Dissociation of gp120 from HIV-1 Virions Induced by Soluble CD4

Moore, John P.; McKeating, Jane A.; Weiss, Robin A.; Sattentau, Quentin J.

doi:10.1126/science.2251501

Cited by 575 publications

(509 citation statements)

References 40 publications

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“…The differential loss of gp120 between X4-and R5-tropic HIV-1 may be due to differences in the inherent stability of the gp120-gp41 complex, or to differences in gp120 conformational changes induced upon CD4 binding. Previous studies have shown that laboratoryadapted strains of HIV-1, which are generally X4-tropic, readily shed gp120 upon addition of soluble CD4 and are more sensitive to inhibition by sCD4 (31,36,50,61). The preferential inhibition of X4-tropic HIV-1 by sCD4 is also in general agreement with the hypothesis that cellular CD4 is more detrimental for replication of X4-tropic HIV-1.…”

Section: Discussionsupporting

confidence: 77%

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: Discussionsupporting

confidence: 77%

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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“…56 The protein content of the resultant lentiGFP was measured using bicinchoninic acid and titers determined by p24 enzyme-linked immunosorbent assay (Aalto, Bio Reagents Ltd, Dublin, Ireland). 57 Viral titer is presented as an M.O.I. ratio defined as the number of infectious virus particles deposited in a tissue culture well divided by the number of cells present in the well.…”

Section: Methodsmentioning

confidence: 99%

Innocuous full-length botulinum neurotoxin targets and promotes the expression of lentiviral vectors in central and autonomic neurons

et al. 2011

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Fragments of botulinum neurotoxin (BoNT) have been explored as potential targeting moieties and carriers of biomolecules into neurons, although with lower binding and translocation efficiency compared with intact proteins. This study exploits a detoxified recombinant form of full-length BoNT/B (BoTIM/B) fused with core streptavidin (CS-BoTIM/B) for lentiviral targeting to central and autonomic neurons. CS-BoTIM/B underwent an activity-dependent entry into cultured spinal cord neurons. Coupling CS-BoTIM/B to biotinylated lentivirus-encoding green fluorescent protein (GFP) endowed considerable neuron selectivity to the vector as evident from the preferential expression of the reporter in neurons co-cultured with skeletal muscle cells. CS-BoTIM/ B-guided lentiviral transduction with the expression of a SNARE protein, SNAP-25 (S25), rendered non-susceptible to proteolysis by three BoNT serotypes, yielded a sizable decrease in cleaved S25 upon exposure of spinal cord neurons to these toxins. This was accompanied by synaptic transmission being spared from blockade by BoNT/A or BoNT/E, reflecting adequate translation and functional competence of recombinant multi-toxin-resistant S25. The augmented neurotropism conveyed on the lentivirus by CS-BoTIM/B was also demonstrated in vivo through enhanced expression of a reporter in intramural ganglionic neurons in the rat trachea, after injection of the targeted GFP-encoding lentivirus. Thus, a novel and realistic prospect for gene therapy of peripheral neuropathies is offered in this study through lentiviral targeting to neurons by CS-BoTIM/B.

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“…A twin-site sandwich ELISA was performed essentially as described (15). Briefly, a polyclonal Ab was adsorbed to a solid phase to capture p24 Ag from a detergent lysate of virions.…”

Section: Hiv P24 Capsid Ag (P24) Elisamentioning

confidence: 99%

TLR7/8 Triggering Exerts Opposing Effects in Acute versus Latent HIV Infection

Schlaepfer¹,

Audigé²,

Joller

et al. 2006

The Journal of Immunology

106

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TLRs trigger innate immunity by recognizing conserved motifs of microorganisms. Recently, ssRNAs from HIV and influenza virus were shown to trigger TLR7 and 8. Thus, we hypothesized that HIV ssRNA, by triggering TLR7/8, affects HIV pathogenesis. Indeed, HIV ssRNA rendered human lymphoid tissue of tonsillar origin or PBMC barely permissive to HIV replication. The synthetic compound R-848, which also triggers TLR7/8, showed similar anti-HIV activity. Loss of R-848’s activity in lymphoid tissue depleted of B cells suggested a role for B cells in innate immunity. TLR7/8 triggering appears to exert antiviral effects through soluble factors: conditioned medium reduced HIV replication in indicator cells. Although a number of cytokines and chemokines were increased upon adding R-848 to lymphoid tissue, blocking those cytokines/chemokines (i.e., IFN-α receptor, IFN-γ, MIP-1α, -1β, RANTES, and stromal cell-derived factor-1) did not result in the reversal of R-848’s anti-HIV activity. Thus, the nature of this soluble factor(s) remains unknown. Unlike lymphoid tissue acutely infected with HIV, triggering latently infected promonocytic cells induced the release of HIV virions. The anti-HIV effects of triggering TLR7/8 may inhibit rapid killing, while pro-HIV effects may guarantee a certain replication level. Compounds triggering TLR7/8 may be attractive drug candidates to purge latent HIV while preventing new infections.

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Dissociation of gp120 from HIV-1 Virions Induced by Soluble CD4

Cited by 575 publications

References 40 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

Innocuous full-length botulinum neurotoxin targets and promotes the expression of lentiviral vectors in central and autonomic neurons

TLR7/8 Triggering Exerts Opposing Effects in Acute versus Latent HIV Infection

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