Analysis of herpes simplex type 1 gB, gD, and gH/gL on production of infectious HIV-1: HSV-1 gD restricts HIV-1 by exclusion of HIV-1 Env from maturing viral particles

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Abstract

Background

We previously showed that the gM of HSV-1 could restrict the release of infectious HIV-1 from cells. In this study, we analyzed if the four HSV-1 glycoproteins (gD, gB, and gH/gL), which are the minimum glycoproteins required for HSV-1 entry, restricted the release of infectious HIV-1.

Results

Of these four glycoproteins, gD and gH/gL restricted the production of infectious HIV-1 from cells transfected with an infectious molecular clone of HIV-1 (strain NL4-3) while gB had no significant effect. Pulse-chase analyses indicated that gD did not affect the biosynthesis and processing of gp160 into gp120/gp41, the transport of the gp120/gp41 to the cell surface, or the release of HIV-1 particles from the cell surface. Our analyses revealed that gD was incorporated into HIV-1 virus particles while gp120/gp41 was excluded from released virus particles. Truncated mutants of gD revealed that the cytoplasmic domain was dispensable but that a membrane bound gD was required for the restriction of release of infectious HIV-1. Finally, cell lines expressing gD also potently restricted the release of infectious virus.

Conclusions

Due to its ability to exclude HIV-1 gp120/gp41 from maturing virus, gD may provide a useful tool in deciphering mechanisms of Env incorporation into maturing virus particles.

Electronic supplementary material

The online version of this article (10.1186/s12977-019-0470-5) contains supplementary material, which is available to authorized users.

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Most cited references 58

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Signals for sorting of transmembrane proteins to endosomes and lysosomes.

Juan Bonifacino, Linton M Traub (2003)

Sorting of transmembrane proteins to endosomes and lysosomes is mediated by signals present within the cytosolic domains of the proteins. Most signals consist of short, linear sequences of amino acid residues. Some signals are referred to as tyrosine-based sorting signals and conform to the NPXY or YXXO consensus motifs. Other signals known as dileucine-based signals fit [DE]XXXL[LI] or DXXLL consensus motifs. All of these signals are recognized by components of protein coats peripherally associated with the cytosolic face of membranes. YXXO and [DE]XXXL[LI] signals are recognized with characteristic fine specificity by the adaptor protein (AP) complexes AP-1, AP-2, AP-3, and AP-4, whereas DXXLL signals are recognized by another family of adaptors known as GGAs. Several proteins, including clathrin, AP-2, and Dab2, have been proposed to function as recognition proteins for NPXY signals. YXXO and DXXLL signals bind in an extended conformation to the mu2 subunit of AP-2 and the VHS domain of the GGAs, respectively. Phosphorylation events regulate signal recognition. In addition to peptide motifs, ubiquitination of cytosolic lysine residues also serves as a signal for sorting at various stages of the endosomal-lysosomal system. Conjugated ubiquitin is recognized by UIM, UBA, or UBC domains present within many components of the internalization and lysosomal targeting machinery. This complex array of signals and recognition proteins ensures the dynamic but accurate distribution of transmembrane proteins to different compartments of the endosomal-lysosomal system.

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Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120.

