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
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wei, B. L.
Right arrow Articles by Garcia, J. V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wei, B. L.
Right arrow Articles by Garcia, J. V.

 Previous Article  |  Next Article 

Journal of Virology, May 2005, p. 5705-5712, Vol. 79, No. 9
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.9.5705-5712.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Inhibition of Lysosome and Proteasome Function Enhances Human Immunodeficiency Virus Type 1 Infection

Bangdong L. Wei,1 Paul W. Denton,1 Eduardo O'Neill,1 Tianci Luo,2 John L. Foster,1* and J. Victor Garcia1*

Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390,1 Advanced Vision Therapeutics Inc., Rockville, Maryland 208502

Received 13 August 2004/ Accepted 23 December 2004

We previously reported that inhibition of endosomal/lysosomal function can dramatically enhance human immunodeficiency virus type 1 (HIV-1) infectivity, suggesting that under these conditions productive HIV-1 infection can occur via the endocytic pathway. Here we further examined this effect with bafilomycin A1 (BFLA-1) and show that this enhancement of infectivity extends to all HIV-1 isolates tested regardless of coreceptor usage. However, isolate-specific differences were observed in the magnitude of the effect. This was particularly evident in the case of the weakly infectious HIV-1SF2, for which we observed the greatest enhancement. Using reciprocal chimeric viruses, we were able to determine that both the disproportionate increase in the infectivity of HIV-1SF2 in response to BFLA-1 and its weak infectivity in the absence of BFLA-1 mapped to its envelope gene. Further, we found HIV-1SF2 to have lower fusion activity and to be 12-fold more sensitive to the fusion inhibitor T-20 than HIV-1NL4-3. Proteasomal inhibitors also enhance HIV-1 infectivity, and we report that the combination of a lysosomal and a proteasomal inhibitor greatly enhanced infectivity of all isolates tested. Again, HIV-1SF2 was unique in exhibiting a synergistic 400-fold increase in infectivity. We also determined that inhibition of proteasomal function increased the infectivity of HIV-1 pseudotyped with vesicular stomatitis virus G protein. The evidence presented here highlights the important role of the lysosomes/proteasomes in the destruction of infectious HIV-1SF2 and could have implications for the development of novel antiviral agents that might take advantage of these innate defenses.

* E-mail for John L. Foster: john.foster{at}utsouthwestern.edu.

* Corresponding author. Mailing address: Department of Internal Medicine, Division of Infectious Diseases, Y9.206 University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9113. Phone: (214) 648-9970. Fax: (214) 648-0231. E-mail for J. Victor Garcia: victor.garcia{at}utsouthwestern.edu.

Journal of Virology, May 2005, p. 5705-5712, Vol. 79, No. 9
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.9.5705-5712.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bergamaschi, A., David, A., Le Rouzic, E., Nisole, S., Barre-Sinoussi, F., Pancino, G. (2009). The CDK Inhibitor p21Cip1/WAF1 Is Induced by Fc{gamma}R Activation and Restricts the Replication of Human Immunodeficiency Virus Type 1 and Related Primate Lentiviruses in Human Macrophages. J. Virol. 83: 12253-12265 [Abstract] [Full Text]  
  • Laguette, N., Bregnard, C., Bouchet, J., Benmerah, A., Benichou, S., Basmaciogullari, S. (2009). Nef-Induced CD4 Endocytosis in Human Immunodeficiency Virus Type 1 Host Cells: Role of p56lck Kinase. J. Virol. 83: 7117-7128 [Abstract] [Full Text]  
  • Cote, M., Kucharski, T. J., Liu, S.-L. (2008). Enzootic Nasal Tumor Virus Envelope Requires a Very Acidic pH for Fusion Activation and Infection. J. Virol. 82: 9023-9034 [Abstract] [Full Text]  
  • Misinzo, G., Delputte, P. L., Nauwynck, H. J. (2008). Inhibition of Endosome-Lysosome System Acidification Enhances Porcine Circovirus 2 Infection of Porcine Epithelial Cells. J. Virol. 82: 1128-1135 [Abstract] [Full Text]  
  • Sun, Z., Denton, P. W., Estes, J. D., Othieno, F. A., Wei, B. L., Wege, A. K., Melkus, M. W., Padgett-Thomas, A., Zupancic, M., Haase, A. T., Garcia, J. V. (2007). Intrarectal transmission, systemic infection, and CD4+ T cell depletion in humanized mice infected with HIV-1. JEM 204: 705-714 [Abstract] [Full Text]  
  • Qi, M., Aiken, C. (2007). Selective Restriction of Nef-Defective Human Immunodeficiency Virus Type 1 by a Proteasome-Dependent Mechanism. J. Virol. 81: 1534-1536 [Abstract] [Full Text]  
  • Chatterji, U., Bobardt, M. D., Gaskill, P., Sheeter, D., Fox, H., Gallay, P. A. (2006). Trim5{alpha} Accelerates Degradation of Cytosolic Capsid Associated with Productive HIV-1 Entry. J. Biol. Chem. 281: 37025-37033 [Abstract] [Full Text]  
  • David, A., Saez-Cirion, A., Versmisse, P., Malbec, O., Iannascoli, B., Herschke, F., Lucas, M., Barre-Sinoussi, F., Mouscadet, J.-F., Daeron, M., Pancino, G. (2006). The Engagement of Activating Fc{gamma}Rs Inhibits Primate Lentivirus Replication in Human Macrophages. J. Immunol. 177: 6291-6300 [Abstract] [Full Text]  
  • Agarwal, S., Harada, J., Schreifels, J., Lech, P., Nikolai, B., Yamaguchi, T., Chanda, S. K., Somia, N. V. (2006). Isolation, characterization, and genetic complementation of a cellular mutant resistant to retroviral infection. Proc. Natl. Acad. Sci. USA 103: 15933-15938 [Abstract] [Full Text]  
  • Santoni de Sio, F. R., Cascio, P., Zingale, A., Gasparini, M., Naldini, L. (2006). Proteasome activity restricts lentiviral gene transfer into hematopoietic stem cells and is down-regulated by cytokines that enhance transduction. Blood 107: 4257-4265 [Abstract] [Full Text]  
  • Stremlau, M., Perron, M., Lee, M., Li, Y., Song, B., Javanbakht, H., Diaz-Griffero, F., Anderson, D. J., Sundquist, W. I., Sodroski, J. (2006). From the Cover: Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5{alpha} restriction factor. Proc. Natl. Acad. Sci. USA 103: 5514-5519 [Abstract] [Full Text]  
  • Huang, I-C., Bosch, B. J., Li, F., Li, W., Lee, K. H., Ghiran, S., Vasilieva, N., Dermody, T. S., Harrison, S. C., Dormitzer, P. R., Farzan, M., Rottier, P. J. M., Choe, H. (2006). SARS Coronavirus, but Not Human Coronavirus NL63, Utilizes Cathepsin L to Infect ACE2-expressing Cells. J. Biol. Chem. 281: 3198-3203 [Abstract] [Full Text]  


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