High concentrations of recombinant soluble CD4 are required to neutralize primary human immunodeficiency virus type 1 isolates.

Daar, Eric S.; Li, Xi Ling; Moudgil, Tarsem; Ho, David D.

doi:10.1073/pnas.87.17.6574

Cited by 424 publications

(322 citation statements)

References 19 publications

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“…Nef-defective virions contained higher levels of CD4 than wild-type HIV-1. Infection by HIV-1 laboratory strains (predominately X4 tropic) is more susceptible to inhibition by sCD4 than are HIV-1 primary isolates (which are normally R5 tropic) (21,49,62). We hypothesized that virion-associated CD4 more potently inhibits infection by X4-tropic viruses, thereby preferentially inhibiting replication of nef-defective X4-tropic replication.…”

Section: Vol 78 2004mentioning

confidence: 99%

Nef Stimulates Human Immunodeficiency Virus Type 1 Replication in Primary T Cells by Enhancing Virion-Associated gp120 Levels: Coreceptor-Dependent Requirement for Nef in Viral Replication

Lundquist

Zhou

Aiken

2004

J Virol

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The Nef protein enhances human immunodeficiency virus type 1 (HIV-1) replication through an unknown mechanism. We and others have previously reported that efficient HIV-1 replication in activated primary CD4 ؉ T cells depends on the ability of Nef to downregulate CD4 from the cell surface. Here we demonstrate that Nef greatly enhances the infectivity of HIV-1 particles produced in primary T cells. Nef-defective HIV-1 particles contained significantly reduced quantities of gp120 on their surface; however, Nef did not affect the levels of virion-associated gp41, indicating that Nef indirectly stabilizes the association of gp120 with gp41. Surprisingly, Nef was not required for efficient replication of viruses that use CCR5 for entry, nor did Nef influence the infectivity or gp120 content of these virions. Nef also inhibited the incorporation of CD4 into HIV-1 particles released from primary T cells. We propose that Nef, by downregulating cell surface CD4, enhances HIV-1 replication by inhibiting CD4-induced dissociation of gp120 from gp41. The preferential requirement for Nef in the replication of X4-tropic HIV-1 suggests that the ability of Nef to downregulate CD4 may be most important at later stages of disease when X4-tropic viruses emerge.

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Section: Vol 78 2004mentioning

confidence: 99%

Nef Stimulates Human Immunodeficiency Virus Type 1 Replication in Primary T Cells by Enhancing Virion-Associated gp120 Levels: Coreceptor-Dependent Requirement for Nef in Viral Replication

Lundquist

Zhou

Aiken

2004

J Virol

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“…HIV infection is blocked in vitro by recombinant sCD4 (Deen et al, 1988;Fisher et al, 1988;Hussey et al, 1988). However, sCD4 poorly neutralizes fresh isolates of HIV-1 (Daar et al, 1990;Moore et aI., 1992). This may suggest that the reduced gpl20-CD4 binding affinity is a consequence of the oligomeric organization of the env protein on intact virions (Moore et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Analysis of the human immunodeficiency virus type 1 envelope protein interaction with the CD4 host cell receptor

Malvoisin

Wild

1994

Journal of General Virology

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A secreted form of human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (gpl60s), expressed in HeLa cells from a vaccinia virus recombinant was analysed by velocity-gradient centrifugation and chemical cross-linking. We showed that gpl60s existed predominantly as a dimer, but higher forms corresponding to trimers and tetramers were also found. Soluble CD4 (sCD4) and native CD4 expressed by recombinant vaccinia viruses were analysed by sucrosegradient sedimentation alone or after complexing with gpl60s. The sCD4 sedimented in sucrose gradients as a monomer, whereas after solubilization the native CD4 was in a dimeric state. Both forms of CD4 were able to form complexes when incubated with gpl60s. In the case of the sCD4, the Mr corresponded to a (sCD4) 2-(gpl60s)2 complex, whereas with CD4 the complexes were of a greater order of magnitude. HIV gpl20 was secreted into the medium in a monomeric state, With sCD4 it gave a one-to-one complex, whereas with the native CD4 high M r complexes were formed. The importance of the oligomeric state of the virus-and cell-receptor proteins are discussed regarding their avidities.

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“…Although sCD4 demonstrated efficacy against many laboratory strains, it exhibited poor activity against primary isolates (31), which may have contributed to disappointing results in clinical trials (31,32). PRO-542 (a CD4-IgG fusion protein) was shown to be effective in neutralizing many clinical HIV-1 strains in culture (15,33) and is efficacious in the clinics (16,34).…”

Section: Discussionmentioning

confidence: 99%

A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding

Lin

Blair

Wang

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

340

302

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High concentrations of recombinant soluble CD4 are required to neutralize primary human immunodeficiency virus type 1 isolates.

Cited by 424 publications

References 19 publications

Nef Stimulates Human Immunodeficiency Virus Type 1 Replication in Primary T Cells by Enhancing Virion-Associated gp120 Levels: Coreceptor-Dependent Requirement for Nef in Viral Replication

Nef Stimulates Human Immunodeficiency Virus Type 1 Replication in Primary T Cells by Enhancing Virion-Associated gp120 Levels: Coreceptor-Dependent Requirement for Nef in Viral Replication

Analysis of the human immunodeficiency virus type 1 envelope protein interaction with the CD4 host cell receptor

A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding

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