The elucidation of the early immune system in percutaneous infection of HSV and HIV and the development of novel methods to prevent their cutaneous infection

• Project/Area Number: 23390282
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Dermatology
• Research Institution: University of Yamanashi
• Principal Investigator: SHIMADA Shinji 山梨大学, 医学工学総合研究部, 教授 (10114505)
• Co-Investigator(Kenkyū-buntansha): KKAWAMURA Tatsuyoshi 山梨大学, 医学部附属病院, 講師 (70262657) ; SHIBAGAKI Naotaka 山梨大学, 医学工学総合研究部, 准教授 (40262662) ; HARADA Kazutoshi 山梨大学, 医学部附属病院, 講師 (20324197)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000); Fiscal Year 2013: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2012: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2011: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
• Keywords: HSV / HIV / 経皮感染 / ランゲルハンス細胞 / 抗菌ペプチド / 性行為感染症 / 自然免疫

Research Abstract

HSV-2 shedding is associated with increased risk for sexually acquiring HIV. Because Langerhans cells (LCs) are suspected to be the initial target cells infected by HIV following sexual exposure, we studied whether HSV-2 affects HIV infection of LCs. HSV-2 enhanced HIV susceptibility in LCs within skin explants, even though relatively few HSV-2/HIV co-infected LCs were detected, suggesting that HSV-2 enhances HIV infection of LCs through indirect mechanisms. Indeed, HSV-2 stimulated production of antimicrobial peptides (AMPs) by epithelial cells, including human defensins and LL-37, and the latter strongly enhanced HIV susceptibility in LCs by up-regulating HIV receptors. Culture supernatants of epithelial cells infected with HSV-2 enhanced HIV susceptibility in LCs, and this effect was abrogated by blocking LL-37 production. These data suggest that HSV-2 enhances sexual transmission of HIV by increasing HIV susceptibility of LCs via epithelial cell production of LL-37.

