Introduction

This laboratory joined in the cooperative graduate school system, as an "affiliated laboratory" of the Nagoya University Graduate School of Medicine in 2009. Our laboratory is located at Clinical Research Center, National Hospital Organization Nagoya Medical Center. The research center was inaugurated on May 1st. 1976 in the National Hospital Organization, Nagoya Medical Center at Naka-ku, Nagoya city near Nagoya Castle, and consists of 5 departments (Advanced Diagnosis, Regenerative Medicine, Clinical Research Promotion, Hematology and Oncology Research, and Infectious Diseases and Immunology). Our research group, department of "Infectious Diseases and Immunology", investigates on basic and clinical sciences for human immunodeficiency viruses (HIV) and the related pathogen-infectious diseases "from bench top through bed side.
In Japan, more than 1,000 people per year are newly diagnosed with HIV at present, and unfortunately, the incidence is still increasing, particularly around Nagoya area. Recent therapies using combinations of anti-HIV drugs have improved the disease progression of the HIV-infected people. However, since the drug therapies must be under the long-term control, we must consider the presumable problem facing the appearance and development of resistance in the virus. To avoid such problem, it is quite requisite to understand how the virus develops resistance to anti-HIV drugs, to survey how such drug-resistant viruses spread in Japan epidemiologically, and to develop more effective strategies for treating HIV infection. Therefore, our research team devotes all the efforts to investigate the fundamental studies by setting up the following five specific projects; 1) Epidemiological survey of drug-resistant HIV in Japan, collaborating with prefectural and municipal public health institutes, National Institutes of Infectious Diseases, and universities. 2) Analysis of molecular/structure-biological mechanism for drug-resistant viruses, 3) Development of anti-HIV compounds having novel targets, 4) Epidemiological and genetical investigations of infectious pathogens related to HIV infection, such as Hepatitis B, C viruses. 5) Analysis of molecular mechanism on anti-HIV factors derived from the host, such as APOBEC3 family, and the application/development for new anti-HIV therapies.

Research Projects

1. Epidemiological Investigation of Drug-resistant HIV in Japan

The emergence and transmission of drug-resistant HIV-1 compromise anti-retroviral treatment for HIV-1. Thus, testing for drug resistance is recommended at diagnosis and before initiating combination Antiretroviral therapy (cART). Our group has been conducting an epidemiological survey enrolling newly diagnosed patients since 2003 in collaboration with our nationwide surveillance network. Since 2012, we have also introduced genotypic tests for HIV-1 integrase inhibitor resistance. Recent prevalence of drug-resistant HIV-1 among 7,506 patients, consisting mainly of Japanese men in their late-30s and infected through male-to-male sexual contacts, has been in a constant level, around 8% in 2015 (Figure 1). The predictive factor for drug-resistant HIV-1 transmission was subtype B and those for recent HIV-1 infection were male gender, MSM behavior, Japanese nationality, and subtype B. Our surveillance studies will help raising awareness of the risks of HIV-1 infection as well as understanding trends of the HIV-1 epidemic in Japan.

2. Analysis of Molecular Mechanism for Anti-HIV and Retroviral Host Factors

Human APOBEC3 proteins are cellular cytidine deaminases that potently restrict the replication of retroviruses by hypermutating viral cDNA and/or inhibiting reverse transcription. There are seven members of this family including APOBEC3A, B, C, D, F, G, and H, all encoded in a tandem array on human chromosome 22. APOBEC3F, G, and H are the most potent inhibitors of HIV-1, but only in the absence of the virus-encoded protein, Vif. HIV-1 utilizes Vif to abrogate APOBEC3 functions in the producer cells. More specifically, Vif, serving as a substrate receptor, facilitates ubiquitination of APOBEC3 proteins by forming a Cullin5-based E3 ubiquitin ligase complex, which targets APOBEC3 proteins for rapid proteasomal degradation. Our group investigates on the molecular mechanisms of the APOBEC3-mediated antiviral activity and of the Vif-mediated antagonism against APOBEC3. In addition, we are exploring novel strategies aiming at disrupting the APOBEC3-Vif interactions (Figure 2) to develop new antiviral inhibitors utilizing potential endogenous inhibitors against HIV-1.