C. A. Derdeyn, J M Decker, J Sfakianos … (2000)

T-20 is a synthetic peptide that potently inhibits replication of human immunodeficiency virus type 1 by interfering with the transition of the transmembrane protein, gp41, to a fusion active state following interactions of the surface glycoprotein, gp120, with CD4 and coreceptor molecules displayed on the target cell surface. Although T-20 is postulated to interact with an N-terminal heptad repeat within gp41 in a trans-dominant manner, we show here that sensitivity to T-20 is strongly influenced by coreceptor specificity. When 14 T-20-naive primary isolates were analyzed for sensitivity to T-20, the mean 50% inhibitory concentration (IC(50)) for isolates that utilize CCR5 for entry (R5 viruses) was 0.8 log(10) higher than the mean IC(50) for CXCR4 (X4) isolates (P = 0. 0055). Using NL4.3-based envelope chimeras that contain combinations of envelope sequences derived from R5 and X4 viruses, we found that determinants of coreceptor specificity contained within the gp120 V3 loop modulate this sensitivity to T-20. The IC(50) for all chimeric envelope viruses containing R5 V3 sequences was 0.6 to 0.8 log(10) higher than that for viruses containing X4 V3 sequences. In addition, we confirmed that the N-terminal heptad repeat of gp41 determines the baseline sensitivity to T-20 and that the IC(50) for viruses containing GIV at amino acid residues 36 to 38 was 1.0 log(10) lower than the IC(50) for viruses containing a G-to-D substitution. The results of this study show that gp120-coreceptor interactions and the gp41 N-terminal heptad repeat independently contribute to sensitivity to T-20. These results have important implications for the therapeutic uses of T-20 as well as for unraveling the complex mechanisms of virus fusion and entry.

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Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family.

Rebecca I Montgomery, Morgyn S Warner, Brian J Lum … (1996)

We identified and cloned a cellular mediator of herpes simplex virus (HSV) entry. Hamster and swine cells resistant to viral entry became susceptible upon expression of a human cDNA encoding this protein, designated HVEM (for herpesvirus entry mediator). HVEM was shown to mediate the entry of several wild-type HSV strains of both serotypes. Anti-HVEM antibodies and a soluble hybrid protein containing the HVEM ectodomain inhibited HVEM-dependent infection but not virus binding to cells. Mutations in the HSV envelope glycoprotein gD significantly reduced HVEM-mediated entry. The contribution of HVEM to HSV entry into human cells was demonstrable in activated T cells. HVEM, the first identified mediator of HSV entry, is a new member of the TNF/NGF receptor family.

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Author and article information

Contributors

Sachith Polpitiya Arachchige: spolpityaarachchige@kumc.edu

Wyatt Henke: w6688h651@kumc.edu

Maria Kalamvoki: mkalamvoki@kumc.edu

Edward B. Stephens:

ORCID: http://orcid.org/0000-0002-6520-3410

913-588-5558 , estephen@kumc.edu

Journal

Journal ID (nlm-ta): Retrovirology

Journal ID (iso-abbrev): Retrovirology

Title: Retrovirology

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-4690

Publication date (Electronic): 2 April 2019

Publication date PMC-release: 2 April 2019

Publication date Collection: 2019

Volume: 16

Electronic Location Identifier: 9

Affiliations

ISNI 0000 0001 2177 6375, GRID grid.412016.0, Department of Microbiology, Molecular Genetics and Immunology, , University of Kansas Medical Center, ; 2000 Hixon Hall, 3901 Rainbow Blvd., Kansas City, KS 66160 USA

Author information

Edward B. Stephens http://orcid.org/0000-0002-6520-3410

Article

Publisher ID: 470

DOI: 10.1186/s12977-019-0470-5

PMC ID: 6444546

PubMed ID: 30940160

SO-VID: 0fdb0c58-797f-4f21-9785-982ca21e2ef6

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 12 December 2018

Date accepted : 23 March 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: R21 AI108391

Award Recipient : Edward B. Stephens

Custom metadata

ScienceOpen disciplines: Microbiology & Virology

Keywords: hsv-1,gd,gb,gh/gl,hiv-1,gp120/gp41,env incorporation,virus restriction

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ScienceOpen disciplines: Microbiology & Virology

Keywords: hsv-1, gd, gb, gh/gl, hiv-1, gp120/gp41, env incorporation, virus restriction

Analysis of herpes simplex type 1 gB, gD, and gH/gL on production of infectious HIV-1: HSV-1 gD restricts HIV-1 by exclusion of HIV-1 Env from maturing viral particles

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Most cited references 58

Signals for sorting of transmembrane proteins to endosomes and lysosomes.

Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120.

Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family.

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