This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Google Scholar
Right arrow Articles by Pan, C.
Right arrow Articles by Jiang, S.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pan, C.
Right arrow Articles by Jiang, S.

 Previous Article  |  Next Article 

Journal of Virology, August 2009, p. 7862-7872, Vol. 83, No. 16
0022-538X/09/$08.00+0     doi:10.1128/JVI.00168-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Combinations of the First and Next Generations of Human Immunodeficiency Virus (HIV) Fusion Inhibitors Exhibit a Highly Potent Synergistic Effect against Enfuvirtide- Sensitive and -Resistant HIV Type 1 Strains{triangledown}

Chungen Pan,1,2 Lifeng Cai,2 Hong Lu,2 Zhi Qi,2 and Shibo Jiang2,3*

College of Life Sciences, Peking University, Beijing 100871, China,1 Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 10065,2 Southern Medical University, Guangzhou, Guangdong 510515, China3

Received 24 January 2009/ Accepted 27 May 2009

T20 (generic name, enfuvirtide; brand name, Fuzeon) is a first-generation human immunodeficiency virus (HIV) fusion inhibitor approved for salvage therapy of HIV-infected patients refractory to current antiretroviral drugs. However, its clinical use is limited because of rapid emergence of T20-resistant viruses in T20-treated patients. Therefore, T1249 and T1144 are being developed as the second- and third-generation HIV fusion inhibitors, respectively, with improved efficacy and drug resistance profiles. Here, we found that combinations of T20 with T1249 and/or T1144 resulted in exceptionally potent synergism (combination index, <0.01) against HIV-1-mediated membrane fusion by 2 to 3 orders of magnitude in dose reduction. Highly potent synergistic antiviral efficacy was also achieved against infection by laboratory-adapted and primary HIV-1 strains, including T20-resistant variants. The mechanism underlying the synergistic effect could be attributed to the fact that T20, T1249, and T1144 all contain different functional domains and have different primary binding sites in gp41. As such, they may work cooperatively to inhibit gp41 six-helix bundle core formation, thereby suppressing virus-cell fusion. Therefore, these findings strongly imply that, rather than replacing T20, combining it with HIV fusion inhibitors of different generations might produce synergistic activity against both T20-sensitive and -resistant HIV-1 strains, suggesting a new therapeutic strategy for the treatment of HIV-1 infection/AIDS.

* Corresponding author. Mailing address: Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065. Phone: (212) 570-3058. Fax: (212) 570-3099. E-mail: sjiang{at}nybloodcenter.org

{triangledown} Published ahead of print on 3 June 2009.

Journal of Virology, August 2009, p. 7862-7872, Vol. 83, No. 16
0022-538X/09/$08.00+0     doi:10.1128/JVI.00168-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»