The Experts below are selected from a list of 280350 Experts worldwide ranked by ideXlab platform
Joseph Sodroski - One of the best experts on this subject based on the ideXlab platform.
-
conformational differences between functional human immunodeficiency virus envelope glycoprotein trimers and stabilized soluble trimers
Journal of Virology, 2018Co-Authors: Luis R Castillomenendez, Hanh T Nguyen, Joseph SodroskiAbstract:ABSTRACT Binding to the receptor CD4 triggers entry-related conformational changes in the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer, (gp120/Gp41) 3 . Soluble versions of HIV-1 Env trimers (sgp140 SOSIP.664) stabilized by a gp120-Gp41 disulfide bond and a change (I559P) in Gp41 have been structurally characterized. Here, we use cross-linking/mass spectrometry to evaluate the conformations of functional membrane Env and sgp140 SOSIP.664. Differences were detected in the gp120 trimer association domain and C terminus and in the Gp41 heptad repeat 1 (HR1) region. Whereas the membrane Env trimer exposes the Gp41 HR1 coiled coil only after CD4 binding, the sgp140 SOSIP.664 HR1 coiled coil was accessible to the Gp41 HR2 peptide even in the absence of CD4. Our results delineate differences in both gp120 and Gp41 subunits between functional membrane Env and the sgp140 SOSIP.664 trimer and provide distance constraints that can assist validation of candidate structural models of the native HIV-1 Env trimer. IMPORTANCE HIV-1 envelope glycoprotein spikes mediate the entry of the virus into host cells and are a major target for vaccine-induced antibodies. Soluble forms of the envelope glycoproteins that are stable and easily produced have been characterized extensively and are being considered as vaccines. Here, we present evidence that these stabilized soluble envelope glycoproteins differ in multiple respects from the natural HIV-1 envelope glycoproteins. By pinpointing these differences, our results can guide the improvement of envelope glycoprotein preparations to achieve greater similarity to the viral envelope glycoprotein spike, potentially increasing their effectiveness as a vaccine.
-
subunit organization of the membrane bound hiv 1 envelope glycoprotein trimer
Nature Structural & Molecular Biology, 2012Co-Authors: Youdong Mao, Joseph Sodroski, Alon Herschhorn, Shi Hua Xiang, Xinzhen Yang, Liping Wang, Hillel HaimAbstract:The trimeric human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) spike is a molecular machine that mediates virus entry into host cells and is the sole target for virusneutralizing antibodies. The mature Env spike results from cleavage of a trimeric gp160 precursor into three gp120 and three Gp41 subunits. Here we describe an ~11-A cryo-EM structure of the trimeric HIV-1 Env precursor in its unliganded state. The three gp120 and three Gp41 subunits form a cage-like structure with an interior void surrounding the trimer axis. Interprotomer contacts are limited to the Gp41 transmembrane region, the torus-like Gp41 ectodomain, and a gp120 trimer association domain composed of the V1/V2 and V3 variable regions. The cage-like architecture, which is unique among characterized viral envelope proteins, restricts antibody access, reflecting requirements imposed by HIV-1 persistence in the host.
