Short Communication: Fine Definition of a Conserved CCR5-Binding Region on the Human Immunodeficiency Virus Type 1 Glycoprotein 120

Rizzuto, Carlo D.; Sodroski, Joseph

doi:10.1089/088922200308747

Cited by 153 publications

(188 citation statements)

References 84 publications

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“…The bridging sheet and structurally adjacent regions of gp120 have been shown to play a role in mediating binding to coreceptors, with mutations in this highly conserved domain affecting the affinity with which gp120 binds to CCR5 (47,48). In addition, we found that a single-amino-acid change (K421D), immediately adjacent to the ␤20 strand of the bridging sheet, not only reduced the affinity with which gp120 bound to CCR5 but increased Env sensitivity to enfuvirtide by approximately 30-fold (42).…”

Section: Resultsmentioning

confidence: 99%

“…1). The effects of these mutations on the CCR5 binding ability of modified YU-2 gp120, with a truncated N terminus and lacking the V1 and V2 loops, has been described previously (47,48).…”

Section: Resultsmentioning

confidence: 99%

“…These changes include the exposure of a conserved region in gp120 that, in conjunction with the V3 loop of gp120, mediates coreceptor binding (12,13,30,48,52,56). Mutations in the coreceptor-binding site of gp120 have been shown to modulate the affinity of gp120 for CCR5 and CXCR4 (5,47,48), although the effects of these mutations on membrane fusion activity have not been investigated in detail (42,53). Coreceptor inhibitors that bind to either CCR5 or gp120-coreceptor interactions induce structural alterations in the membrane-spanning gp41 subunit of Env that lead to membrane fusion (20).…”

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confidence: 99%

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Impact of Mutations in the Coreceptor Binding Site on Human Immunodeficiency Virus Type 1 Fusion, Infection, and Entry Inhibitor Sensitivity

Reeves

Miamidian

Biscone

et al. 2004

J Virol

106

111

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An increasingly large number of antiviral agents that prevent entry of human immunodeficiency virus (HIV) into cells are in preclinical and clinical development. The envelope (Env) protein of HIV is the major viral determinant that affects sensitivity to these compounds. To understand how changes in Env can impact entry inhibitor sensitivity, we introduced six mutations into the conserved coreceptor binding site of the R5 HIV-1 strain YU-2 and measured the effect of these changes on CD4 and coreceptor binding, membrane fusion levels and rates, virus infection, and sensitivity to the fusion inhibitors enfuvirtide (T-20) and T-1249, the CCR5 inhibitor TAK-779, and an antibody to CD4. The mutations had little effect on CD4 binding but reduced CCR5 binding to various extents. In general, reductions in coreceptor binding efficiency resulted in slower fusion kinetics and increased sensitivity to TAK-779 and enfuvirtide. In addition, low CCR5 binding usually reduced overall fusion and infection levels. However, one mutation adjacent to the bridging sheet ␤21 strand, P438A, had little effect on fusion activity, fusion rate, infectivity, or sensitivity to enfuvirtide or T-1249 despite causing a marked reduction in CCR5 binding and a significant increase in TAK-779 sensitivity. Thus, our findings indicate that changes in the coreceptor binding site of Env can modulate its fusion activity, infectivity, and entry inhibitor sensitivity by multiple mechanisms and suggest that reductions in coreceptor binding do not always result in prolonged fusion kinetics and increased sensitivity to enfuvirtide.

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Section: Resultsmentioning

confidence: 99%

“…1). The effects of these mutations on the CCR5 binding ability of modified YU-2 gp120, with a truncated N terminus and lacking the V1 and V2 loops, has been described previously (47,48).…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Impact of Mutations in the Coreceptor Binding Site on Human Immunodeficiency Virus Type 1 Fusion, Infection, and Entry Inhibitor Sensitivity

Reeves

Miamidian

Biscone

et al. 2004

J Virol

106

111

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“…Targeting stages of the HIV entry process with antiretroviral drugs is a productive method of inhibiting HIV replication, as demonstrated by the potent antiviral effects of small-molecule CCR5 antagonists and fusion inhibitors (23,35,49). As with other antiretroviral drugs, HIV can develop resistance to entry inhibitors, and a detailed understanding of viral and host determinants of resistance will be critical to the optimal clinical use of these agents.The coreceptor binding site that is induced by CD4 engagement consists of noncontiguous regions in the bridging sheet and V3 loop of gp120 (4,18,42,43,50). Interactions between gp120 and CCR5 occur in at least two distinct areas: (i) the bridging sheet and the stem of the V3 loop interact with sul-…”

mentioning

confidence: 99%

“…The coreceptor binding site that is induced by CD4 engagement consists of noncontiguous regions in the bridging sheet and V3 loop of gp120 (4,18,42,43,50). Interactions between gp120 and CCR5 occur in at least two distinct areas: (i) the bridging sheet and the stem of the V3 loop interact with sulfated tyrosine residues in the NЈ terminus of CCR5, and (ii) the crown of the V3 loop is thought to engage the extracellular loops (ECLs), particularly ECL2, of CCR5 (10-12, 14, 18, 28).…”

