Research

Studies on host factors related to HIV infection

The Project Leader's Profile

Tatsuo Shioda

Department of Viral Infections. Research Institute for Microbial Diseases, Professor

Project Leader
  • Tatsuo Shioda, D.Med.Sc. Professor
Research Members
  • Jun-ichi Sakuragi, D.Med.Sc. Assistant professor
  • Emi E. Nakayama, M.D., D.Med.Sc. Assistant professor   
  • Sayuri Sakuragi, D.Med.Sc. Research Associate

Summary

The main focus in this department is to elucidate the molecular mechanisms of viral diseases.  For this purpose, we analyze the viral and host factors that affect the replication and pathogenesis of human immunodeficiency virus (HIV).  The following projects are currently underway in our laboratory.

(1) Host factors in HIV replication.
HIV does not establish a productive infection in any other monkey except for the chimpanzee; this is thought to be due to an inhibitor in simian lymphocytes that acts at the early stage (reverse transcription) of viral infection.  We aim to identify the HIV-RIF (resistance inducing factor) in the simian genome by in vitro experimentation.  To date, TRIM5α and cyclophilin A were identified as RIFs. TRIM5α recognizes the multimerized capsid (core) of incoming viruses and is believed to be involved in innate immunity to control retroviral infection. TRIM5α carries RING domain that was frequently found in E3 ubiquitin ligases and was shown to degrade HIV core via ubiquitin-proteasome pathway. In addition, we have identified an RING-independent pathway of HIV core destruction (Figure). Once all the RIFs in monkey cells have been identified, it would then be possible to establish an animal model for experimental AIDS.  This would greatly facilitate the development of a vaccine against AIDS and would help determine new targets for AIDS treatment.
 
(2) Human genome study on the side effects of anti-retroviral therapy
We have compared the genome sequences of HIV-infected patients and uninfected individuals and found (a) the deletion mutant of coreceptor CCR5 gene that fails to produce a co-receptor needed for HIV entry, (b) a polymorphism in the promoter of the chemokine RANTES, and (c) a polymorphism in the promoter of IL4, which regulates the expression of the co-receptor, and have demonstrated that these mutations do actually affect susceptibility to HIV infection and the rate of disease progression to AIDS. Although highly active anti-retroviral therapies are available now, anti-HIV drugs frequently cause severe side effects. We are currently trying to identify human genetic polymorphisms which affect the side-effects of anti-HIV drugs in collaboration with Thai researchers to improve the therapeutic strategy of HIV infection.

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Some of Recent Papers

  1. Nakayama EE and Shioda T. Anti-retroviral activity of TRIM5 (alpha). Reviews in Medical Virology 20,77-92, 2010. 
  2. Likanonsakul S, Rattanatham T, Feangvad S, Uttayamakul S, Prasithsirikul W, Tunthanathip P, Nakayama EE and Shioda T. HLA-Cw*04 allele associated with nevirapine-induced rash in HIV-infected Thai patients. AIDS Research and Therapy 6,22, 2009.  
  3. Nakajima T, Nakayama EE, Kaur G, Terunuma H, Mimaya JI, Ohtani H, Mehra N, Shioda T, and Kimura A. Impact of novel TRIM5alpha variants, Gly110Arg and G176del, on the anti-HIV-1 activity and the susceptibility to HIV-1 infection. AIDS 23, 2091-100, 2009.
  4. Kono K, Song H, Singai Y, Shioda T and Nakayama EE.Comparison of anti-viral activity of rhesus monkey and cynomolgus monkey TRIM5alphas against HIV-2 infection.  Virology 373, 447-456, 2008.
  5. Nakayama EE, Shingai Y, Kono K and Shioda T. TRIM5alpha-independent anti-human immunodeficiency virus type 1 activity mediated by cyclophilin A in Old World monkey cells. Virology 375, 514-520, 2008.