-
a v3 loop dependent gp120 element disrupted by cd4 binding stabilizes the human immunodeficiency virus envelope glycoprotein trimer
Journal of Virology, 2010Co-Authors: Shi Hua Xiang, Beatriz Pacheco, Andres Finzi, Kevin M Alexander, Wen Yuan, Carlo Rizzuto, Chih Chin Huang, Peter D Kwong, Joseph SodroskiAbstract:Human immunodeficiency virus (HIV-1) entry into cells is mediated by a trimeric complex consisting of noncovalently associated gp120 (exterior) and Gp41 (transmembrane) envelope glycoproteins. The binding of gp120 to receptors on the target cell alters the gp120-Gp41 relationship and activates the membrane-fusing capacity of Gp41. Interaction of gp120 with the primary receptor, CD4, results in the exposure of the gp120 third variable (V3) loop, which contributes to binding the CCR5 or CXCR4 chemokine receptors. We show here that insertions in the V3 stem or polar substitutions in a conserved hydrophobic patch near the V3 tip result in decreased gp120-Gp41 association (in the unliganded state) and decreased chemokine receptor binding (in the CD4-bound state). Subunit association and syncytium-forming ability of the envelope glycoproteins from primary HIV-1 isolates were disrupted more by V3 changes than those of laboratory-adapted HIV-1 envelope glycoproteins. Changes in the gp120 β2, β19, β20, and β21 strands, which evidence suggests are proximal to the V3 loop in unliganded gp120, also resulted in decreased gp120-Gp41 association. Thus, a gp120 element composed of the V3 loop and adjacent beta strands contributes to quaternary interactions that stabilize the unliganded trimer. CD4 binding dismantles this element, altering the gp120-Gp41 relationship and rendering the hydrophobic patch in the V3 tip available for chemokine receptor binding.
-
role of the gp120 inner domain β sandwich in the interaction between the human immunodeficiency virus envelope glycoprotein subunits
Virology, 2003Co-Authors: Xinzhen Yang, Erin Mahony, Geoff H Holm, Aemro Kassa, Joseph SodroskiAbstract:The inner domain of the human immunodeficiency virus (HIV-1) gp120 glycoprotein has been proposed to mediate the noncovalent interaction with the Gp41 transmembrane envelope glycoprotein. We used mutagenesis to investigate the functional importance of a conserved beta-sandwich located within the gp120 inner domain. Changes in aliphatic residues lining a hydrophobic groove on the surface of the beta-sandwich decreased the association of the gp120 and Gp41 glycoproteins. Other changes in the base of the hydrophobic groove resulted in envelope glycoproteins that were structurally intact and able to bind receptors, but were inefficient in mediating either syncytium formation or virus entry. These results support a model in which the beta-sandwich in the gp120 inner domain contributes to gp120-Gp41 contacts, thereby maintaining the integrity of the envelope glycoprotein complex and allowing adjustments in the gp120-Gp41 interaction required for membrane fusion.
-
analysis of the interaction of the human immunodeficiency virus type 1 gp120 envelope glycoprotein with the Gp41 transmembrane glycoprotein
Journal of Virology, 1997Co-Authors: Richard T Wyatt, Elizabeth Desjardin, Udy Olshevsky, Christopher C Nixon, James M Binley, Varda Olshevsky, Joseph SodroskiAbstract:The human immunodeficiency virus type 1 (HIV-1) gp120 exterior envelope glycoprotein interacts with the viral receptor (CD4) and with the Gp41 transmembrane envelope glycoprotein. To study the interaction of the gp120 and Gp41 envelope glycoproteins, we compared the abilities of anti-gp120 monoclonal antibodies to bind soluble gp120 and a soluble glycoprotein, sgp140, that contains gp120 and Gp41 exterior domains. The occlusion or alteration of a subset of gp120 epitopes on the latter molecule allowed the definition of a Gp41 "footprint" on the gp120 antibody competition map. The occlusion of these epitopes on the sgp140 glycoprotein was decreased by the binding of soluble CD4. The gp120 epitopes implicated in the interaction with the Gp41 ectodomain were disrupted by deletions of the first (C1) and fifth (C5) conserved gp120 regions. These deletions did not affect the integrity of the discontinuous binding sites for CD4 and neutralizing monoclonal antibodies. Thus, the Gp41 interface on the HIV-1 gp120 glycoprotein, which elicits nonneutralizing antibodies, can be removed while retaining immunologically desirable gp120 structures.
Miriam Gochin - One of the best experts on this subject based on the ideXlab platform.