Faculty Members

Faculty	Position	Department
IWATANI Yasumasa	Professor	AIDS Research

Bibliography

• 2016

  1. Tsuzuki Y, Watanabe T, Iio E, Fujisaki S, Ibe S, Kani S, Hamada-Tsutsumi S, Yokomaku Y, Iwatani Y, Sugiura W, Okuse C, Okumura A, Sato Y and Tanaka Y. Virological characteristics of hepatitis B genotype G/A2 recombination virus in Japan. Hepatol Res, 2016; 46: 775-783.
  2. Ogawa S, Hachiya A, Hosaka M, Matsuda M, Ode H, Shigemi U, Okazaki R, Sadamasu K, Nagashima M, Toyokawa T, Tateyama M, Tanaka Y, Sugiura W, Yokomaku Y and Iwatani Y. A Novel Drug-Resistant HIV-1 Circulating Recombinant Form CRF76_01B Identified by 1Near Full-Length Genome Analysis. AIDS Res Hum Retroviruses, 2016; 32: 284-289.
  3. Nomaguchi M, Doi N, Sakai Y, Ode H, Iwatani Y, Ueno T, Matsumoto Y, Miyazaki Y, Masuda T and Adachi A. Natural Single-Nucleotide Variations in the HIV-1 Genomic SA1prox Region Can Alter Viral Replication Ability by Regulating Vif Expression Levels. J Virol, 2016; 90: 4563-4578.
  4. Nakashima M, Ode H, Suzuki K, Fujino M, Maejima M, Kimura Y, Masaoka T, Hattori J, Matsuda M, Hachiya A, Yokomaku Y, Suzuki A, Watanabe N, Sugiura W and Iwatani Y. Unique Flap Conformation in an HIV-1 Protease with High-Level Darunavir Resistance. Front Microbiol, 2016; 7: 61.
  5. Nakamura N, Kobayashi S, Minagawa H, Matsushita T, Sugiura W and Iwatani Y. Molecular epidemiology of enteric viruses in patients with acute gastroenteritis in Aichi prefecture, Japan, 2008/09-2013/14. J Med Virol, 2016; 88: 1180-1186.
  6. Inoue N, Watanabe M, Ishido N, Kodu A, Maruoka H, Katsumata Y, Hidaka Y and Iwatani Y. Involvement of genes encoding apoptosis regulatory factors (FAS, FASL, TRAIL, BCL2, TNFR1 and TNFR2) in the pathogenesis of autoimmune thyroid diseases. Hum Immunol, 2016; 77: 944-951.
  7. Hosaka M, Fujisaki S, Masakane A, Hattori J, Shiino T, Gatanaga H, Shigemi U, Okazaki R, Hachiya A, Matsuda M, Ibe S, Iwatani Y, Yokomaku Y, Sugiura W and Japanese Drug Resistance HIVSNT. HIV-1 CRF01_AE and Subtype B Transmission Networks Crossover: A New AE/B Recombinant Identified in Japan. AIDS Res Hum Retroviruses, 2016; 32: 412-419.
  8. Baudi I, Iijima S, Chin'ombe N, Mtapuri-Zinyowera S, Murakami S, Isogawa M, Hachiya A, Iwatani Y and Tanaka Y. Molecular epidemiology of co-infection with hepatitis B virus and human immunodeficiency virus (HIV) among adult patients in Harare, Zimbabwe. J Med Virol, 2016.

