This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by LaBonte, J. A. Articles by Sodroski, J. Search for Related Content PubMed PubMed Citation Articles by LaBonte, J. A. Articles by Sodroski, J.

 Previous Article  |  Next Article 

Journal of Virology, June 2003, p. 6645-6659, Vol. 77, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.12.6645-6659.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Cytolysis by CCR5-Using Human Immunodeficiency Virus Type 1 Envelope Glycoproteins Is Dependent on Membrane Fusion and Can Be Inhibited by High Levels of CD4 Expression

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute,¹ Department of Pathology, Division of AIDS, Harvard Medical School,² Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115³

Received 27 November 2002/ Accepted 24 March 2003

T-tropic (X4) and dualtropic (R5X4) human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins kill primary and immortalized CD4⁺ CXCR4⁺ T cells by mechanisms involving membrane fusion. However, because much of HIV-1 infection in vivo is mediated by M-tropic (R5) viruses whose envelope glycoproteins use CCR5 as a coreceptor, we tested a panel of R5 and R5X4 envelope glycoproteins for their ability to lyse CCR5⁺ target cells. As is the case for CXCR4⁺ target cells, HIV-1 envelope glycoproteins expressed by single-round HIV-1 vectors killed transduced CD4⁺ CCR5⁺ cells in a membrane fusion-dependent manner. Furthermore, a CD4-independent R5 HIV-1 envelope glycoprotein was able to kill CD4-negative target cells expressing CCR5, demonstrating that CD4 is not intrinsically required for the induction of death. Interestingly, high levels of CD4 expression protected cells from lysis and syncytium formation mediated by the HIV-1 envelope glycoproteins. Immunoprecipitation experiments showed that high levels of CD4 coexpression inhibited proteolytic processing of the HIV-1 envelope glycoprotein precursor gp160. This inhibition could be overcome by decreasing the CD4 binding ability of gp120. Studies were also undertaken to investigate the ability of virion-bound HIV-1 envelope glycoproteins to kill primary CD4⁺ T cells. However, neither X4 nor R5X4 envelope glycoproteins on noninfectious virions caused death in primary CD4⁺ T cells. These results demonstrate that the interaction of CCR5 with R5 HIV-1 envelope glycoproteins capable of inducing membrane fusion leads to cell lysis; overexpression of CD4 can inhibit cell killing by limiting envelope glycoprotein processing.

This article has been cited by other articles:

• Zhou, Y., Shen, L., Yang, H.-C., Siliciano, R. F. (2008). Preferential Cytolysis of Peripheral Memory CD4+ T Cells by In Vitro X4-Tropic Human Immunodeficiency Virus Type 1 Infection before the Completion of Reverse Transcription. J. Virol. 82: 9154-9163 [Abstract] [Full Text]  
• Gutierrez-Sanmartin, D., Varela-Ledo, E., Aguilera, A., Romero-Yuste, S., Romero-Jung, P., Gomez-Tato, A., Regueiro, B. J. (2008). Implication of p38 mitogen-activated protein kinase isoforms ({alpha}, {beta}, {gamma} and {delta}) in CD4+ T-cell infection with human immunodeficiency virus type I. J. Gen. Virol. 89: 1661-1671 [Abstract] [Full Text]  
• Madani, N., Hubicki, A. M., Perdigoto, A. L., Springer, M., Sodroski, J. (2007). Inhibition of Human Immunodeficiency Virus Envelope Glycoprotein- Mediated Single Cell Lysis by Low-Molecular-Weight Antagonists of Viral Entry. J. Virol. 81: 532-538 [Abstract] [Full Text]  
• Garg, H., Blumenthal, R. (2006). HIV gp41-induced apoptosis is mediated by caspase-3-dependent mitochondrial depolarization, which is inhibited by HIV protease inhibitor nelfinavir. J. Leukoc. Biol. 79: 351-362 [Abstract] [Full Text]  
• Holm, G. H., Gabuzda, D. (2005). Distinct Mechanisms of CD4+ and CD8+ T-Cell Activation and Bystander Apoptosis Induced by Human Immunodeficiency Virus Type 1 Virions. J. Virol. 79: 6299-6311 [Abstract] [Full Text]  
• Jin, H., Carlile, C., Nolan, S., Grote, E. (2004). Prm1 Prevents Contact-Dependent Lysis of Yeast Mating Pairs. Eukaryot Cell 3: 1664-1673 [Abstract] [Full Text]  
• Evans, D. T., Bricker, J. E., Desrosiers, R. C. (2004). A Novel Approach for Producing Lentiviruses That Are Limited to a Single Cycle of Infection. J. Virol. 78: 11715-11725 [Abstract] [Full Text]  
• Blanco, J., Barretina, J., Clotet, B., Este, J. A. (2004). R5 HIV gp120-mediated cellular contacts induce the death of single CCR5-expressing CD4 T cells by a gp41-dependent mechanism. J. Leukoc. Biol. 76: 804-811 [Abstract] [Full Text]  
• Holm, G. H., Zhang, C., Gorry, P. R., Peden, K., Schols, D., De Clercq, E., Gabuzda, D. (2004). Apoptosis of Bystander T Cells Induced by Human Immunodeficiency Virus Type 1 with Increased Envelope/Receptor Affinity and Coreceptor Binding Site Exposure. J. Virol. 78: 4541-4551 [Abstract] [Full Text]