-
biochemistry and biophysics of hiv 1 Gp41 membrane interactions and implications for hiv 1 envelope protein mediated viral cell fusion and fusion inhibitor design
Current Topics in Medicinal Chemistry, 2011Co-Authors: Miriam GochinAbstract:Human immunodeficiency virus type 1 (HIV-1), the pathogen of acquired immunodeficiency syndrome (AIDS), causes ∼2 millions death every year and still defies an effective vaccine. HIV-1 infects host cells through envelope protein - mediated virus-cell fusion. The transmembrane subunit of envelope protein, Gp41, is the molecular machinery which facilitates fusion. Its ectodomain contains several distinguishing functional domains, fusion peptide (FP), Nterminal heptad repeat (NHR), C-terminal heptad repeat (CHR) and membrane proximal extracellular region (MPER). During the fusion process, FP inserts into the host cell membrane, and an extended Gp41 prehairpin conformation bridges the viral and cell membranes through MPER and FP respectively. Subsequent conformational change of the unstable prehairpin results in a coiled-coil 6-helix bundle (6HB) structure formed between NHR and CHR. The energetics of 6HB formation drives membrane apposition and fusion. Drugs targeting Gp41 functional domains to prevent 6HB formation inhibit HIV-1 infection. T20 (enfuvirtide, Fuzeon) was approved by the US FDA in 2003 as the first fusion inhibitor. It is a 36-residue peptide from the Gp41 CHR, and it inhibits 6HB formation by targeting NHR and lipids. Development of new fusion inhibitors, especially small molecule drugs, is encouraged to overcome the shortcomings of T20 as a peptide drug. Hydrophobic characteristics and membrane association are critical for Gp41 function and mechanism of action. Research in Gp41-membrane interactions, using peptides corresponding to specific functional domains, or constructs including several interactive domains, are reviewed here to get a better understanding of Gp41 mediated virus-cell fusion that can inform or guide the design of new HIV-1 fusion inhibitors.
-
biochemistry and biophysics of hiv 1 Gp41 membrane interactions and implications for hiv 1 envelope protein mediated viral cell fusion and fusion inhibitor design
Current Topics in Medicinal Chemistry, 2011Co-Authors: Lifeng Cai, Miriam Gochin, Keliang LiuAbstract:Human immunodeficiency virus type 1 (HIV-1), the pathogen of acquired immunodeficiency syndrome (AIDS), causes ∼2 millions death every year and still defies an effective vaccine. HIV-1 infects host cells through envelope protein - mediated virus-cell fusion. The transmembrane subunit of envelope protein, Gp41, is the molecular machinery which facilitates fusion. Its ectodomain contains several distinguishing functional domains, fusion peptide (FP), Nterminal heptad repeat (NHR), C-terminal heptad repeat (CHR) and membrane proximal extracellular region (MPER). During the fusion process, FP inserts into the host cell membrane, and an extended Gp41 prehairpin conformation bridges the viral and cell membranes through MPER and FP respectively. Subsequent conformational change of the unstable prehairpin results in a coiled-coil 6-helix bundle (6HB) structure formed between NHR and CHR. The energetics of 6HB formation drives membrane apposition and fusion. Drugs targeting Gp41 functional domains to prevent 6HB formation inhibit HIV-1 infection. T20 (enfuvirtide, Fuzeon) was approved by the US FDA in 2003 as the first fusion inhibitor. It is a 36-residue peptide from the Gp41 CHR, and it inhibits 6HB formation by targeting NHR and lipids. Development of new fusion inhibitors, especially small molecule drugs, is encouraged to overcome the shortcomings of T20 as a peptide drug. Hydrophobic characteristics and membrane association are critical for Gp41 function and mechanism of action. Research in Gp41-membrane interactions, using peptides corresponding to specific functional domains, or constructs including several interactive domains, are reviewed here to get a better understanding of Gp41 mediated virus-cell fusion that can inform or guide the design of new HIV-1 fusion inhibitors.
