshimura K, Mistuya H. · Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer, Institute, Center for Cancer Research, National Institutes of Health, Bldg. 10, Rm. 5A11, 9000 Rockville Pike, Bethesda, MD 20892, USA. · J Virol. · Pubmed #15479842 links to  free full text

Abstract: A variety of amino acid substitutions in the protease and Gag proteins have been reported to contribute to the development of human immunodeficiency virus type 1 (HIV-1) resistance to protease inhibitors. In the present study, full-length molecular infectious HIV-1 clones were generated by using HIV-1 variants isolated from heavily drug-experienced and therapy-failed AIDS patients. Of six full-length infectious clones generated, four were found to have unique insertions (TGNS, SQVN, AQQA, SRPE, APP, and/or PTAPPA) near the p17/p24 and p1/p6 Gag cleavage sites, in addition to the known resistance-related multiple amino acid substitutions within the protease. The addition of such Gag inserts mostly compromised the replication of wild-type HIV-1, whereas the primary multidrug-resistant HIV infectious clones containing inserts replicated significantly better than those modified to lack the inserts. Western blot analyses revealed that the processing of Gag proteins by wild-type protease was impaired by the presence of the inserts, whereas that by mutant protease was substantially improved. The present study represents the first report clearly demonstrating that the inserts seen in the proximity of the Gag cleavage sites in highly multi-PI resistant HIV-1 variants restore the otherwise compromised enzymatic activity of mutant protease, enabling the multi-PI-resistant HIV-1 variants to remain replication competent.

Ryo A, Tsurutani N, Ohba K, Kimura R, Komano J, Nishi M, Soeda H, Hattori S, Perrem K, Yamamoto M, Chiba J, Mimaya J, Yoshimura K, Matsushita S, Honda M, Yoshimura A, Sawasaki T, Aoki I, Morikawa Y, Yamamoto N. · Department of Pathology, Yokohama City University School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan. · Proc Natl Acad Sci U S A. · Pubmed #18172216 links to  free full text

Abstract: Human immunodeficiency virus type 1 (HIV-1) utilizes the macromolecular machinery of the infected host cell to produce progeny virus. The discovery of cellular factors that participate in HIV-1 replication pathways has provided further insight into the molecular basis of virus-host cell interactions. Here, we report that the suppressor of cytokine signaling 1 (SOCS1) is an inducible host factor during HIV-1 infection and regulates the late stages of the HIV-1 replication pathway. SOCS1 can directly bind to the matrix and nucleocapsid regions of the HIV-1 p55 Gag polyprotein and enhance its stability and trafficking, resulting in the efficient production of HIV-1 particles via an IFN signaling-independent mechanism. The depletion of SOCS1 by siRNA reduces both the targeted trafficking and assembly of HIV-1 Gag, resulting in its accumulation as perinuclear solid aggregates that are eventually subjected to lysosomal degradation. These results together indicate that SOCS1 is a crucial host factor that regulates the intracellular dynamism of HIV-1 Gag and could therefore be a potential new therapeutic target for AIDS and its related disorders.

Nakayama EE, Carpentier W, Costagliola D, Shioda T, Iwamoto A, Debre P, Yoshimura K, Autran B, Matsushita S, Theodorou I. · Department of Viral Infections, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita-shi, Osaka, Japan. · Immunogenetics. · Pubmed #17406861 No free full text.

Abstract: Polymorphisms in human genes have been shown to affect the rate of disease progression to acquired immune deficiency syndrome in human immunodeficiency virus type 1 (HIV-1)-infected individuals. Recently, tripartite motif 5alpha (TRIM5alpha) was identified as a factor that confers resistance to HIV-1 infection in Old World monkey cells. Subsequently, Sawyer et al. (Curr Biol 16:95-100, 2006) reported a single nucleotide polymorphism (H43Y) in the human TRIM5alpha gene and TRIM5alpha protein with 43Y was found to lose its ability to restrict HIV-1. In the present study, we reevaluated effects of this allele on in vitro anti-HIV-1 activity as well as on HIV-1 disease progression in European and Asian cohorts of HIV-1-infected individuals. Our epidemiological and molecular biological findings clearly indicate H43Y has a very minor effect on anti-HIV-1 activity of TRIM5alpha, suggesting that this allele is immaterial, at least in HIV-1-infected Europeans and Asians.

Yoshimura K, Ido E, Akiyama H, Kimura T, Aoki M, Suzuki H, Mitsuya H, Hayami M, Matsushita S. · Division of Clinical Retrovirology and Infectious Diseases, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto, 860-0811, Japan. · J Virol Methods. · Pubmed #12951220 No free full text.

Abstract: The objective of this study was to assess the impact of highly active antiretroviral therapy (HAART) by an oral route on the peripheral blood CD8 subset in the monkeys infected persistently with a pathogenic strain, SHIV(89.6P). Two rhesus macaques were inoculated intravenously with SHIV(89.6P), then treated with the combination of AZT, 3TC and Lopinavir/Ritonavir (LPV/RTV) as recommended in humans by the oral route with confectionery continued for 28 days. In one of two chronically infected macaques, MM260, the viral load was maintained in the range of 10(4)-10(5) copies/ml before HAART. The plasma viral load and proviral DNA decreased dramatically during the treatment, and cessation of this therapy the viral load rebounded to the pre-treatment level but the proviral DNA rebound was delayed. The other monkey, MM242, had low viral loads (1.2x10(3)-<5x10(2) copies/ml) both before and after HAART. CD4(+) and CD8(+) T cell counts and proviral DNA level were not significantly changed after the treatment. The percentages of CD8(+)CD45RA(-)Ki67(+)cells increased during (MM260) or after (MM242) HAART and the subset was maintained at a high percentage until 18 weeks post HAART in MM242. These findings suggest that this primate model might serve an important role in testing the virological and immunological efficacy of novel therapeutic strategies combined with HAART.