Acquired Immunodeficiency Syndrome: Miyazawa M

Tanaka-Takahashi Y, Yasunami M, Naruse T, Hinohara K, Matano T, Mori K, Miyazawa M, Honda M, Yasutomi Y, Nagai Y, Kimura A. · Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. · Electrophoresis. · Pubmed #17309048 No free full text.

Abstract: The rhesus macaque exhibits individual differences in susceptibility and resistance to infectious agents such as simian immunodeficiency virus (SIV) under experimental conditions, and these may be genetically determined at least in part by major histocompatibility complex (MHC) class I polymorphism. Although the importance of defining MHC class I polymorphism is well recognized, development of a generic and comprehensive molecular typing method of MHC class I alleles of the rhesus macaque has been hampered because, during the evolution of this species, multiple copies of similar DNA sequences have been generated by duplication events including the coding sequences of Mamu-A and Mamu-B loci. We report here a newly developed reference strand-mediated conformation analysis (RSCA)-based typing method of multiple Mamu-A and Mamu-B cDNAs that allowed us to estimate the number of expressed alleles. This technique detected 1-7 Mamu-A signals and 2-12 Mamu-B signals in a single sample, indicating that the number of functional alleles may vary. By comparing the data from the parents with those from the descendants in the breeding colony, several MHC class I haplotypes consisting of variable numbers of functional Mamu-A and Mamu-B alleles could be assigned.

Yamamoto H, Kawada M, Tsukamoto T, Takeda A, Igarashi H, Miyazawa M, Naruse T, Yasunami M, Kimura A, Matano T. · International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Tokyo 108-8639, Japan. · J Gen Virol. · Pubmed #17251584 links to  free full text

Abstract: The X4-tropic simian/human immunodeficiency virus (SHIV) 89.6P (or 89.6PD) causes rapid CD4(+) T-cell depletion leading to an acute crash of the host immune system, whereas pathogenic R5-tropic simian immunodeficiency virus (SIV) infection, like HIV-1 infection in humans, results in chronic disease progression in macaques. Recent pre-clinical vaccine trials inducing cytotoxic T lymphocyte (CTL) responses have succeeded in controlling replication of the former but shown difficulty in control of the latter. Analysis of the immune responses involved in consistent control of SHIV would contribute to elucidation of the mechanism for consistent control of SIV replication. This study followed up rhesus macaques that showed vaccine-based control of primary SHIV89.6PD replication and found that all of these controllers maintained viraemia control for more than 2 years. SHIV89.6PD control was observed in vaccinees of diverse major histocompatibility complex (MHC) haplotypes and was maintained without rapid selection of CTL escape mutations, a sign of particular CTL pressure. Despite the vaccine regimen not targeting Env, all of the SHIV controllers showed efficient elicitation of de novo neutralizing antibodies by 6 weeks post-challenge. These results contrast with our previous observation of particular MHC-associated control of SIV replication without involvement of neutralizing antibodies and suggest that vaccine-based control of SHIV89.6PD replication can be stably maintained in the presence of multiple functional immune effectors.

Matano T, Kobayashi M, Igarashi H, Takeda A, Nakamura H, Kano M, Sugimoto C, Mori K, Iida A, Hirata T, Hasegawa M, Yuasa T, Miyazawa M, Takahashi Y, Yasunami M, Kimura A, O'Connor DH, Watkins DI, Nagai Y. · Department of Microbiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. · J Exp Med. · Pubmed #15210746 links to  free full text

Abstract: Recently, encouraging AIDS vaccine trials in macaques have implicated cytotoxic T lymphocytes (CTLs) in the control of the simian human immunodeficiency virus SHIV89.6P that induces acute CD4(+) T cell depletion. However, none of these vaccine regimens have been successful in the containment of replication of the pathogenic simian immunodeficiency viruses (SIVs) that induce chronic disease progression. Indeed, it has remained unclear if vaccine-induced CTL can control SIV replication. Here, we show evidence suggesting that vaccine-induced CTLs control SIVmac239 replication in rhesus macaques. Eight macaques vaccinated with DNA-prime/Gag-expressing Sendai virus vector boost were challenged intravenously with SIVmac239. Five of the vaccinees controlled viral replication and had undetectable plasma viremia after 5 wk of infection. CTLs from all of these five macaques rapidly selected for escape mutations in Gag, indicating that vaccine-induced CTLs successfully contained replication of the challenge virus. Interestingly, analysis of the escape variant selected in three vaccinees that share a major histocompatibility complex class I haplotype revealed that the escape variant virus was at a replicative disadvantage compared with SIVmac239. These findings suggested that the vaccine-induced CTLs had "crippled" the challenge virus. Our results indicate that vaccine induction of highly effective CTLs can result in the containment of replication of a highly pathogenic immunodeficiency virus.