The Absence of DHHC3 Affects Primary and Latent Herpes Simplex Virus 1 Infection

Wang, Shaohui; Mott, Kevin R.; Cilluffo, Marianne; Kilpatrick, Casey L.; Murakami, Shoko; Ljubimov, Alexander V.; Kousoulas, Konstantin G.; Awasthi, Sita; Lüscher, Bernhard; Ghiasi, Homayon

doi:10.1128/jvi.01599-17

Cited by 14 publications

(23 citation statements)

References 62 publications

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“…Absence of SPP in SPP-inducible knockout mice alters cellular transcript expression in cornea and TG of infected mice. We have previously shown that virus replication directly correlates with the presence of immune infiltrates in corneas of infected mice (40)(41)(42)(43). This result suggests that mice lacking SPP have less virus replication and fewer viral transcripts in their corneas and TG ( Fig.…”

Section: Resultsmentioning

confidence: 80%

Absence of Signal Peptide Peptidase, an Essential Herpes Simplex Virus 1 Glycoprotein K Binding Partner, Reduces Virus InfectivityIn Vivo

Wang

Ghiasi

2019

J Virol

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We previously reported that herpes simplex virus (HSV) glycoprotein K (gK) binds to signal peptide peptidase (SPP), also known as minor histocompatibility antigen H13. Binding of gK to SPP is required for HSV-1 infectivity in vitro. SPP is a member of the γ-secretase family, and mice lacking SPP are embryonic lethal. To determine how SPP affects HSV-1 infectivity in vivo, the SPP gene was deleted using a tamoxifen-inducible Cre recombinase driven by the ubiquitously expressed ROSA26 promoter. SPP mRNA was reduced by more than 93% in the cornea and trigeminal ganglia (TG) and by 99% in the liver of tamoxifen-injected mice, while SPP protein expression was reduced by 90% compared to the level in control mice. Mice lacking SPP had significantly less HSV-1 replication in the eye as well as reduced gK, UL20, ICP0, and gB transcripts in the cornea and TG compared to levels in control mice. In addition, reduced infiltration of CD45+, CD4+, CD8+, F4/80+, CD11c+, and NK1.1+ T cells was observed in the cornea and TG of SPP-inducible knockout mice compared to that in control mice. Finally, in the absence of SPP, latency was significantly reduced in SPP-inducible knockout mice compared to that in control mice. Thus, in this study we have generated SPP-inducible knockout mice and shown that the absence of SPP affects virus replication in the eye of ocularly infected mice and that this reduction is correlated with the interaction of gK and SPP. These results suggest that blocking this interaction may have therapeutic potential in treating HSV-1-associated eye disease. IMPORTANCE Glycoprotein K (gK) is an essential and highly conserved HSV-1 protein. Previously, we reported that gK binds to SPP, an endoplasmic reticulum (ER) protein, and blocking this binding reduces virus infectivity in vitro and also affects gK and UL20 subcellular localization. To evaluate the function of gK binding to SPP in vivo, we generated SPP-inducible knockout mice and observed the following in the absence of SPP: (i) that significantly less HSV-1 replication was seen in ocularly infected mice than in control mice; (ii) that expression of various HSV-1 genes and cellular infiltrates in the eye and trigeminal ganglia of infected mice was less than that in control mice; and (iii) that latency was significantly reduced in infected mice. Thus, blocking of gK binding to SPP may be a useful tool to control HSV-1-induced eye disease in patients with herpes stromal keratitis (HSK).

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Section: Resultsmentioning

confidence: 80%

Absence of Signal Peptide Peptidase, an Essential Herpes Simplex Virus 1 Glycoprotein K Binding Partner, Reduces Virus InfectivityIn Vivo

Wang

Ghiasi

2019

J Virol

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“…We recently reported exacerbated eye disease in BALB/c mice infected with HSV-CD80 compared to mice infected with the parental, LAT(Ϫ) virus (35). In contrast to BALB/c mice, C57BL/6 mice are refractory to eye disease following ocular infection with HSV-1 strain McKrae or McKrae-derived recombinant viruses (37,38). To determine whether HSV-CD80 infection exacerbates eye disease in C57BL/6 mice, mice were ocularly infected with 2 ϫ 10 5 PFU per eye of HSV-CD80 or WT McKrae.…”

Section: Resultsmentioning

confidence: 99%

“…Ocular infection. Mice were infected ocularly with 2 ϫ 10 5 PFU of HSV-1 strain McKrae per eye in 2 l of tissue culture medium as an eye drop without corneal scarification, as we described previously (37,38).…”

Section: Methodsmentioning

confidence: 99%

Expression of Murine CD80 by Herpes Simplex Virus 1 in Place of Latency-Associated Transcript (LAT) Can Compensate for Latency Reactivation and Anti-apoptotic Functions of LAT