Pantelis Poumbourios - One of the best experts on this subject based on the ideXlab platform.
-
functional links between the fusion peptide proximal polar segment and membrane proximal region of human immunodeficiency virus Gp41 in distinct phases of membrane fusion
Journal of Biological Chemistry, 2007Co-Authors: Anna Kathryn Bellamymcintyre, Chansien Lay, Severine Baar, Anne L Maerz, Gert H Talbo, Heidi E Drummer, Pantelis PoumbouriosAbstract:The binding of CD4 and chemokine receptors to the gp120 attachment glycoprotein of human immunodeficiency virus triggers refolding of the associated Gp41 fusion glycoprotein into a trimer of hairpins with a 6-helix bundle (6HB) core. These events lead to membrane fusion and viral entry. Here, we examined the functions of the fusion peptide-proximal polar segment and membrane-proximal Trp-rich region (MPR), which are exterior to the 6HB. Alanine substitution of Trp(666), Trp(672), Phe(673), and Ile(675) in the MPR reduced entry by up to 120-fold without affecting gp120-Gp41 association or cell-cell fusion. The L537A polar segment mutation led to the loss of gp120 from the gp120-Gp41 complex, reduced entry by approximately 10-fold, but did not affect cell-cell fusion. Simultaneous Ala substitution of Leu(537) with Trp(666), Trp(672), Phe(673), or Ile(675) abolished entry with 50-80% reductions in cell-cell fusion. gp120-Gp41 complexes of fusion-defective double mutants were resistant to soluble CD4-induced shedding of gp120, suggesting that their ability to undergo receptor-induced conformational changes was compromised. Consistent with this idea, a representative mutation, L537A/W666A, led to an approximately 80% reduction in lipophilic fluorescent dye transfer between gp120-Gp41-expressing cells and receptor-expressing targets, indicating a block prior to the lipid-mixing phase. The L537A/W666A double mutation increased the chymotrypsin sensitivity of the polar segment in a trimer of hairpins model, comprising the 6HB core, the polar segment, and MPR linked N-terminally to maltose-binding protein. The data indicate that the polar segment and MPR of Gp41 act synergistically in forming a fusion-competent gp120-Gp41 complex and in stabilizing the membrane-interactive end of the trimer of hairpins.
-
functional links between the fusion peptide proximal polar segment and membrane proximal region of human immunodeficiency virus Gp41 in distinct phases of membrane fusion
Journal of Biological Chemistry, 2007Co-Authors: Anna Kathryn Bellamymcintyre, Chansien Lay, Severine Baar, Anne L Maerz, Gert H Talbo, Heidi E Drummer, Pantelis PoumbouriosAbstract:Abstract The binding of CD4 and chemokine receptors to the gp120 attachment glycoprotein of human immunodeficiency virus triggers refolding of the associated Gp41 fusion glycoprotein into a trimer of hairpins with a 6-helix bundle (6HB) core. These events lead to membrane fusion and viral entry. Here, we examined the functions of the fusion peptide-proximal polar segment and membrane-proximal Trp-rich region (MPR), which are exterior to the 6HB. Alanine substitution of Trp666, Trp672, Phe673, and Ile675 in the MPR reduced entry by up to 120-fold without affecting gp120-Gp41 association or cell-cell fusion. The L537A polar segment mutation led to the loss of gp120 from the gp120-Gp41 complex, reduced entry by ∼10-fold, but did not affect cell-cell fusion. Simultaneous Ala substitution of Leu537 with Trp666, Trp672, Phe673, or Ile675 abolished entry with 50–80% reductions in cell-cell fusion. gp120-Gp41 complexes of fusion-defective double mutants were resistant to soluble CD4-induced shedding of gp120, suggesting that their ability to undergo receptor-induced conformational changes was compromised. Consistent with this idea, a representative mutation, L537A/W666A, led to an ∼80% reduction in lipophilic fluorescent dye transfer between gp120-Gp41-expressing cells and receptor-expressing targets, indicating a block prior to the lipid-mixing phase. The L537A/W666A double mutation increased the chymotrypsin sensitivity of the polar segment in a trimer of hairpins model, comprising the 6HB core, the polar segment, and MPR linked N-terminally to maltose-binding protein. The data indicate that the polar segment and MPR of Gp41 act synergistically in forming a fusion-competent gp120-Gp41 complex and in stabilizing the membrane-interactive end of the trimer of hairpins.
