16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

ROLE OF THE HIGHLY CONSERVED LWYIK MOTIF OF THE TRANSMEMBRANE PROTEIN gp41 OF HIV IN ENV-MEDIATED MEMBRANE FUSION

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. MoAa0103

Chen S.S.-L., Chan W.-E.
Academia Sinica, Institute of Biomedical Sciences, Taipei, Taiwan, Republic of China

BACKGROUND: It has been proposed that the highly-conserved LWYIK motif located immediately proximal to the membrane-spanning domain of the HIV-1 gp41 plays a role in gp41-mediated membrane fusion and Env association with lipid rafts. However, the significance of this domain in virus replication is still unclear.

METHODS: Virus mutants encoding deletions and substitutions in the LWYIK motif were constructed by site-directed mutagenesis. Virus infectivity was determined by continuous cell culture and one-cycle replication assays. The ability of Env proteins to mediate virus entry was assessed by an env trans-complementation assay. The membrane fusion ability of Env was assessed by the HIV-1 LTR-Tat transactivation and three color transfer assays.

RESULTS: None of the mutants examined showed altered synthesis, precursor processing, CD4-binding, oligomerization, or cell surface expression of the Env, nor altered Env incorporation into the virus. However, all of the mutant viruses, in particular, the ΔYI, ΔIK, and ΔLWYIK mutants, significantly reduced their one-cycle viral replication and the trans-complementation ability of the mutant proteins. Nevertheless, all deletion mutant Env proteins were still localized in the lipid raft membranes. Furthermore, all of these mutants exhibited reduced membrane fusion ability, especially, the membrane fusion ability of the three deletion mutants were almost abrogated to the background level. Three color dye transfer assays showed that deletion of the entire LWYIK would arrest viral entry at hemifusion whereas deletion of the YI or IK two dipeptides impaired the step of fusion pore enlargement.

CONCLUSIONS: Our study shows that localization of Env in lipid rafts is not sufficient for Env-mediated membrane fusion. The results also demonstrate that the immediate membrane-proximal LWYIK motif is not necessary for Env maturation or incorporation into the virus, but does play a critical role in membrane fusion by promoting formation of a functional fusion pore.

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2006-08-13
MoAa0103

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