Genomes and Genes
hiv envelope protein gp41
Summary: Transmembrane envelope protein of the HUMAN IMMUNODEFICIENCY VIRUS which is encoded by the HIV env gene. It has a molecular weight of 41,000 and is glycosylated. The N-terminal part of gp41 is thought to be involved in CELL FUSION with the CD4 ANTIGENS of T4 LYMPHOCYTES, leading to syncytial formation. Gp41 is one of the most common HIV antigens detected by IMMUNOBLOTTING.
- Merk A, Subramaniam S. HIV-1 envelope glycoprotein structure. Curr Opin Struct Biol. 2013;23:268-76 pubmed publisher..Here, we review recent developments in these fields as they relate to our understanding of the structure and function of HIV-1 envelope glycoproteins. ..
- Kim M, Sun Z, Rand K, Shi X, Song L, Cheng Y, et al. Antibody mechanics on a membrane-bound HIV segment essential for GP41-targeted viral neutralization. Nat Struct Mol Biol. 2011;18:1235-43 pubmed publisher..Hence, target neutralization through this lipid-embedded viral segment places stringent requirements on the plasticity of the antibody combining site. ..
- Lay C, Ludlow L, Stapleton D, Bellamy McIntyre A, Ramsland P, Drummer H, et al. Role for the terminal clasp of HIV-1 gp41 glycoprotein in the initiation of membrane fusion. J Biol Chem. 2011;286:41331-43 pubmed publisher..These findings reveal a novel conserved functional target for the discovery of fusion inhibitors. ..
- Bonora S, Calcagno A, Cometto C, Fontana S, Aguilar D, D Avolio A, et al. Short-term additional enfuvirtide therapy is associated with a greater immunological recovery in HIV very late presenters: a controlled pilot study. Infection. 2012;40:69-75 pubmed publisher..Induction strategies using an enfuvirtide-based approach in such subjects warrant further investigation. ..
- Qiu S, Yi H, Hu J, Cao Z, Wu Y, Li W. The binding mode of fusion inhibitor T20 onto HIV-1 gp41 and relevant T20-resistant mechanisms explored by computational study. Curr HIV Res. 2012;10:182-94 pubmed..Besides, mutations G36D, Q39H and L45M only caused minor conformational and energetic changes. In all, these results could provide new clues for the design of T20-like peptide inhibitors to target the T20-resistant virus. ..
- McCoy L, Weiss R. Neutralizing antibodies to HIV-1 induced by immunization. J Exp Med. 2013;210:209-23 pubmed publisher..A greater understanding of the successes and failures for inducing a neutralizing response upon immunization is required to accelerate the development of an effective HIV vaccine. ..
- Mao Y, Wang L, Gu C, Herschhorn A, Desormeaux A, Finzi A, et al. Molecular architecture of the uncleaved HIV-1 envelope glycoprotein trimer. Proc Natl Acad Sci U S A. 2013;110:12438-43 pubmed publisher..The Env trimer architecture provides mechanistic insights into the metastability of the unliganded state, receptor-induced conformational changes, and quaternary structure-based strategies for immune evasion. ..
- Garg H, Joshi A, Ye C, Shankar P, Manjunath N. Single amino acid change in gp41 region of HIV-1 alters bystander apoptosis and CD4 decline in humanized mice. Virol J. 2011;8:34 pubmed publisher..We conclude that Env fusion activity is one of the determinants of HIV pathogenesis and it may be possible to attenuate HIV by targeting gp41. ..
- Gnanakaran S, Daniels M, Bhattacharya T, Lapedes A, Sethi A, Li M, et al. Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies. PLoS Comput Biol. 2010;6:e1000955 pubmed publisher..Five sites were in the CD4-induced coreceptor binding site of gp120, suggesting an important role for this region in the elicitation of broadly neutralizing antibody responses against HIV-1. ..
- Denner J. Towards an AIDS vaccine: the transmembrane envelope protein as target for broadly neutralizing antibodies. Hum Vaccin. 2011;7 Suppl:4-9 pubmed..These data may help to design antigens able to induce specific broadly neutralizing antibodies. ..
- Pejchal R, Wilson I. Structure-based vaccine design in HIV: blind men and the elephant?. Curr Pharm Des. 2010;16:3744-53 pubmed
- Liu S, Kondo N, Long Y, Xiao D, Iwamoto A, Matsuda Z. Membrane topology analysis of HIV-1 envelope glycoprotein gp41. Retrovirology. 2010;7:100 pubmed publisher..It is likely that a single MSD model for HIV-1 gp41 holds true even in the presence of membrane fusion. The degree of the augmentation of membrane permeability we observed was dependent on the membrane fusion and sequence of the MSD. ..