-
crystal structure of human t cell leukemia virus type 1 gp21 ectodomain crystallized as a maltose binding protein chimera reveals structural evolution of retroviral transmembrane proteins
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Bostjan Kobe, Bruce E Kemp, Pantelis PoumbouriosAbstract:Retroviral entry into cells depends on envelope glycoproteins, whereby receptor binding to the surface-exposed subunit triggers membrane fusion by the transmembrane protein (TM) subunit. We determined the crystal structure at 2.5-A resolution of the ectodomain of gp21, the TM from human T cell leukemia virus type 1. The gp21 fragment was crystallized as a maltose-binding protein chimera, and the maltose-binding protein domain was used to solve the initial phases by the method of molecular replacement. The structure of gp21 comprises an N-terminal trimeric coiled coil, an adjacent disulfide-bonded loop that stabilizes a chain reversal, and a C-terminal sequence structurally distinct from HIV type 1/simian immunodeficiency virus Gp41 that packs against the coil in an extended antiparallel fashion. Comparison of the gp21 structure with the structures of other retroviral TMs contrasts the conserved nature of the coiled coil-forming region and adjacent disulfide-bonded loop with the variable nature of the C-terminal ectodomain segment. The structure points to these features having evolved to enable the dual roles of retroviral TMs: conserved fusion function and an ability to anchor diverse surface-exposed subunit structures to the virion envelope and infected cell surface. The structure of gp21 implies that the N-terminal fusion peptide is in close proximity to the C-terminal transmembrane domain and likely represents a postfusion conformation.
Shibo Jiang - One of the best experts on this subject based on the ideXlab platform.
-
an amphiphilic conjugate approach toward the design and synthesis of betulinic acid polyphenol conjugates as inhibitors of the hiv 1 Gp41 fusion core formation
ChemMedChem, 2011Co-Authors: Zhuofeng Ke, Shibo Jiang, Kwok Yiu Wu, Wenhua Chen, Zhihong JiangAbstract:Exploration of potent inhibitors of the HIV-1 Gp41 fusion core formation is a promising strategy to discover small-molecule HIV-1 entry inhibitors for the treatment of HIV-1 infection. In this paper, a series of novel betulinic acid–polyphenol conjugates was designed, guided by molecular modeling of the binding of betulinic acid (BA) and phenolic galloyl/caffeoyl groups in the groove on the Gp41 N-terminal heptad repeat (NHR) trimeric coiled coil. These conjugates were synthesized via conjugation of galloyl and caffeoyl groups with BA at the C-28 position. Their inhibitory activities of HIV Gp41 six-helix bundle (6-HB) formation between the NHR peptide N36 and the C-terminal heptad repeat (CHR) peptide C34 were evaluated with size-exclusion HPLC. Conjugates bearing a galloyl group were found to exhibit four to sixfold higher inhibitory activities than that of parent compound BA, suggesting that they may be exploitable as HIV-1 fusion/entry inhibitors targeting Gp41. The docking study on BA and its derivatives suggests that hydrophobic and hydrogen-bonding pockets exist in the groove of the Gp41 NHR trimeric coiled coil and that a potent inhibitor should have amphiphilic structures to cooperatively interact with both pockets. This possibility was explored by incorporating both lipophilic and hydrophilic groups into the conjugates in a well-defined orientation to bind with both pockets in the Gp41 NHR-trimer.
