AIDSWEEKLY Plus; Monday, January 14, 2008
Staff Medical Writers

NewsRx -- "HIV-1 envelope glycoprotein (Env) induces membrane fusion as a result of sequential binding to CD4 and chemokine receptors (CCR5 or CXCR4) (see also HIV/AIDS). The critical determinants of CCR5 coreceptor function are the N-terminal domain (Nt) and the second extracellular loop," scientists writing in the journal Retrovirology report.

"However, mutations in gp120 adapt HIV-1 to grow on cells expressing the N-terminally truncated CCR5(Δ18) (Platt et al., J Virol. 2005 Apr;79(7):4357-68). We have functionally characterized the adapted Env ( designated Env( NYP)) using a quantitative cell- cell fusion assay. The rate of fusion with target cells expressing wild-type CCR5 and the resistance to fusion inhibitors was virtually identical for wild-type Env and Env( NYP), implying that the coreceptor affinity had not increased as a result of adaptation. In contrast, Env( NYP)-induced fusion with cells expressing CCR5(Δ18) occurred at a slower rate and was extremely sensitive to the CCR5 binding inhibitor, Sch-C. Resistance to Sch-C drastically increased after pre-incubation of Env( NYP)- and CCR5(Δ18)-expressing cells at a temperature that was not permissive to fusion. This indicates that ternary Env( NYP)- CD4- CCR5(Δ18) complexes accumulate at sub-threshold temperature and that low-affinity interactions with the truncated coreceptor are sufficient for triggering conformational changes in the gp41 of Env(NYP) but not in wild-type Env. We also demonstrated that the ability of CCR5(Δ18) to support fusion and infection mediated by wild- type Env can be partially reconstituted in the presence of a synthetic sulfated peptide corresponding to the CCR5 Nt. Pre-incubation of wild- type Env- and CCR5(Δ18)expressing cells with the sulfated peptide at sub-threshold temperature markedly increased the efficiency of fusion. We propose that, upon binding the Nt region of CCR5, wild-type Env acquires the ability to productively engage the extracellular loop(s) of CCR5 - an event that triggers gp41 refolding and membrane merger," wrote G.B. Melikyan and colleagues, University of Maryland.

The researchers concluded: "The adaptive mutations in Env( NYP) enable it to more readily release its hold on gp41, even when it interacts weakly with a severely damaged coreceptor in the absence of the sulfopeptide."

Melikyan and colleagues published their study in Retrovirology (The role of the N-terminal segment of CCR5 in HIV-I Env-mediated membrane fusion and the mechanism of virus adaptation to CCR5 lacking this segment. Retrovirology. 2007 Aug 8;4:55.

Additional information can be obtained by contacting G.B. Melikyan, University of Maryland, School Medical, Institute Human Virology, 725 W Lombard St., Baltimore, MD 21201, USA.

The publisher of the journal Retrovirology can be contacted at: Biomedical Central Ltd., Middlesex House, 34-42 Cleveland St., London W1T 4LB, England.

Keywords: United States, Baltimore, HIV/AIDS, AIDS, Acquired Immunodeficiency Syndrome, Drug Resistance, Fusion Inhibitor, HIV, Human Immunodeficiency Virus, Retrovirology, Therapy, Treatment, Virology, University of Maryland.

This article was prepared by AIDS Weekly editors from staff and other reports.

2008-01-14
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