Analysis of molecular basis for modulation of HIV-1 replication by naturally-occurring single nucleotide polymorphisms within the SLSA1 structure of the pol gene

• Project/Area Number: 26460556
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: The University of Tokushima
• Principal Investigator: NOMAGUCHI Masako 徳島大学, 大学院医歯薬学研究部(医学系), 教授 (80452647)
• Co-Investigator(Kenkyū-buntansha): 宮崎 恭行 徳島大学, 大学院医歯薬学研究部(医学系), 助教 (70607233) ; 足立 昭夫 徳島大学, 大学院医歯薬学研究部(医学系), 特命教授 (90127043)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: HIV / Vif / APOBEC3G / ウイルス複製 / 変異・適応 / 遺伝子発現 / 選択的スプライシング / 適応・進化

Outline of Final Research Achievements

Power balance between HIV-1 Vif and APOBEC3G is critical for viral replication. Through HIV-1 adaptation study, we found that virus replication capacity varies by naturally-occurring single nucleotide polymorphisms (nsSNP) within the region proximal to the splicing acceptor 1 (SA1prox) and SLSA1 structure on the HIV-1 genome. Molecular virological analysis in this study revealed that the change of viral growth ability results from the increase and decrease in Vif expression levels by nsSNPs. Thus, the nucleotide sequence of SA1prox region is important for determining the Vif expression level. To investigate how viruses expressing an extremely low level of Vif adapt themselves to environments with a high APOBEC3G level, we performed virus adaptation experiments. The results showed that the region other than SA1prox is also involved in vif mRNA production, and that HIV-1 displays a high adaptation ability even under circumstances where virus replication is strongly restricted.