Research Products

• [Journal Article] A case of oral mucosal fixed eruption caused by methacrylate (2014)
  • Author(s): Inozume T, Nakazawa R, Tanaka K, Harada K, Kawamura T, Shibagaki N, Shimada S
  • Journal Title: Contact Dermatitis Volume: 70(6) Issue: 6 Pages: 387-8
  • DOI: 10.1111/cod.12183
  • Peer Reviewed
• [Journal Article] Case of primary cutaneous peripheral T-cell lymphoma, not otherwise specified, with characteristics of follicular helper T cells (2014)
  • Author(s): Takaki M, Inozume T, Matsuzawa T, Ando N, Y amaguchi M, Harada K, Kawamura T, Shibagaki N, Shimada S
  • Journal Title: J Dermatol Volume: (In press) Issue: 6 Pages: 529-532
  • DOI: 10.1111/1346-8138.12493
  • Peer Reviewed
• [Journal Article] EFdA, a reverse transcriptase inhibitor , potently blocks HIV -1 ex vivo infection of Langerhans cells within epithelium (2014)
  • Author(s): Matsuzawa T, Kawamura T, Ogawa Y, Maeda K, Nakata H, Moriishi K, Koyanagi Y, Gatanaga H, Shimada S, Mitsuya H
  • Journal Title: J Invest Dermatol Volume: 134(4) Issue: 4 Pages: 1158-61
  • DOI: 10.1038/jid.2013.467
  • Peer Reviewed / Open Access
• [Journal Article] Oral administration of the CCR5 inhibitor , maraviroc, blocks HIV ex vivo infection of Langerhans cells within the epithelium (2013)
  • Author(s): Matsuzawa T, Kawamura T, Ogawa Y, Takahashi M, Aoki R, Moriishi K, Koyanagi Y, Gatanaga H, Blauvelt A, Shimada S
  • Journal Title: J Invest Dermatol Volume: 133(12) Issue: 12 Pages: 2803-5
  • DOI: 10.1038/jid.2013.215
  • Peer Reviewed
• [Journal Article] Two cases of autosomal recessive woolly hair with LIPH gene mutations (2013)
  • Author(s): Harada K, Inozume T, Kawamura T, Shibagaki N, Kinoshita T, Deguchi N, Shimada S
  • Journal Title: Int J Dermatol Volume: 52(5) Pages: 572-4
  • Peer Reviewed
• [Journal Article] Mast cells play a key role in host defense against herpes simplex virus infection through TNF-α and IL-6 production (2013)
  • Author(s): Aoki R, Kawamura T, Goshima F, Ogawa Y, Nakae S, Nakao A, Moriishi K, Nishiyama Y, Shimada S
  • Journal Title: J Invest Dermatol Volume: 133(9) Issue: 9 Pages: 2170-9
  • DOI: 10.1038/jid.2013.150
  • Peer Reviewed
• [Journal Article] Antimicrobial peptide LL-37 produced by HSV-2-infected keratinocytes enhances HIV infection of Langerhans cells (2013)
  • Author(s): Ogawa Y, Kawamura T, Matsuzawa T, Aoki R, Gee P, Yamashita A, Moriishi K, Yamasaki K, Koyanagi Y. Blauvelt A, Shimada S.
  • Journal Title: Cell Host and Microbe Volume: 13 Issue: 1 Pages: 77-86
  • DOI: 10.1016/j.chom.2012.12.002
  • Peer Reviewed
• [Journal Article] A case of dermatomyositis accompanied by spontaneous intramuscular hemorrhage despite normal coagulability (2013)
  • Author(s): Hanawa F, Inozume T, Harada K, Andou N, Kawamura T, Shibagaki N, Shimada S
  • Journal Title: Rheumatol Int Volume: 33(11) Issue: 11 Pages: 2949-50
  • DOI: 10.1007/s00296-012-2492-3
  • Peer Reviewed
• [Journal Article] Antimicrobial Peptide LL-37 Produced by HSV-2-Infected Keratinocytes Enhances HIV Infection of (2013)
  • Author(s): 小川陽一, 川村龍吉, 松澤高光, 青木類, Peter Gee, 山下篤哉, 森石恆司, 山崎研志, 小柳義夫, Andrew Blauvelt, 島田眞路
  • Journal Title: Cell Host & Microbe Volume: 13 Pages: 77-86
  • Peer Reviewed
• [Journal Article] Antimicrobial Peptide LL-37 Produced by HSV-2-Infected Keratinocytes Enhances HIV Infection of Langerhans Cells (2013)
  • Author(s): 小川 陽一
  • Journal Title: Cell Host & Microbe Volume: 13 Pages: 77-86
  • Peer Reviewed
• [Journal Article] Case of rheumatoid papules : is this a link between vasculitis and rheumatoid nodules? (2012)
  • Author(s): Inozume T, Ando N, Sano S, Harada K, Kawamura T, Shibagaki N, Shimada S
  • Journal Title: J Dermatol Volume: 39(12) Pages: 1091-2
  • Peer Reviewed
• [Journal Article] Neutrophilic panniculitis with non-caseating granulomas in a Crohn's disease patient (2012)
  • Author(s): Ogawa Y, Aoki R, Harada K, Matsuzawa T, Inozume T, Shibagaki N, Kawamura T, Shimada S
  • Journal Title: Eur J Dermatol Volume: 22(3) Issue: 3 Pages: 404-5
  • DOI: 10.1684/ejd.2012.1737
  • Peer Reviewed
• [Journal Article] Gutter method : noninvasive management of ingrown nails caused by epidermal growth factor inhibitor treatment (2012)
  • Author(s): Harada K, Y amaguchi M, Miyajima S, Kawamura T, Shibagaki S, Shimada S
  • Journal Title: Clin Exp Dermatol Volume: 37(6) Pages: 703-4
  • Peer Reviewed
• [Journal Article] Case of mucous membrane pemphigoid characterized by circulating immunoglobulin A and immunoglobulin G autoantibodies to the gamma-2 subunit of laminin-332 (2012)
  • Author(s): Hanawa F, Harada K, Andou N, Kawamura T, Shibagaki N, Fukuda S, Hashimoto T, Shimada S
  • Journal Title: J Dermatol Volume: 39(11) Pages: 962-3
  • Peer Reviewed
• [Journal Article] Sev ere dermatitis with loss of epidermal Langerh ans cells in human and mouse zinc deficiency. (2011)
  • Author(s): Kawamura T, Ohta Y, et al.
  • Journal Title: The Journal of Clinical Investigation Volume: 84 Issue: 2 Pages: 722-732
  • DOI: 10.1172/jci58618
  • Peer Reviewed
• [Presentation] Antimicrobial peptide LL-37 produced by HSV-2-infected keratinocytes enhances HIV infection of Langerhans cells (2013)
  • Author(s): 小川陽一, 川村龍吉, 松澤高光, 青木類, Peter Gee, 山下篤哉, 森石恆司, 山崎研志, 小柳義夫, Andrew Blauvelt, 島田眞路
  • Organizer: International Investigative Dermatology
  • Place of Presentation: エジンバラ国際会議場（エジンバラ, スコットランド）
• [Remarks] 皮膚科学講座 - 山梨大学 医学部
  • URL: http://www.med.yamanashi.ac.jp/clinical/dermatol/index.html
• [Remarks]