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confidence: 99%

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells

Pfaff

Wilen

Harrison

et al. 2010

J Virol

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We previously reported on a panel of HIV-1 clade B envelope (Env) proteins isolated from a patient treated with the CCR5 antagonist aplaviroc (APL) that were drug resistant. These Envs used the APL-bound conformation of CCR5, were cross resistant to other small-molecule CCR5 antagonists, and were isolated from the patient's pretreatment viral quasispecies as well as after therapy. We analyzed viral and host determinants of resistance and their effects on viral tropism on primary CD4 ؉ T cells. The V3 loop contained residues essential for viral resistance to APL, while additional mutations in gp120 and gp41 modulated the magnitude of drug resistance. However, these mutations were context dependent, being unable to confer resistance when introduced into a heterologous virus. The resistant virus displayed altered binding between gp120 and CCR5 such that the virus became critically dependent on the N terminus of CCR5 in the presence of APL. In addition, the drug-resistant Envs studied here utilized CCR5 very efficiently: robust virus infection occurred even when very low levels of CCR5 were expressed. However, recognition of drug-bound CCR5 was less efficient, resulting in a Entry of human immunodeficiency virus (HIV) into target cells is a complex, multistep process that is initiated by interactions between the viral envelope (Env) protein gp120 and the host cell receptor CD4, which trigger conformational changes in gp120 that form and orient the coreceptor binding site (9,24). Upon binding to coreceptor, which is either CCR5 or CXCR4 for primary HIV isolates, Env undergoes further conformational changes resulting in insertion of the gp41 fusion peptide into the host cell membrane and gp41-mediated membrane fusion (8,15,26). Targeting stages of the HIV entry process with antiretroviral drugs is a productive method of inhibiting HIV replication, as demonstrated by the potent antiviral effects of small-molecule CCR5 antagonists and fusion inhibitors (23,35,49). As with other antiretroviral drugs, HIV can develop resistance to entry inhibitors, and a detailed understanding of viral and host determinants of resistance will be critical to the optimal clinical use of these agents.The coreceptor binding site that is induced by CD4 engagement consists of noncontiguous regions in the bridging sheet and V3 loop of gp120 (4,18,42,43,50). Interactions between gp120 and CCR5 occur in at least two distinct areas: (i) the bridging sheet and the stem of the V3 loop interact with sul-

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HIV and Molecular Biology of the Virus‐Host Interplay

Clementi

2001

Cellular Aspects of HIV Infection

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INTRODUCTIONThe precise understanding of the molecular mechanisms in each step of the human immunode®ciency virus (HIV) life cycle has provided an essential basis for designing antiviral compounds and strategies aimed at blocking viral replication and preventing or delaying disease progression. As in other retroviral infections, the replication cycle of HIV can be described as proceeding in two phases. The ®rst phase includes entry of the virion into the cell cytoplasm, synthesis of double-stranded DNA (provirus) using the single-stranded genome RNA as a template, transfer of the proviral DNA to the nucleus, and intergration of the DNA into the host genome. The second phase includes synthesis of new copies of the viral genome, expression of viral genes, virion assembly by encapsidation of the genome by precursors of the HIV structural proteins, budding, and ®nal processing of the viral proteins. Whereas the former phase is mediated by proteins that are present within the virion and occurs in the absence of viral gene expression, the latter, leading to production of infectious virions, is a complex process requiring the interplay of viral and cellular factors.The precise understanding of the molecular mechanisms of HIV replication and the use of new technologies in virology has lead to exciting discoveries on many aspects of the biology of this virus. In particular, a growing body of new data on the HIV replication mechanisms together with the results from molec-3 Cellular Aspects of HIV Infection. Edited

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Short Communication: Fine Definition of a Conserved CCR5-Binding Region on the Human Immunodeficiency Virus Type 1 Glycoprotein 120

Cited by 153 publications

References 84 publications

Impact of Mutations in the Coreceptor Binding Site on Human Immunodeficiency Virus Type 1 Fusion, Infection, and Entry Inhibitor Sensitivity

Impact of Mutations in the Coreceptor Binding Site on Human Immunodeficiency Virus Type 1 Fusion, Infection, and Entry Inhibitor Sensitivity

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells

HIV and Molecular Biology of the Virus‐Host Interplay

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Short Communication: Fine Definition of a Conserved CCR5-Binding Region on the Human Immunodeficiency Virus Type 1 Glycoprotein 120

Cited by 153 publications

References 84 publications

Impact of Mutations in the Coreceptor Binding Site on Human Immunodeficiency Virus Type 1 Fusion, Infection, and Entry Inhibitor Sensitivity

Impact of Mutations in the Coreceptor Binding Site on Human Immunodeficiency Virus Type 1 Fusion, Infection, and Entry Inhibitor Sensitivity

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 + T Cells

HIV and Molecular Biology of the Virus‐Host Interplay

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Resources

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HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells