Junichi Sakuragi, Emi E. Nakayama

Sayuri Sakuragi (Research Associate of COE)

Acquired immunodeficiency syndrome (AIDS) is one of the most threatening infectious diseases the human race is faced with today. There are a few cases where the subjects were not infected after the repeated exposure to HIV, and where HIV-positive patients did not develop symptoms of AIDS without receiving any anti-retroviral treatment. In these cases, the existence of a resistance inducing factor (RIF) against HIV is suspected. We have conducted a polymorphism analysis of the human genome, comparing the genome sequences from subjects from these particular cases, the genome sequences from HIV-infected patients, and the genome sequences from non-infected individuals as a control. We found a deletion mutant, CCR5-893 (-), lacking a co-receptor which is indispensable for entry of HIV into target cells, a promoter polymorphism in chemokine RANTES, which inhibits the entry of HIV into target cells, and a promoter polymorphism in cytokine IL4, which regulates the expression of the co-receptor. In addition, we have demonstrated that these mutations actually affected the susceptibility to HIV infection and the rate of disease progression to AIDS. In this project, we seek to identify the unknown RIF by carrying out further comprehensive analyses. As no animal model of AIDS has been established, the above-mentioned epidemiological procedure is suitable to examine AIDS at the individual level.
In addition, the fact that this disease lacks a suitable animal model itself suggests the presence of another RIF. HIV does not establish productive infection in any other monkey except for the chimpanzee; this is thought to be due to an inhibitor in simian lymphocytes which acts at an early stage (reverse transcription) of viral infection. The figure shows the HIV life cycle in cells and RIF which inhibits the particular step of HIV life cycle. Even though the presence of the RIF has been suggested, few candidate molecules have been identified; thus, we aim to identify an HIV-RIF in a simian genome by an in vitro experiment. Once a RIF has been identified, it may be feasible to establish an animal model for experimental AIDS, which would facilitate the development of a vaccine against AIDS and would determine a new target for AIDS treatment. Furthermore, we are certain that such research will contribute to the understanding of the innate immune system.


The host factors which affect the growth cycle of HIV.
+ indicates a positive regulator of HIV proliferation, while - indicates a negative regulator (resistance inducing factor).

1. Polymorphism in RANTES chemokine promoter affects HIV-1 disease progression.
Huanliang Liu, David Chao, Emi E. Nakayama, Hitomi Taguchi, Mieko Gotoh, Xiaomi Xin, Jun-ki Takamatsu, Hidehiko Saito, Yoshihide Ishikawa, Tatsuya Akaza, Takeo Juji, Yutaka Takebe, Takeshi Ohishi, Katsuyuki Fukutake, Yoshikazu Maruyama, Shinji Yashiki, Shunro Sonoda, Tetsuya Nakamura, Yoshiyuki Nagai, Aikichi Iwamoto and Tatsuo Shioda. Proc. Natl. Acad. Sci. USA. 96, 4581-4585, 1999.

2. Polymorphism in IL-4 promoter affects acquisition of human immunodeficiency virus type 1 syncytium inducing phenotype. Emi E. Nakayama, Yoshihiko Hoshino, Xiaomi Xin, Huanliang Liu, Mieko Goto, Nobukazu Watanabe, Hitomi Taguchi, Akihiro Hitani , Ai Kawana-Tachikawa, Masao Fukushima, Kaneo Yamada, Wataru Sugiura, Shin-ichi Oka, Atsushi Ajisawa, Hironori Sato, Yutaka Takebe, Tetsuya Nakamura, Yoshiyuki Nagai, Aikichi Iwamoto, and Tatsuo Shioda. J.Virol. 74, 5452-5459, 2000.

3. Naturally occurring deletional mutation in the C-terminal cytoplasmic tail of CCR5 affects surface trafficking of CCR5. Tatsuo Shioda, Emi E. Nakayama, Yuetsu Tanaka, Xiaomi Xin, Huanliang Liu, Ai Kawana-Tachikawa, Atsushi Kato, Yuko Sakai, Yoshiyuki Nagai, and Aikichi Iwamoto. J. Virol. 75, 3462-3468, 2001.

4. Protective effect of IL4 -589T polymorphism on HIV-1 disease progression: Relationship with viral load. Emi E. Nakayama, Laurence Meyer, Aikichi Iwamoto, Anne Persoz, Yoshiyuki Nagai, Christine Rouzioux, Jean-Francois Delfraissy, SEROCO Study Group, Patrice Debre, Dorian McIlroy, Ioannis Theodorou and Tatsuo Shioda. J. Infectious Diseases. 185, 1183-1186, 2002.

5. A CCR2-V64I polymorphism affects stability of CCR2A isoform. Emi E. Nakayama, Yuetsu Tanaka, Yoshiyuki Nagai, Aikichi Iwamoto, and Tatsuo Shioda. AIDS in press.