Research Products

• [Journal Article] Expression profiles of Vpx/Vpr proteins are co-related with the primate lentiviral lineage. (2016)
  • Author(s): Sakai, Y., Miyake, A., Doi, N., Sasada, H., Miyazaki, Y., Adachi, A, and Nomaguchi, M.
  • Journal Title: Frontiers in Microbiology Volume: 7 Pages: 1211-1211
  • DOI: 10.3389/fmicb.2016.01211
  • NAID: 120006937686
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Phylogenetic insights into the functional relationship between primate lentiviral reverse transcriptase and accessory proteins Vpx/Vpr. (2016)
  • Author(s): Sakai, Y., Doi, N., Miyazaki, Y., Adachi, A, and Nomaguchi, M.
  • Journal Title: Frontiers in Microbiology Volume: 7 Pages: 1655-1655
  • DOI: 10.3389/fmicb.2016.01655
  • NAID: 120006937687
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Natural single-nucleotide variations in the HIV-1 genomic SA1prox region can alter viral replication ability by regulating Vif expression levels. (2016)
  • Author(s): Nomaguchi, M., Doi, N., Sakai, Y., Ode, H., Iwatani, Y., Ueno, T., Matsumoto, Y., Miyazaki, Y., Masuda, T., and Adachi, A.
  • Journal Title: Journal of Virology Volume: 90 Pages: 4563-4578
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Novel mutant human immunodeficiency virus type 1 strains with high degree of resistance to cynomolgus macaque TRIMCyp generated by randam mutagenesis. (2016)
  • Author(s): Sultana, T., Nakayama, E.E., Tobita, S., Yokoyama, M., Seki, Y., Saito, A., Nomaguchi, M., Adachi, A., Akari, H., Sato, H., and Shioda, T.
  • Journal Title: Journal of General Virology Volume: 97 Issue: 4 Pages: 963-976
  • DOI: 10.1099/jgv.0.000408
  • Peer Reviewed / Open Access
• [Journal Article] Single-amino acid mutation 66SR in Gag-matrix enhances viral single-cycle infectivity of R5-tropic HIV-1rmt. (2015)
  • Author(s): Doi, N., Sakai, Y., Miyazaki, T., Adachi, A., and Nomaguchi, M.
  • Journal Title: Journal of Medical Investigation Volume: 62 Pages: 228-232
  • NAID: 130005099140
  • Peer Reviewed
• [Journal Article] In silico analysis of HIV-1 Env-gp120 reveals structural bases for viral adaptation in growth-restrictive cells. (2015)
  • Author(s): Yokoyama, M., Nomaguchi, M., Doi, N., Kanda, T., Adachi, A., and Sato, H.
  • Journal Title: Frontiers in Microbiology Volume: 7
  • DOI: 10.3389/fmicb.2016.00110
  • NAID: 120006937684
  • Peer Reviewed / Open Access
• [Journal Article] Distinct combinations of amino acid substitutions in N-terminal domain of Gag-capsid afford HIV-1 resistance to rhesus TRIM5α. (2014)
  • Author(s): Nomaguchi M, Nakayama EE,Yokoyama M, Doi N,Igarashi T, Shioda T, Sato H, Adachi A.
  • Journal Title: Microbes and Infection Volume: 16 Issue: 11 Pages: 936-944
  • DOI: 10.1016/j.micinf.2014.08.017
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Growth properties of macaque-tropic HIV-1 clones carrying <i>vpr/vpx </i>genes derived from simian immunodeficiency viruses in place of their <i>vpr </i>regions (2014)
  • Author(s): Doi, N., Adachi, A., and Nomaguchi, M.
  • Journal Title: The Journal of Medical Investigation Volume: 61 Issue: 3.4 Pages: 374-379
  • DOI: 10.2152/jmi.61.374
  • NAID: 130004822744
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed / Open Access
• [Journal Article] Virological characterization of HIV-2 vpx gene mutants in various cell systems. (2014)
  • Author(s): Nomaguchi, M., Doi, N., and Adachi, A.
  • Journal Title: Microbes and Infection Volume: 16 Issue: 8 Pages: 695-701
  • DOI: 10.1016/j.micinf.2014.06.004
  • Peer Reviewed / Open Access
• [Journal Article] Natural single-nucleotide polymorphisms in the 3' region of HIV-1 pol gene modulate viral replication ability. (2014)
  • Author(s): Nomaguchi, M. Miyake, A., Doi, N., Fujiwara, S., Miyazaki, Y., Tsunetsugu-Yokota, Y., Yokoyama, M., Sato, H., Masuda, T., and Adachi, A.
  • Journal Title: Journal of Virology Volume: 88 Issue: 8 Pages: 4145-4160
  • DOI: 10.1128/jvi.01859-13
  • Peer Reviewed / Open Access
• [Presentation] Effects of mutations HIV-1 Gag-CA helix 7 and linker domain on the virion production. (2016)
