Cellular Entry of Retroviruses

Lindemann, Dirk; Steffen, Imke; Pöhlmann, Stefan

doi:10.1007/978-1-4614-7651-1_7

Cited by 23 publications

(16 citation statements)

References 213 publications

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“…Retroviral envelopes are the major determinant of viral entry and receptor usage (47). To study HERV-K ENV in the context of an infectious virus, therefore, we generated a recombinant VSV in which the glycoprotein G was replaced by HERV-K ENV (VSV-HERVK) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Infectious Entry Pathway Mediated by the Human Endogenous Retrovirus K Envelope Protein

Robinson

Whelan

2016

J Virol

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Endogenous retroviruses (ERVs), the majority of which exist as degraded remnants of ancient viruses, comprise approximately 8% of the human genome. The youngest human ERVs (HERVs) belong to the HERV-K(HML-2) subgroup and were endogenized within the past 1 million years. The viral envelope protein (ENV) facilitates the earliest events of endogenization (cellular attachment and entry), and here, we characterize the requirements for HERV-K ENV to mediate infectious cell entry. Cell-cell fusion assays indicate that a minimum of two events are required for fusion, proteolytic processing by furin-like proteases and exposure to acidic pH. We generated an infectious autonomously replicating recombinant vesicular stomatitis virus (VSV) in which the glycoprotein was replaced by HERV-K ENV. HERV-K ENV imparts an endocytic entry pathway that requires dynamin-mediated membrane scission and endosomal acidification but is distinct from clathrin-dependent or macropinocytic uptake pathways. The lack of impediments to the replication of the VSV core in eukaryotic cells allowed us to broadly survey the HERV-K ENV-dictated tropism. Unlike extant betaretroviral envelopes, which impart a narrow species tropism, we found that HERV-K ENV mediates broad tropism encompassing cells from multiple mammalian and nonmammalian species. We conclude that HERV-K ENV dictates an evolutionarily conserved entry pathway and that the restriction of HERV-K to primate genomes reflects downstream stages of the viral replication cycle. IMPORTANCEApproximately 8% of the human genome is of retroviral origin. While many of those viral genomes have become inactivated, some copies of the most recently endogenized human retrovirus, HERV-K, can encode individual functional proteins. Here, we characterize the envelope protein (ENV) of the virus to define how it mediates infection of cells. We demonstrate that HERV-K ENV undergoes a proteolytic processing step and triggers membrane fusion in response to acidic pH-a strategy common to many viral fusogens. Our data suggest that the infectious entry pathway mediated by this ENV requires endosomal acidification and the GTPase dynamin but does not require clathrin-dependent uptake. In marked contrast to other betaretroviruses, HERV-K ENV imparts broad species tropism in cultured cells. This work provides new insights into the entry pathway of an extinct human virus and provides a powerful tool to further probe the endocytic route by which HERV-K infects cells. E ndogenous retroviruses (ERVs) comprise approximately 8% of the human genome (1). Such ERVs provide a physical record of ancient infections by once exogenous retroviruses; however, the degraded states of most sequences largely obscure their biological properties. Consequently, relatively little is known about the earliest events of endogenization, including how the viruses initially entered the germ line to become vertically transmitted elements. The process of endogenization begins with cellular attachment and viral entry, which is mediated by the envel...

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Section: Resultsmentioning

confidence: 99%

Infectious Entry Pathway Mediated by the Human Endogenous Retrovirus K Envelope Protein

Robinson

Whelan

2016

J Virol

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“…To infect a cell, a virion must attach itself to the cell surface. This can occur via ancillary attachment factors or directly via the major receptor used by the virus for entry; some viruses then interact with a second receptor, or coreceptor [65][66][67][68][69][70][71][72][73][74][75][76][77][78][79]. Naked viruses need to penetrate a cellular membrane to enter the cytoplasm or instead they may inject their genome through a membrane [80]; enveloped viruses must fuse their envelope with a cellular membrane in order to translocate their core and genome into the cytoplasm [79,[81][82][83][84][85].…”