- Dennison S, Anasti K, Scearce R, Sutherland L, Parks R, Xia S, et al. Nonneutralizing HIV-1 gp41 envelope cluster II human monoclonal antibodies show polyreactivity for binding to phospholipids and protein autoantigens. J Virol. 2011;85:1340-7 pubmed publisher..These results demonstrate that lipid-reactive gp41 cluster II antibodies are nonneutralizing due to their inability to bind to the relevant neutralizing epitopes on gp41. ..
- Montero M, Gulzar N, Klaric K, Donald J, Lepik C, Wu S, et al. Neutralizing epitopes in the membrane-proximal external region of HIV-1 gp41 are influenced by the transmembrane domain and the plasma membrane. J Virol. 2012;86:2930-41 pubmed publisher..Replacement of the gp41 TM and CT of MPER-TM1 with the PDGFR TM reduced binding by MAb 4E10, but not 2F5, indicating that the gp41 TM plays a pivotal role in orienting the 4E10 epitope, and more globally, in affecting MPER exposure. ..
- Archary D, Gordon M, Green T, Coovadia H, Goulder P, Ndung u T. HIV-1 subtype C envelope characteristics associated with divergent rates of chronic disease progression. Retrovirology. 2010;7:92 pubmed publisher..These data also indicate that the pattern of envelope evolution is an important correlate of disease progression in chronic HIV-1 subtype C infection. ..
- Liao H, Chen X, Munshaw S, Zhang R, Marshall D, Vandergrift N, et al. Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated. J Exp Med. 2011;208:2237-49 pubmed publisher..These data suggest that the majority of gp41-binding antibodies produced after acute HIV-1 infection are cross-reactive responses generated by stimulating memory B cells that have previously been activated by non-HIV-1 antigens. ..
- Jain S, Patrick A, Rosenthal K. Multiple tandem copies of conserved gp41 epitopes incorporated in gag virus-like particles elicit systemic and mucosal antibodies in an optimized heterologous vector delivery regimen. Vaccine. 2010;28:7070-80 pubmed publisher..This alternative design strategy and the implementation of optimized heterologous immunization regimens can serve to 'immuno-focus' and significantly increase epitope-specific titers. ..
- Gallien S, Braun J, Delaugerre C, Charreau I, Reynes J, Jeanblanc F, et al. Efficacy and safety of raltegravir in treatment-experienced HIV-1-infected patients switching from enfuvirtide-based regimens: 48 week results of the randomized EASIER ANRS 138 trial. J Antimicrob Chemother. 2011;66:2099-106 pubmed publisher..In well-suppressed patients with multidrug-resistant HIV infection, a switch from enfuvirtide to raltegravir is generally well tolerated and has sustained antiviral efficacy when combined with a potent background regimen. ..
- Wang W, De Feo C, Zhuang M, Vassell R, Weiss C. Selection with a peptide fusion inhibitor corresponding to the first heptad repeat of HIV-1 gp41 identifies two genetic pathways conferring cross-resistance to peptide fusion inhibitors corresponding to the first and second heptad repeats (HR1 and HR. J Virol. 2011;85:12929-38 pubmed publisher..The gp120 mutations alone enhanced fusion but did not appear to directly contribute to resistance. The implications of these findings for resistance mechanisms and regulation of envelope-mediated fusion are discussed. ..
- Zhou G, Wu D, Snyder B, Ptak R, Kaur H, Gochin M. Development of indole compounds as small molecule fusion inhibitors targeting HIV-1 glycoprotein-41. J Med Chem. 2011;54:7220-31 pubmed publisher..The results enhance our understanding of indole compounds as inhibitors of gp41. ..
- Mao Y, Wang L, Gu C, Herschhorn A, Xiang S, Haim H, et al. Subunit organization of the membrane-bound HIV-1 envelope glycoprotein trimer. Nat Struct Mol Biol. 2012;19:893-9 pubmed publisher..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. ..