  • Author(s): Fujimoto, K., Doi, N., Sakai, Y., Adachi, A., and Nomaguchi, M.
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌コンベンションセンター (北海道札幌市）
  • Year and Date: 2016-10-23
• [Presentation] An ultra-low vif type of HIV-1 SA1D2prox variant can adapt and evolve under the high level of APOVEC3G. (2016)
  • Author(s): Adachi, A., Doi, N., Sakai, Y., Fujimoto, K., and Nomaguchi, M.
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌コンベンションセンター (北海道札幌市)
  • Year and Date: 2016-10-23
• [Presentation] Identification of cis-elements involved in the HIV-1 vif mRNA production. (2016)
  • Author(s): Nomaguchi, M., Doi, N., Fujimoto, K., Sakai, Y., Nakanishi, S., and Adachi A.
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌コンベンションセンター (北海道札幌市)
  • Year and Date: 2016-10-23
• [Presentation] Replication and pathogenicity of HIV-1rmt: towards evaluation of viral growth ability in gut-derived cells. (2016)
  • Author(s): Doi, N., Ishifune, C., Yasutomo, K., Miura, T., Sakai, Y., Fujimoto, K., Harada, S., Yoshimura, K., Nomaguchi, M., and Adachi, A.
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌コンベンションセンター (北海道札幌市)
  • Year and Date: 2016-10-23
• [Presentation] Studies on the adaptation process of HIV-1 Env in macaque cells. (2016)
  • Author(s): Sakai, Y., Fujimoto, K., Doi, N., Nomaguchi, M., and Adachi, A.
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌コンベンションセンター (北海道札幌市)
  • Year and Date: 2016-10-23
• [Presentation] Novel mutant human immunodeficiency virus type 1 strans with high degree of resistance to cynomolgus macaque TRIMCyp generated by random mutagenesis. (2016)
  • Author(s): Sultana, T., Nakayama, E.E., Tobita, S., Yokoyama, M., Seki, Y., Saito, A., Nomaguchi, M., Adachi, A., Akari, H., Sato, H., Shioda, T.
  • Organizer: The 23rd Conference on Retroviruses and Opportunistic Infections
  • Place of Presentation: Boston, USA
  • Year and Date: 2016-02-22
  • Int'l Joint Research
• [Presentation] サル指向性HIV-1構築の視点から. (2015)
  • Author(s): 野間口雅子
  • Organizer: 第29回日本エイズ学会学術集会
  • Place of Presentation: 東京ドームホテル（東京都文京区）
  • Year and Date: 2015-11-29
• [Presentation] SA1proxの1塩基置換によるHIV-1 Vif発現量変動機構 (2015)
  • Author(s): 野間口雅子、土肥直哉、吉田知哉、酒井遥介、宮崎恭行、足立昭夫
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-11-22
• [Presentation] HIV-1 Vif発現量を増減させるSA1D2prox塩基配列の同定 (2015)
  • Author(s): 足立昭夫、土肥直哉、酒井遥介、吉田知哉、宮崎恭行、野間口雅子
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-11-22
• [Presentation] CCR5-tropicアカゲザル指向性HIV-1の構築とウイルス学的性状解析 (2015)
  • Author(s): 土肥直哉、野間口雅子、酒井遥介、足立昭夫
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-11-22
• [Presentation] HIV-1 Gag-CA I134/I135/S149の1アミノ酸変異はウイルス複製後期過程に影響する (2015)
  • Author(s): 酒井遥介、土肥直哉、宮崎恭行、足立昭夫、野間口雅子
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-11-22
• [Presentation] Novel mutant HIV-1 strains with high degree of resistance to cynomolgus macaque TRIMCyp generated by random mutagenesis. (2015)
  • Author(s): Sultana, T,. Nanayama, E.E., Tobita, S., Saito, A., Nomaguchi, M., Adachi, A., Akari, H., Shioda, T.
  • Organizer: The 63rd Annual Meeting of The Japanese Society for Virology
  • Place of Presentation: Fukuoka International Congress Center (Fukuoka, Fukuoka)
  • Year and Date: 2015-11-22
• [Presentation] In vitro構築系を用いたHIV-1/HIV-2 CA重合能に関する研究. (2014)
  • Author(s): 宮崎恭行、泉泰輔、野間口雅子、内山恒夫、足立昭夫
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市）
  • Year and Date: 2014-11-11
• [Presentation] HIV-1 Gag-CAへリックス7の変異がウイルス複製後期過程に及ぼす影響の解析. (2014)
  • Author(s): 土肥直哉、宮崎恭行、酒井遥介、泉泰輔、内山恒夫、足立昭夫、野間口雅子
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市）
  • Year and Date: 2014-11-11
• [Presentation] SA1proxの遺伝子配列はVif/APOBEC3G依存的にウイルス複製能を変動させる. (2014)
  • Author(s): 野間口雅子、土肥直哉、酒井遥介、泉泰輔、宮崎恭行、足立昭夫
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市）
  • Year and Date: 2014-11-10
• [Presentation] HIV/SIV Vpx蛋白質の発現調節に寄与する領域の解析. (2014)
  • Author(s): 酒井遥介、笹田ひかり、土肥直哉、泉泰輔、宮崎恭行、足立昭夫、野間口雅子
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市）
  • Year and Date: 2014-11-10