Abstract
BackgroundHIV envelope glycoprotein (Env)-mediated fusion is driven by the concerted coalescence of the HIV gp41 N-helical and C-helical regions, which results in the formation of 6 helix bundles. Kinetics of HIV Env-mediated fusion is an important determinant of sensitivity to entry inhibitors and antibodies. However, the parameters that govern the HIV Env fusion cascade have yet to be fully elucidated. We address this issue by comparing the kinetics HIV-1IIIB Env with those mediated by HIV-2 from two strains with different affinities for CD4 and CXCR4.ResultsHIV-1 and HIV-2 Env-mediated cell fusion occurred with half times of about 60 and 30 min, respectively. Binding experiments of soluble HIV gp120 proteins to CD4 and co-receptor did not correlate with the differences in kinetics of fusion mediated by the three different HIV Envs. However, escape from inhibition by reagents that block gp120-CD4 binding, CD4-induced CXCR4 binding and 6-helix bundle formation, respectively, indicated large difference between HIV-1 and HIV-2 envelope glycoproteins in their CD4-induced rates of engagement with CXCR4.ConclusionThe HIV-2 Env proteins studied here exhibited a significantly reduced window of time between the engagement of gp120 with CD4 and exposure of the CXCR4 binding site on gp120 as compared with HIV-1IIIB Env. The efficiency with which HIV-2 Env undergoes this CD4-induced conformational change is the major cause of the relatively rapid rate of HIV-2 Env mediated-fusion.
Highlights
Human Immunodeficiency Virus (HIV) envelope glycoprotein (Env)-mediated fusion is driven by the concerted coalescence of the HIV gp41 N-helical and C-helical regions, which results in the formation of 6 helix bundles
HIV-2SBL and HIV-2ROD Env-mediated fusion, on the other hand, showed no appreciable lag time and 50% of maximum fusion was reached in 23 ± 4 and 28 ± 2 minutes, respectively
Binding of HIV-1 and HIV-2 gp120 to CD4 and CXCR4 In previous studies we have found that fusion rates can be dependent on the affinity with which an Env binds to its coreceptor [9,10]
Summary
HIV envelope glycoprotein (Env)-mediated fusion is driven by the concerted coalescence of the HIV gp N-helical and C-helical regions, which results in the formation of 6 helix bundles. The parameters that govern the HIV Env fusion cascade have yet to be fully elucidated. We address this issue by comparing the kinetics HIV-1IIIB Env with those mediated by HIV-2 from two strains with different affinities for CD4 and CXCR4. Retrovirology 2006, 3:90 http://www.retrovirology.com/content/3/1/90 are quite similar Both membrane-anchored proteins eventually form the 6-helix bundles from the N-terminal and C-terminal regions of the ectodomain [3], which is common to many viral and cellular fusion proteins and which seems to drive fusion [4]. HIV-1IIIB gp helical regions can form more stable 6-helix bundles than HIV2SBL gp helical regions [3,5]; HIV-2 fusion occurs at a lower threshold temperature (25°C), does not require Ca2+ in the medium, is insensitive to treatment of target cells with cytochalasin B [6], and is not affected by target membrane glycosphingolipid composition [7]
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