Role for the Terminal Clasp of HIV-1 gp41 Glycoprotein in the Initiation of Membrane Fusion

Lay, Chan-Sien; Ludlow, Louise E.; Stapleton, David; Bellamy-McIntyre, Anna; Ramsland, Paul A.; Drummer, Heidi E.; Poumbourios, Pantelis

doi:10.1074/jbc.m111.299826

Cited by 10 publications

(14 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other authors had shown an interaction between MPER and FPPR during infection [18][19][20][21][22]. These findings suggested that the interaction between the MPER and the FPPR during infection may generate a conformation able to induce 2F5/4E10-like neutralising antibodies.…”

Section: Discussionmentioning

confidence: 67%

“…There may be several reasons for the failure of many of the attempts to induce 2F5/4E10-like neutralising antibodies including our new approach: First, although it has been shown, that peptides derived from the FPPR increase the binding of mAb 2F5 to its epitope in the MPER/ E2 domain [14] and there is an interaction between MPER and FFPPR [18][19][20][21][22], it is still unknown whether this interaction is also required for the induction of 2F5/4E10-like broadly neutralising antibodies. Second, it remains unclear, whether the DNA immunisation generated the correct membrane associated context.…”

Section: Discussionmentioning

confidence: 99%

“…Interaction of both antibodies with lipids, their long hydrophobic CDR3 loop and cross-reactivity with cardiolipin have been discussed controversially as possible reasons for the failure of all previous immunisation attempts [15][16][17]. Since there is evidence for intramolecular interactions between the MPER and the FPPR during infection and neutralisation [18][19][20][21][22] and a peptide corresponding to the sequence of the FPPR has been shown to increase binding of mAb 2F5 to its epitope [14], it was suggested that the FPPR may be required to generate a conformation which will be able to induce broadly neutralising antibodies of the 2F5 and 4E10.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Induction of Antibodies Specific for Gp41 of HIV-1 by Gene Gun DNA Vaccination

Behrendt¹,

Fiebig²

2012

J Vaccines Vaccin

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Induction of Antibodies Specific for Gp41 of HIV-1 by Gene Gun DNA Vaccination

Behrendt¹,

Fiebig²

2012

J Vaccines Vaccin

View full text Add to dashboard Cite

“…Conserved aromatic and hydrophobic residues penetrate into the hydrophobic phase of the membrane (37)(38)(39). Mutational studies revealed that the conserved W 666 -W 670 -W 672 -W 678 -W 680 motif of the MPER functions cooperatively in the membrane fusion process (40,41) and that hydrophobic and aromatic MPER residues participate in forming a clasp that stabilizes the membrane-interactive end of the 6-helix bundle conformation of gp41 to initiate membrane fusion (42,43).…”

mentioning

confidence: 99%

Distinct functions for the membrane-proximal ectodomain region (MPER) of HIV-1 gp41 in cell-free and cell–cell viral transmission and cell–cell fusion

Narasimhulu

Bellamy-McIntyre

Laumaea

et al. 2018

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

HIV-1 is spread by cell-free virions and by cell-cell viral transfer. We asked whether the structure and function of a broad neutralizing antibody (bNAb) epitope, the membrane-proximal ectodomain region (MPER) of the viral gp41 transmembrane glycoprotein, differ in cell-free and cell-cell-transmitted viruses and whether this difference could be related to Ab neutralization sensitivity. Whereas cell-free viruses bearing W666A and I675A substitutions in the MPER lacked infectivity, cell-associated mutant viruses were able to initiate robust spreading infection. Infectivity was restored to cell-free viruses by additional substitutions in the cytoplasmic tail (CT) of gp41 known to disrupt interactions with the viral matrix protein. We observed contrasting effects on cell-free virus infectivity when W666A was introduced to two transmitted/founder isolates, but both mutants could still mediate cell-cell spread. Domain swapping indicated that the disparate W666A phenotypes of the cell-free transmitted/founder viruses are controlled by sequences in variable regions 1, 2, and 4 of gp120. The sequential passaging of an MPER mutant (W672A) in peripheral blood mononuclear cells enabled selection of viral revertants with loss-of-glycan suppressor mutations in variable region 1, suggesting a functional interaction between variable region 1 and the MPER. An MPER-directed bNAb neutralized cell-free virus but not cell-cell viral spread. Our results suggest that the MPER of cell-cell-transmitted virions has a malleable structure that tolerates mutagenic disruption but is not accessible to bNAbs. In cell-free virions, interactions mediated by the CT impose an alternative MPER structure that is less tolerant of mutagenic alteration and is efficiently targeted by bNAbs.