- Herrera E, Tenckhoff S, Gomara M, Galatola R, Bleda M, Gil C, et al. Effect of synthetic peptides belonging to E2 envelope protein of GB virus C on human immunodeficiency virus type 1 infection. J Med Chem. 2010;53:6054-63 pubmed publisher..We also show how GBV-C E2 domains notably decrease cellular membrane fusion and interfere with the HIV-1 infectivity in a dose-dependent manner, highlighting their potential utility in future anti-HIV-1 therapies. ..
- Mouquet H, Warncke M, Scheid J, Seaman M, Nussenzweig M. Enhanced HIV-1 neutralization by antibody heteroligation. Proc Natl Acad Sci U S A. 2012;109:875-80 pubmed publisher..Heterotypic bivalent binding enhanced neutralization compared with the parental antibodies. We conclude that antibody recognition and viral neutralization of HIV can be improved by heteroligation. ..
- Bianchi E, Joyce J, Miller M, Finnefrock A, Liang X, Finotto M, et al. Vaccination with peptide mimetics of the gp41 prehairpin fusion intermediate yields neutralizing antisera against HIV-1 isolates. Proc Natl Acad Sci U S A. 2010;107:10655-60 pubmed publisher..Our findings serve as a starting point for the design of more potent immunogens to elicit a broadly neutralizing response against the gp41 prehairpin intermediate. ..
- Lai A, Moorthy A, Li Y, Tamm L. Fusion activity of HIV gp41 fusion domain is related to its secondary structure and depth of membrane insertion in a cholesterol-dependent fashion. J Mol Biol. 2012;418:3-15 pubmed publisher..Provided that their membrane insertion is deep, ?-helical and ?-sheet conformations contribute to membrane fusion. ..
- Mader A, Kunert R. Humanization strategies for an anti-idiotypic antibody mimicking HIV-1 gp41. Protein Eng Des Sel. 2010;23:947-54 pubmed publisher..In this study, we developed humanized Ab2/3H6 variants that retained the same affinity as the parental antibody, and are therefore of potential interest for future clinical trails. ..
- Ashkenazi A, Viard M, Wexler Cohen Y, Blumenthal R, Shai Y. Viral envelope protein folding and membrane hemifusion are enhanced by the conserved loop region of HIV-1 gp41. FASEB J. 2011;25:2156-66 pubmed publisher..The significant conservation of the loop region within many envelope proteins suggests a general mechanism, which is exploited by viruses to enhance entry into their host cells. ..
- Frey G, Chen J, Rits Volloch S, Freeman M, Zolla Pazner S, Chen B. Distinct conformational states of HIV-1 gp41 are recognized by neutralizing and non-neutralizing antibodies. Nat Struct Mol Biol. 2010;17:1486-91 pubmed publisher..These results have important implications for gp41-based vaccine design. ..
- Ye L, Wen Z, Dong K, Wang X, Bu Z, Zhang H, et al. Induction of HIV neutralizing antibodies against the MPER of the HIV envelope protein by HA/gp41 chimeric protein-based DNA and VLP vaccines. PLoS ONE. 2011;6:e14813 pubmed publisher..These results show that induction of MPER-specific HIV neutralizing antibodies can be achieved through a rationally designed vaccine strategy. ..
- Guenaga J, Dosenovic P, Ofek G, Baker D, Schief W, Kwong P, et al. Heterologous epitope-scaffold prime:boosting immuno-focuses B cell responses to the HIV-1 gp41 2F5 neutralization determinant. PLoS ONE. 2011;6:e16074 pubmed publisher..Together, these results indicate that heterologous ES prime:boost immunization regimens effectively focus the humoral immune response on the structurally defined and immunogen-conserved HIV-1 2F5 epitope. ..
- Whitby L, Boyle K, Cai L, Yu X, Gochin M, Boger D. Discovery of HIV fusion inhibitors targeting gp41 using a comprehensive ?-helix mimetic library. Bioorg Med Chem Lett. 2012;22:2861-5 pubmed publisher..6-1.3 ?M) that not only match or exceed the potency of those disclosed over the past decade, but that also exhibit effective activity in a cell-cell fusion assay (IC(50) 5-8 ?M). ..
- Zhu Y, Lu L, Xu L, Yang H, Jiang S, Chen Y. Identification of a gp41 core-binding molecule with homologous sequence of human TNNI3K-like protein as a novel human immunodeficiency virus type 1 entry inhibitor. J Virol. 2010;84:9359-68 pubmed publisher..Therefore, this peptide can be used as a lead for developing novel HIV fusion inhibitors and as a probe for studying the membrane-fusogenic mechanism of HIV. ..