• 2015

  1. Sakurai D, Iwatani Y, Ohtani H, Naruse TK, Terunuma H, Sugiura W and Kimura A. APOBEC3H polymorphisms associated with the susceptibility to HIV-1 infection and AIDS progression in Japanese. Immunogenetics, 2015; 67: 253-257.
  2. Ode H, Matsuda M, Matsuoka K, Hachiya A, Hattori J, Kito Y, Yokomaku Y, Iwatani Y and Sugiura W. Quasispecies Analyses of the HIV-1 Near-full-length Genome With Illumina MiSeq. Front Microbiol, 2015; 6: 1258.
  3. Mitra M, Singer D, Mano Y, Hritz J, Nam G, Gorelick RJ, Byeon IJ, Gronenborn AM, Iwatani Y and Levin JG. Sequence and structural determinants of human APOBEC3H deaminase and anti-HIV-1 activities. Retrovirology, 2015; 12: 3.
  4. Matsunaga S, Masaoka T, Sawasaki T, Morishita R, Iwatani Y, Tatsumi M, Endo Y, Yamamoto N, Sugiura W and Ryo A. A cell-free enzymatic activity assay for the evaluation of HIV-1 drug resistance to protease inhibitors. Front Microbiol, 2015; 6: 1220.
  5. Hachiya A, Ode H, Matsuda M, Kito Y, Shigemi U, Matsuoka K, Imamura J, Yokomaku Y, Iwatani Y and Sugiura W. Natural polymorphism S119R of HIV-1 integrase enhances primary INSTI resistance. Antiviral Res, 2015; 119: 84-88.
  6. Ciftci HI, Fujino H, Koga R, Yamamoto M, Kawamura S, Tateishi H, Iwatani Y, Otsuka M and Fujita M. Mutational analysis of HIV-2 Vpx shows that proline residue 109 in the poly-proline motif regulates degradation of SAMHD1. FEBS Lett, 2015; 589: 1505-1514.

• 2014

  1. Shiino T, Hattori J, Yokomaku Y, Iwatani Y, Sugiura W and Japanese Drug Resistance HIVSN. Phylodynamic analysis reveals CRF01_AE dissemination between Japan and neighboring Asian countries and the role of intravenous drug use in transmission. PLoS One, 2014; 9: e102633.
  2. Miyake A, Fujita M, Fujino H, Koga R, Kawamura S, Otsuka M, Ode H, Iwatani Y, Sakai Y, Doi N, Nomaguchi M, Adachi A and Miyazaki Y. Poly-proline motif in HIV-2 Vpx is critical for its efficient translation. J Gen Virol, 2014; 95: 179-189.
  3. Imahashi M, Izumi T, Watanabe D, Imamura J, Matsuoka K, Ode H, Masaoka T, Sato K, Kaneko N, Ichikawa S, Koyanagi Y, Takaori-Kondo A, Utsumi M, Yokomaku Y, Shirasaka T, Sugiura W, Iwatani Y and Naoe T. Lack of Association between Intact/Deletion Polymorphisms of the APOBEC3B Gene and HIV-1 Risk. PLoS One, 2014; 9: e92861.
  4. Chaurasiya KR, McCauley MJ, Wang W, Qualley DF, Wu T, Kitamura S, Geertsema H, Chan DS, Hertz A, Iwatani Y, Levin JG, Musier-Forsyth K, Rouzina I and Williams MC. Oligomerization transforms human APOBEC3G from an efficient enzyme to a slowly dissociating nucleic acid-binding protein. Nature Chemistry, 2014; 6: 28-33.