show abstract

“…It is also possible that D674E directly enhances an MPER-related function in virus-cell fusion [25,49]. For example, greater flexibility in the MPER may facilitate its relocation from the lipid-polar head group interfacial region of the envelope for interaction with the fusion peptide-proximal segment during terminal clasp formation at the membrane-proximal end of the 6-helix bundle during the initiation of fusion [28,30]. Alternatively, the membrane perturbing properties of the MPER may be enhanced by D674E [26,50-52].…”

Section: Discussionmentioning

confidence: 99%

Forced virus evolution reveals functional crosstalk between the disulfide bonded region and membrane proximal ectodomain region of HIV-1 gp41

et al. 2013

Self Cite

View full text Add to dashboard Cite

Background: The disulfide-bonded region (DSR) of HIV-1 gp41 mediates association with gp120 and plays a role in transmission of receptor-induced conformational changes in gp120 to gp41 that activate membrane fusion function. In this study, forced viral evolution of a DSR mutant that sheds gp120 was employed to identify domains within gp120-gp41 that are functionally linked to the glycoprotein association site. Results: The HIV-1 AD8 mutant, W596L/K601D, was serially passaged in U87.CD4.CCR5 cells until replication was restored. Whereas the W596L mutation persisted throughout the cultures, a D601H pseudoreversion in the DSR partially restored cell-free virus infectivity and virion gp120-gp41 association, with further improvements to cell-free virus infectivity following a 2nd-site D674E mutation in the membrane-proximal external region (MPER) of gp41. In an independent culture, D601H appeared with a deletion in V4 (Thr-394-Trp-395) and a D674N substitution in the MPER, however this MPER mutation was inhibitory to W596L/K601H cell-free virus infectivity. While cell-free virus infectivity was not fully restored for the revertant genotypes, their cell-to-cell transmission approached the levels observed for WT. Interestingly, the functional boost associated with the addition of D674E to W596L/K601H was not observed for cell-cell fusion where the cell-surface expressed glycoproteins function independently of virion assembly. The W596L/K601H and W596L/K601H/D674E viruses exhibited greater sensitivity to neutralization by the broadly reactive MPER directed monoclonal antibodies, 2F5 and 4E10, indicating that the reverting mutations increase the availability of conserved neutralization epitopes in the MPER. Conclusions: The data indicate for the first time that functional crosstalk between the DSR and MPER operates in the context of assembled virions, with the Leu-596-His-601-Glu-674 combination optimizing viral spread via the cell-to-cell route. Our data also indicate that changes in the gp120-gp41 association site may increase the exposure of conserved MPER neutralization epitopes in virus.

show abstract

Role for the Terminal Clasp of HIV-1 gp41 Glycoprotein in the Initiation of Membrane Fusion

Cited by 10 publications

References 62 publications

Induction of Antibodies Specific for Gp41 of HIV-1 by Gene Gun DNA Vaccination

Induction of Antibodies Specific for Gp41 of HIV-1 by Gene Gun DNA Vaccination

Distinct functions for the membrane-proximal ectodomain region (MPER) of HIV-1 gp41 in cell-free and cell–cell viral transmission and cell–cell fusion

Forced virus evolution reveals functional crosstalk between the disulfide bonded region and membrane proximal ectodomain region of HIV-1 gp41

Contact Info

Product

Resources

About