- Araújo L, Junqueira D, de Medeiros R, Matte M, Almeida S. Naturally occurring resistance mutations to HIV-1 entry inhibitors in subtypes B, C, and CRF31_BC. J Clin Virol. 2012;54:6-10 pubmed publisher..However, further studies will be necessary to elucidate if the differential genetic background of HIV subtypes can affect the efficacy of treatment with entry inhibitors. ..
- Redd A, Collinson Streng A, Martens C, Ricklefs S, Mullis C, Manucci J, et al. Identification of HIV superinfection in seroconcordant couples in Rakai, Uganda, by use of next-generation deep sequencing. J Clin Microbiol. 2011;49:2859-67 pubmed publisher..Our results indicate that NGS can be used for detection of HIV superinfection within large cohorts, which could assist in determining the incidence and the epidemiologic, virologic, and immunological correlates of this phenomenon. ..
- Gach J, Leaman D, Zwick M. Targeting HIV-1 gp41 in close proximity to the membrane using antibody and other molecules. Curr Top Med Chem. 2011;11:2997-3021 pubmed..Such design efforts will likely need to draw upon knowledge of MPER structure and function, and may in turn inform analogous approaches to MPERs of other enveloped viruses and systems. ..
- Cai L, Jiang S. Development of peptide and small-molecule HIV-1 fusion inhibitors that target gp41. ChemMedChem. 2010;5:1813-24 pubmed publisher..Herein we present a brief overview of the development of this class of anti-HIV-1 drug by focusing on the achievements, challenges, and lessons learned. We cite hallmark studies of the past and comment on future drug development. ..
- Joshi A, Nyakeriga A, Ravi R, Garg H. HIV ENV glycoprotein-mediated bystander apoptosis depends on expression of the CCR5 co-receptor at the cell surface and ENV fusogenic activity. J Biol Chem. 2011;286:36404-13 pubmed publisher..Our findings suggest that R5 HIV-1-mediated bystander apoptosis is dependent on both CCR5 expression levels as well as fusogenic activity of the Env glycoprotein. ..
- Blumenthal R, Durell S, Viard M. HIV entry and envelope glycoprotein-mediated fusion. J Biol Chem. 2012;287:40841-9 pubmed publisher..However, the coupling between the lipid and protein pathways that give rise to fusion has not been resolved. Here, we discuss the known and unknown about the overall HIV Env-mediated fusion process. ..
- Eggink D, Bontjer I, Langedijk J, Berkhout B, Sanders R. Resistance of human immunodeficiency virus type 1 to a third-generation fusion inhibitor requires multiple mutations in gp41 and is accompanied by a dramatic loss of gp41 function. J Virol. 2011;85:10785-97 pubmed publisher..It requires the accumulation of multiple mutations in gp41, is accompanied with a dramatic loss of gp41 function, and induces compensatory mutations in gp120. ..
- Anastassopoulou C, Ketas T, Sanders R, Klasse P, Moore J. Effects of sequence changes in the HIV-1 gp41 fusion peptide on CCR5 inhibitor resistance. Virology. 2012;428:86-97 pubmed publisher..Examining the interplay of these changes will enhance our understanding of Env complex interactions that influence both HIV-1 entry and resistance to CCR5 inhibitors. ..
- Postler T, Desrosiers R. The cytoplasmic domain of the HIV-1 glycoprotein gp41 induces NF-?B activation through TGF-?-activated kinase 1. Cell Host Microbe. 2012;11:181-93 pubmed publisher..These findings demonstrate an evolutionarily conserved role for gp41CD in activating NF-?B to promote infection. ..
- Dennison S, Sutherland L, Jaeger F, Anasti K, Parks R, Stewart S, et al. Induction of antibodies in rhesus macaques that recognize a fusion-intermediate conformation of HIV-1 gp41. PLoS ONE. 2011;6:e27824 pubmed publisher..Nonetheless, the Env-liposome prime-boost immunization strategy induced antibodies that recognized a gp41 fusion intermediate protein and was successful in focusing the antibody response to the desired epitope...
- Yu X, Yuan L, Huang Y, Xu W, Fang Z, Liu S, et al. Susceptibility of HIV-1 subtypes B', CRF07_BC and CRF01_AE that are predominantly circulating in China to HIV-1 entry inhibitors. PLoS ONE. 2011;6:e17605 pubmed publisher..This study provides useful information for rational design of optimal therapeutic regimens for HIV-1-infected patients in China. ..