-
surface exposure of the hiv 1 env cytoplasmic tail llp2 domain during the membrane fusion process interaction with Gp41 fusion core
Journal of Biological Chemistry, 2008Co-Authors: Lu Lu, Shibo Jiang, Xi Chen, Jinghe Huang, Hengwen Yang, Yinghua ChenAbstract:Abstract HIV-1 Gp41 cytoplasmic tail (CT) is highly conserved among HIV-1 isolates, particularly the region designated lentivirus lytic peptide (LLP1–2), which includes two α-helical domains LLP1 and LLP2. Although the Gp41 CT is recognized as a modulator of viral fusogenicity, little is known about the regulatory mechanism of this region in the viral fusion process. Here we report that anti-LLP1–2 and anti-LLP2 antibodies (IgG) inhibited HIV-1 Env-mediated cell fusion and bound to the interface between effector and target cells at a suboptimal temperature (31.5 °C), which slows down the fusion process and prolongs the fusion intermediate state. This suggests that LLP1–2, especially the LLP2 region located inside the viral membrane, is transiently exposed on the membrane surface during the fusion process. Synthetic LLP2 peptide could bind to the Gp41 six-helix bundle core with high binding affinity. These results suggest that the Gp41 CT may interact with the Gp41 core, via the surface-exposed LLP2 domain, to regulate Env-mediated membrane fusion.
-
HIV entry inhibitors targeting Gp41: from polypeptides to small-molecule compounds.
Current pharmaceutical design, 2007Co-Authors: Shu Wen Liu, Shibo JiangAbstract:HIV envelope glycoprotein transmembrane subunit Gp41 plays a critical role in the fusion between viral and target cell membranes. Upon gp120 binding to CD4 and a coreceptor (CCR5 or CXCR4), Gp41 changes its conformation by forming N-helix trimer between N-heptad repeats (NHRs) and then six-helix bundle between the N-trimer and the Cheptad repeats (CHRs). Peptides derived from the NHR and CHR of Gp41 extracellular region have demonstrated potent inhibitory activity on the HIV mediated cell fusion. One of these peptides, T-20, became the first success of a new class of anti-HIV agents, named HIV entry inhibitors. However, a relatively long peptide such as T-20 suffers from several limitations including lack of oral bioavailability and high cost of production. Great efforts have been made to develop alternative peptides and proteins with improved anti-HIV-1 activity, increased bioavailability and reduced cost of production. The most promising approach is the development of small molecule HIV entry inhibitors targeting Gp41. Any molecule that blocks the process of NHR homotrimerization and the six-helix bundle formation by targeting the Gp41 NHR, NHR trimer and CHR may inhibit HIV-mediated membrane fusion. The progress in development of those anti-HIV agents targeting Gp41, from polypeptides to small-molecule compounds, is reviewed.
-
different from the hiv fusion inhibitor c34 the anti hiv drug fuzeon t 20 inhibits hiv 1 entry by targeting multiple sites in Gp41 and gp120
Journal of Biological Chemistry, 2005Co-Authors: Shu Wen Liu, Jinkui Niu, Shibo JiangAbstract:Fuzeon (also known as T-20 or enfuvirtide), one of the C-peptides derived from the HIV-1 envelope glycoprotein transmembrane subunit Gp41 C-terminal heptad repeat (CHR) region, is the first member of a new class of anti-HIV drugs known as HIV fusion inhibitors. It has been widely believed that T-20 shares the same mechanism of action with C34, another C-peptide. The C34 is known to compete with the CHR of Gp41 to form a stable 6-helix bundle (6-HB) with the Gp41 N-terminal heptad repeat (NHR) and prevent the formation of the fusogenic Gp41 core between viral Gp41 NHR and CHR, thereby inhibiting fusion between viral and target cell membranes. Here we present data to demonstrate that, contrary to this belief, T-20 cannot form stable 6-HB with N-peptides derived from the NHR region, nor can it inhibit the 6-HB formation of the fusogenic core. Instead, it may interact with N-peptides to form unstable or insoluble complexes. Our data suggest that T-20 has a different mechanism of action from C34. The interaction of T-20 with viral NHR region alone may not prevent the formation of the fusion active Gp41 core. We also demonstrate that the T-20-mediated anti-HIV activity can be significantly abrogated by peptides derived from the membrane-spanning domain in Gp41 and coreceptor binding site in gp120. These new findings imply that T-20 inhibits HIV-1 entry by targeting multiple sites in Gp41 and gp120. Further elucidation of the mechanism of action of T-20 will provide new target(s) for development of novel HIV entry inhibitors.
