Membrane Fusion between Retroviral Particles: Host-Range Extension and Vaccine Prospects

Sparacio, Sandra; Zeilfelder, Udo; Pfeiffer, Tanya; Henzler, Tanja; Bosch, Valerie

doi:10.1006/viro.2000.0294

Cited by 7 publications

(4 citation statements)

References 20 publications

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“…Infection required CD4 and an appropriate coreceptor on target virions and a functional Env protein complex on donor virions. In a related study, Sparacio et al also reported infection upon mixing of receptor-pseudotyped particles and enveloped particles (33). However, in the latter study, alternative mechanisms of complementation not involving intervirion fusion were not excluded.…”

Section: Discussionmentioning

confidence: 95%

Nef Enhances Human Immunodeficiency Virus Type 1 Infectivity Resulting from Intervirion Fusion: Evidence Supporting a Role for Nef at the Virion Envelope

Zhou

Aiken

2001

J Virol

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The human immunodeficiency virus type 1 (HIV-1) accessory protein Nef stimulates viral infectivity by facilitating an early event in the HIV-1 life cycle. Although no structural or biochemical defects in Nef-defective HIV-1 particles have been demonstrated, the Nef protein is incorporated into HIV-1 particles. To localize the function of Nef within the virus particle, we developed a novel technology involving fusion of enveloped donor HIV-1 particles bearing core defects with envelope-defective target virions bearing HIV-1 receptors. Although neither virus alone was capable of infecting CD4؉ target cells, the incubation of donor and target virions prior to addition to target cells resulted in infection. This effect, termed "virion transcomplementation," required a functional Env protein on the donor virus and CD4 and an appropriate coreceptor on target virions. To provide evidence for intervirion fusion as the mechanism of complementation, experiments were performed using dual-enveloped HIV-1 particles bearing both HIV-1 and ecotropic murine leukemia virus (E-MLV) Env proteins as donor virions. Infection of CD4-negative target cells bearing E-MLV receptors was prevented by HIV-1 entry inhibitors when added before, but not after, incubation of donor and target virions prior to the addition to cells. When we used Nef ؉ and Nef ؊ donor and target virions, Nef enhanced infection when present in donor virions. In contrast, no effect of Nef was detected when present in the target virus. These results reveal a potential mechanism for enhancing HIV-1 diversity in vivo through the rescue of defective viral genomes and provide a novel genetic system for the functional analysis of virion-associated proteins in HIV-1 infection.

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Section: Discussionmentioning

confidence: 95%

Nef Enhances Human Immunodeficiency Virus Type 1 Infectivity Resulting from Intervirion Fusion: Evidence Supporting a Role for Nef at the Virion Envelope

Zhou

Aiken

2001

J Virol

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“…Membrane fusion between the virions carrying SARS-CoV S and those with ACE2 is indicated by transfer of the genome encoding luciferase to HeLa͞tva cells expressing the cellular receptor for ASLV-A but not SARS-CoV. A similar cell-free membrane-fusion assay has been used to analyze HIV and MLV-envelope-mediated membrane fusion and, in both instances, has been shown to accurately reflect normal virus infection requirements (15,16).…”

