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J. Biol. Chem., Vol. 282, Issue 23, 16899-16906, June 8, 2007

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Site-specific Mutations in HIV-1 gp41 Reveal a Correlation between HIV-1-mediated Bystander Apoptosis and Fusion/Hemifusion^*

Himanshu Garg, Anjali Joshi, Eric O. Freed, and Robert Blumenthal¹

From the Membrane Structure and Function Section, Center for Cancer Research Nanobiology Program, and Virus Cell Interaction Section, HIV Drug Resistance Program, NCI, National Institutes of Health, Frederick, Maryland 21702

The loss of CD4⁺ T cells in HIV-1 infections is hypothesized to be caused by apoptosis of bystander cells mediated by cell surface-expressed HIV-1 Env glycoprotein. However, the mechanism by which Env mediates this process remains controversial. Specifically, the role of HIV-1 gp120 binding to CD4 and CXCR4 versus the fusion process mediated by gp41 remains unresolved. Env-induced apoptosis in bystander cells has been shown to be gp41-dependent and correlates with the redistribution of membrane lipids between Env-expressing cells and target cells (hemifusion). Using a rational mutagenesis approach aimed at targeting Env function via the gp41 subunit, we examined the role of HIV gp41 in bystander apoptosis. A mutation in the fusion domain of gp41 (V513E) resulted in a fusion-defective Env that failed to induce apoptosis. A mutation in the gp41 N-terminal helix (G547D) reduced cell fusion capacity and apoptosis; conversely, an Env mutant with a deletion of the gp41 cytoplasmic tail (Ct Del) enhanced both cell-to-cell fusion and apoptosis. Most significantly, an Env mutant containing a substitution in the loop region of gp41 (D589L) mediated transfer of lipids (hemifusion) to bystander cells but was defective in cell-to-cell and to a lesser degree virus-to-cell fusion. This mutant was still able to induce apoptosis in bystander cells. Hence, we have provided the first direct evidence that gp41-mediated hemifusion is both required and sufficient for induction of apoptosis in bystander cells. These results may help to explain the mechanism of HIV-1 Env-induced T cell depletion.

Received for publication, February 27, 2007 , and in revised form, April 5, 2007.

^* This research was supported, in part, by the Intramural Research Program of the Center for Cancer Research, NCI National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed: Center for Cancer Research, NCI-Frederick, P.O. Box B, Bldg. 469, Rm. 152, Miller Dr., Frederick, MD 21702-1201. Tel.: 301-846-5532; Fax: 301-846-5598; E-mail: blumen{at}helix.nih.gov.

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