-
structure based identification of small molecule antiviral compounds targeted to the Gp41 core structure of the human immunodeficiency virus type 1
Journal of Medicinal Chemistry, 1999Co-Authors: Asim Kumar Debnath, Lin Radigan, Shibo JiangAbstract:Recent X-ray crystallographic determination of the HIV-1 envelope glycoprotein Gp41 core structure opened up a new avenue to discover antiviral agents for chemotherapy of HIV-1 infection and AIDS. We have undertaken a systematic study to search for anti-HIV-1 lead compounds targeted to Gp41. Using molecular docking techniques to screen a database of 20 000 organic molecules, we found 16 compounds with the best fit for docking into the hydrophobic cavity within the Gp41 core and with maximum possible interactions with the target site. Further testing of these compounds by an enzyme-linked immunosorbent assay and virus inhibition assays discerned two compounds (ADS-J1 and ADS-J2) having inhibitory activity at micromolar concentrations on the formation of the Gp41 core structure and on HIV-1 infection. These two compounds will be used as leads to design more effective HIV-1 inhibitors targeted to the HIV-1 Gp41 core structure.
Keliang Liu - One of the best experts on this subject based on the ideXlab platform.
-
biochemistry and biophysics of hiv 1 Gp41 membrane interactions and implications for hiv 1 envelope protein mediated viral cell fusion and fusion inhibitor design
Current Topics in Medicinal Chemistry, 2011Co-Authors: Lifeng Cai, Miriam Gochin, Keliang LiuAbstract:Human immunodeficiency virus type 1 (HIV-1), the pathogen of acquired immunodeficiency syndrome (AIDS), causes ∼2 millions death every year and still defies an effective vaccine. HIV-1 infects host cells through envelope protein - mediated virus-cell fusion. The transmembrane subunit of envelope protein, Gp41, is the molecular machinery which facilitates fusion. Its ectodomain contains several distinguishing functional domains, fusion peptide (FP), Nterminal heptad repeat (NHR), C-terminal heptad repeat (CHR) and membrane proximal extracellular region (MPER). During the fusion process, FP inserts into the host cell membrane, and an extended Gp41 prehairpin conformation bridges the viral and cell membranes through MPER and FP respectively. Subsequent conformational change of the unstable prehairpin results in a coiled-coil 6-helix bundle (6HB) structure formed between NHR and CHR. The energetics of 6HB formation drives membrane apposition and fusion. Drugs targeting Gp41 functional domains to prevent 6HB formation inhibit HIV-1 infection. T20 (enfuvirtide, Fuzeon) was approved by the US FDA in 2003 as the first fusion inhibitor. It is a 36-residue peptide from the Gp41 CHR, and it inhibits 6HB formation by targeting NHR and lipids. Development of new fusion inhibitors, especially small molecule drugs, is encouraged to overcome the shortcomings of T20 as a peptide drug. Hydrophobic characteristics and membrane association are critical for Gp41 function and mechanism of action. Research in Gp41-membrane interactions, using peptides corresponding to specific functional domains, or constructs including several interactive domains, are reviewed here to get a better understanding of Gp41 mediated virus-cell fusion that can inform or guide the design of new HIV-1 fusion inhibitors.