Section: Sensitivity Of Sars-cov S Protein-mediated Entry To Proteasementioning

confidence: 99%

Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry

Simmons

Gosalia

Rennekamp

et al. 2005

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

1,012

1,170

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Severe acute respiratory syndrome (SARS) is caused by an emergent coronavirus (SARS-CoV), for which there is currently no effective treatment. SARS-CoV mediates receptor binding and entry by its spike (S) glycoprotein, and infection is sensitive to lysosomotropic agents that perturb endosomal pH. We demonstrate here that the lysosomotropic-agent-mediated block to SARSCoV infection is overcome by protease treatment of target-cellassociated virus. In addition, SARS-CoV infection was blocked by specific inhibitors of the pH-sensitive endosomal protease cathepsin L. A cell-free membrane-fusion system demonstrates that engagement of receptor followed by proteolysis is required for SARS-CoV membrane fusion and indicates that cathepsin L is sufficient to activate membrane fusion by SARS-CoV S. These results suggest that SARS-CoV infection results from a unique, three-step process: receptor binding and induced conformational changes in S glycoprotein followed by cathepsin L proteolysis within endosomes. The requirement for cathepsin L proteolysis identifies a previously uncharacterized class of inhibitor for SARSCoV infection.SARS ͉ viral entry ͉ proteolysis ͉ membrane fusion ͉ viral envelope S evere acute respiratory syndrome (SARS) is an acute respiratory illness caused by a newly described coronavirus (SARS-CoV) (1), the result of a zoonosis of a highly related animal coronavirus (2). There continues to be potential for further zoonotic transmission events, leading to the reintroduction of SARS-CoV into the human population. No effective antiviral treatments have been described for SARS, and, although several promising studies are ongoing, there is currently no licensed protective vaccine.SARS-CoV entry into target cells is initiated by engagement of its cellular receptor, angiotensin-converting enzyme 2 (ACE2) by spike (S) glycoprotein (3). Subsequent infection is sensitive to inhibitors of endosomal acidification such as ammonium chloride (4-6), suggesting that SARS-CoV requires a low-pH milieu for infection. On the other hand, S protein can mediate cell-cell fusion at neutral pH (3, 4), indicating that S protein-mediated fusion does not include an absolute requirement for an acidic environment. Given these discordant findings, we hypothesized that cellular factors sensitive to ammonium chloride, such as pH-dependent endosomal proteins, may play a role in mediating SARS-CoV entry. In this study, the requirements for proteases in the activation of viral infectivity and the effect of protease inhibitors on SARS-CoV infection are examined. Our results are consistent with a model in which SARS-CoV employs a unique three-step method for membrane fusion, involving receptorbinding and induced conformational changes in S glycoprotein followed by cathepsin L (CTSL) proteolysis and activation of membrane fusion within endosomes. Cells were maintained in DMEM10 (DMEM supplemented with 10% FBS). A HeLa͞Tva cell line was produced by using pcDNA6-Tva and selection with blasticidin. The 293T cells were transiently transfected wit...

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“…Virus-virus fusion has been shown to occur between modified HIV particles or VSV and HIV [14,15], and the resulting fused viral particles were infectious to the hosts of both component particles. Hunter-HIV fusion was also suggested with a hunter derived from VSV [11] because of the occurrence of cells that were positive for VSV proteins but contained undetectable levels of HIV proteins.…”

Section: Introductionmentioning

confidence: 99%

“…The purpose of this study is to use computer simulation of an infection system to evaluate activated healthy CD4 + cell recovery (and thus therapeutic potential) in a hunter virus therapy targeted to both HIV-infected cells and free HIV virions. The fusion between different types of viruses may have practical applications, such as in the development of a HIV vaccine [14]. …”

Section: Introductionmentioning

confidence: 99%

A hunter virus that targets both infected cells and HIV free virions: Implications for therapy

Greer

Garcı́a-Ramos

2012

Theor Biol Med Model

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The design of ‘hunter’ viruses aimed at destroying human immunodeficiency virus (HIV) infected cells is an active area of research that has produced promising results in vitro. Hunters are designed to target exposed viral envelope proteins in the membranes of infected cells, but there is evidence that the hunter may also target envelope proteins of free HIV, inducing virus-virus fusion. In order to predict the effects of this fusion on therapy outcomes and determine whether fusion ability is advantageous for hunter virus design, we have constructed a model to account for the possibility of hunter-HIV fusion. The study was based on a target cell-limited model of HIV infection and it examined the hunter therapeutic effect on recovering the HIV main target cells, the activated CD4+ T lymphocytes. These cells assist in setting up an immune response to opportunistic infections. The study analyzed the hunter dual mechanisms to control infection and because of diverse estimates for viral production and clearance of HIV, simulations were examined at rates spanning an order of magnitude. Results indicate that without hunter-HIV fusion ability, hunters that kill HIV-infected cells lead to a substantial recovery of healthy cell population at both low and high HIV turnover rates. When hunter-HIV fusion is included, cell recovery was particularly enhanced at lower HIV turnover rates. This study shows that the fusion ability, in addition to hunter infection ability, could be a favorable attribute for improving the efficacy of hunter-viral therapy. These results provide support for the potential use of engineered viruses to control HIV and other viral infections.

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Membrane Fusion between Retroviral Particles: Host-Range Extension and Vaccine Prospects

Cited by 7 publications

References 20 publications

Nef Enhances Human Immunodeficiency Virus Type 1 Infectivity Resulting from Intervirion Fusion: Evidence Supporting a Role for Nef at the Virion Envelope

Nef Enhances Human Immunodeficiency Virus Type 1 Infectivity Resulting from Intervirion Fusion: Evidence Supporting a Role for Nef at the Virion Envelope

Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry

A hunter virus that targets both infected cells and HIV free virions: Implications for therapy

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