Section: The Definition Of Virus Neutralizationmentioning

confidence: 99%

Neutralization of Virus Infectivity by Antibodies: Old Problems in New Perspectives

Klasse

2014

Advances in Biology

205

208

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Neutralizing antibodies (NAbs) can be both sufficient and necessary for protection against viral infections, although they sometimes act in concert with cellular immunity. Successful vaccines against viruses induce NAbs but vaccine candidates against some major viral pathogens, including HIV-1, have failed to induce potent and effective such responses. Theories of how antibodies neutralize virus infectivity have been formulated and experimentally tested since the 1930s; and controversies about the mechanistic and quantitative bases for neutralization have continually arisen. Soluble versions of native oligomeric viral proteins that mimic the functional targets of neutralizing antibodies now allow the measurement of the relevant affinities of NAbs. Thereby the neutralizing occupancies on virions can be estimated and related to the potency of the NAbs. Furthermore, the kinetics and stoichiometry of NAb binding can be compared with neutralizing efficacy. Recently, the fundamental discovery that the intracellular factor TRIM21 determines the degree of neutralization of adenovirus has provided new mechanistic and quantitative insights. Since TRIM21 resides in the cytoplasm, it would not affect the neutralization of enveloped viruses, but its range of activity against naked viruses will be important to uncover. These developments bring together the old problems of virus neutralization—mechanism, stoichiometry, kinetics, and efficacy—from surprising new angles.

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“… SUMMARY For many enveloped viruses, binding to a receptor(s) on a host cell acts as a first step in a series of events culminating in fusion with the host cell membrane and transfer of genetic material for replication [for review see 1,2 ]. The envelope glycoprotein (Env) trimer on the surface of HIV is responsible for receptor binding and fusion.…”

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confidence: 99%

Open and closed structures reveal allostery and pliability in the HIV-1 envelope spike

Ozorowski

Pallesen

Val

et al. 2017

Nature

238

466

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SUMMARY For many enveloped viruses, binding to a receptor(s) on a host cell acts as a first step in a series of events culminating in fusion with the host cell membrane and transfer of genetic material for replication [for review see1,2]. The envelope glycoprotein (Env) trimer on the surface of HIV is responsible for receptor binding and fusion. While Env can tolerate a high degree of mutation in five variable regions (V1-V5), and also at N-linked glycosylation sites that contribute roughly half the mass of Env, the functional sites for recognition of receptor CD4 and co-receptor CXCR4/CCR5 are conserved and essential for viral fitness. Soluble SOSIP Env trimers are structural and antigenic mimics of the pre-fusion native, surface-presented Env3,4, targets of broadly neutralizing antibodies (bnAbs). Thus, they are attractive immunogens for vaccine development [for review see5–8]. Here we present high-resolution cryo-electron microscopy (cryoEM) structures of subtype B B41 SOSIP Env trimers in complex with CD4 and antibody 17b, or with antibody b12, at resolutions of ~3.7 Å and ~3.6 Å, respectively, and compare them to cryoEM reconstructions of ligand-free B41 SOSIP Env trimers or in complex with either CD4 or CD4bs antibody PGV04, at ~5.6 Å, ~5.2 Å and ~7.4 Å, respectively. Consequently, we present the most complete description and understanding of the CD4/17b-induced intermediate and provide the molecular basis of the receptor-binding induced conformational change required for HIV-1 entry into host cells. Both CD4 and b12 induce large, previously uncharacterized conformational rearrangements in the gp41 subunits, and the fusion peptide becomes more buried in a newly formed pocket. These structures provide key details on the biological function of the type I viral fusion machine from HIV-1 as well as new templates for inhibitor design.

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Cellular Entry of Retroviruses

Cited by 23 publications

References 213 publications

Infectious Entry Pathway Mediated by the Human Endogenous Retrovirus K Envelope Protein

Infectious Entry Pathway Mediated by the Human Endogenous Retrovirus K Envelope Protein

Neutralization of Virus Infectivity by Antibodies: Old Problems in New Perspectives

Open and closed structures reveal allostery and pliability in the HIV-1 envelope spike

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