• 2013

  1. Tu E, Swenson LC, Land S, Pett S, Emery S, Marks K, Kelleher AD, Kaye S, Kaiser R, Schuelter E and Harrigan R. Results of external quality assessment for proviral DNA testing of HIV tropism in the Maraviroc Switch collaborative study. Journal of Clinical Microbiology, 2013; 51: 2063-2071.
  2. Saito A, Nomaguchi M, Kono K, Iwatani Y, Yokoyama M, Yasutomi Y, Sato H, Shioda T, Sugiura W, Matano T, Adachi A, Nakayama EE and Akari H. TRIM5 genotypes in cynomolgus monkeys primarily influence inter-individual diversity in susceptibility to monkey-tropic human immunodeficiency virus type 1. Journal of General Virology, 2013; 94: 1318-1324.
  3. Nomaguchi M, Yokoyama M, Kono K, Nakayama EE, Shioda T, Doi N, Fujiwara S, Saito A, Akari H, Miyakawa K, Ryo A, Ode H, Iwatani Y, Miura T, Igarashi T, Sato H and Adachi A. Generation of rhesus macaque-tropic HIV-1 clones that are resistant to major anti-HIV-1 restriction factors. Journal of Virology, 2013.
  4. Jahanbakhsh F, Ibe S, Hattori J, Monavari SH, Matsuda M, Maejima M, Iwatani Y, Memarnejadian A, Keyvani H, Azadmanesh K and Sugiura W. Molecular epidemiology of HIV type 1 infection in Iran: genomic evidence of CRF35_AD predominance and CRF01_AE infection among individuals associated with injection drug use. AIDS Research and Human Retroviruses, 2013; 29: 198-203.
  5. Hergott CB, Mitra M, Guo J, Wu T, Miller JT, Iwatani Y, Gorelick RJ and Levin JG. Zinc finger function of HIV-1 nucleocapsid protein is required for removal of 5'-terminal genomic RNA fragments: a paradigm for RNA removal reactions in HIV-1 reverse transcription. Virus Research, 2013; 171: 346-355.

• 2012

  1. Li J, Hakata Y, Takeda E, Liu Q, Iwatani Y, Kozak CA and Miyazawa M. Two genetic determinants acquired late in mus evolution regulate the inclusion of exon 5, which alters mouse APOBEC3 translation efficiency. PLoS Pathogens, 2012; 8: e1002478.
  2. Kitamura S, Ode H, Nakashima M, Imahashi M, Naganawa Y, Kurosawa T, Yokomaku Y, Yamane T, Watanabe N, Suzuki A, Sugiura W and Iwatani Y. The APOBEC3C crystal structure and the interface for HIV-1 Vif binding. Nature Structural & Molecular Biology, 2012; 19: 1005-1010.
  3. Imahashi M, Nakashima M and Iwatani Y. Antiviral Mechanism and Biochemical Basis of the Human APOBEC3 Family. Frontiers in Microbiology, 2012; 3: 250.
  4. Fujisaki S, Yokomaku Y, Shiino T, Koibuchi T, Hattori J, Ibe S, Iwatani Y, Iwamoto A, Shirasaka T, Hamaguchi M and Sugiura W. Outbreak of infections by hepatitis B virus genotype A and transmission of genetic drug resistance in patients coinfected with HIV-1 in Japan. Journal of Clinical Microbiology, 2012; 49: 1017-1024.
  5. Bunupuradah T, Imahashi M, Iampornsin T, Matsuoka K, Iwatani Y, Puthanakit T, Ananworanich J, Sophonphan J, Mahanontharit A, Naoe T, Vonthanak S, Phanuphak P and Sugiura W. Association of APOBEC3G genotypes and CD4 decline in Thai and Cambodian HIV-infected children with moderate immune deficiency. AIDS Research and Therapy, 2012; 9: 34.

Research Keywords

AIDS、 HIV、 Infectious Diseases、 Virus、 Drug Resistance、 Drug Discovery、 APOBEC3、 Cellular Defense Factors、 Anti-viral

Others

We are interested in “epidemiology, retrovirology, structure biology, and basic sciences in HIV/AIDS and the related pathogens”. Our mission is to provide graduate students with the highest quality of research environment, and thereby to educate them to be scientists who can contribute international medical sciences. We welcome interested students with various backgrounds in the research major for their graduations. We hope many students to join in our group and to enjoy the research projects.You can access our lab web site (http://www.nnh.go.jp/en/crc/infectious_diseases/).