Jaggi

Matundan

Tormanen

et al. 2020

J Virol

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High rates of wild-type (WT) herpes simplex virus 1 (HSV-1) latency reactivation depend on the anti-apoptotic activities of latency-associated transcript (LAT). Replacing LAT with the baculovirus inhibitor of apoptosis protein (cpIAP) or cellular FLIP (FLICE-like inhibitory protein) gene restored the WT latency reactivation phenotype to that of a LAT-minus [LAT(−)] virus, while similar recombinant viruses expressing interleukin-4 (IL-4) or interferon gamma (IFN-γ) did not. However, HSV-1 recombinant virus expressing cpIAP did not restore all LAT functions. Recently, we reported that a similar recombinant virus expressing CD80 in place of LAT had higher latency reactivation than a LAT-null virus. The present study was designed to determine if this CD80-expressing recombinant virus can restore all LAT functions as observed with WT virus. Our results suggest that overexpression of CD80 fully rescues LAT function in latency reactivation, apoptosis, and immune exhaustion, suggesting that LAT and CD80 have multiple overlapping functions. IMPORTANCE Recurring ocular infections caused by HSV-1 can cause corneal scarring and blindness. A major function of the HSV-1 latency-associated transcript (LAT) is to establish high levels of latency and reactivation, thus contributing to the development of eye disease. Here, we show that the host CD80 T cell costimulatory molecule functions similarly to LAT and can restore the ability of LAT to establish latency, reactivation, and immune exhaustion as well as induce the expression of caspase 3, caspase 8, caspase 9, and Bcl2. Our results suggest that, in contrast to several other previously tested genes, CD80-expressing virus can completely compensate for all known and tested LAT functions.

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“…Unsurprisingly, bioinformatics analysis identified a long list of targeted genes ( Supplementary Table S3). A few of these genes have previously been reported to be associated with HSV productive infection (Supplementary Table S3, genes marked with asterisks), such as phosphatidylinositol binding clathrin assembly protein (PICALM) (Carter 2011), zinc finger DHHC-type containing 3 (ZDHHC3) (Wang et al 2018), aquaporin 4 (AQP4) (Martinez-Torres et al 2007), SUMO1/sentrin specific peptidase 7 (SENP7) (Cui et al 2017), and inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKBKB) (Gregory et al 2004). These candidate targets offer opportunities for further studies to understand the detailed mechanisms of the molecular mechanisms underlying HSV infection and establishment toward developing new treatment strategies.…”

Section: Discussionmentioning

confidence: 99%

Effect of Loss-of-function of the Herpes Simplex Virus-1 microRNA H6-5p on Virus Replication

et al. 2019

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To date, 29 distinct microRNAs (miRNAs) have been reported to be expressed during herpes simplex virus infections. Sequence analysis of mature herpes simplex virus-1 (HSV-1) miRNAs revealed five sets of miRNAs that are complementary to each other: miR-H6-5p/H1-3p, miR-H6-3p/H1-5p, H2-5p/H14-3p, miR-H2-3p/H14-5p, and miR-H7/H27. However, the roles of individual miRNAs and consequences of this complementarity remain unclear. Here, we focus on two of these complementary miRNAs, miR-H6-5p and miR-H1-3p, using loss-of-function experiments in vitro and in a mouse model of infection using an miRNA sponge approach, including tandem multiplex artificial miRNA-binding sequences that do not match perfectly to the target miRNA inserted downstream of a green fluorescent protein reporter gene. Infection with recombinant virus expressing the miR-H6-5p sponge reduced viral protein levels and virus yield. Decreased accumulation of viral proteins was also observed at early stages of infection in the presence of both an miR-H6-5p inhibitor and plasmid-expressed miR-H1-3p. Moreover, establishment of latency and reactivation did not differ between the recombinant virus expressing the miR-H6-5p sponge and wild-type HSV-1. Taken together, these data suggest that miR-H6-5p has an as-yet-unidentified role in the early stages of viral infection, and its complement miR-H1-3p suppresses this role in later stages of infection. This report extends understanding of the roles of miRNAs in infection by herpes simplex viruses, supporting a model of infection in which the production of virus and its virulent effects are tightly controlled to maximize persistence in the host and population. Keywords miR-H6-5p Á miR-H1-3p Á Sponge Á Replication Á Herpes simplex virus-1 (HSV-1) Rongquan Huang and Xusha Zhou contributed equally to this work.

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The Absence of DHHC3 Affects Primary and Latent Herpes Simplex Virus 1 Infection

Cited by 14 publications

References 62 publications

Absence of Signal Peptide Peptidase, an Essential Herpes Simplex Virus 1 Glycoprotein K Binding Partner, Reduces Virus InfectivityIn Vivo

Absence of Signal Peptide Peptidase, an Essential Herpes Simplex Virus 1 Glycoprotein K Binding Partner, Reduces Virus InfectivityIn Vivo

Expression of Murine CD80 by Herpes Simplex Virus 1 in Place of Latency-Associated Transcript (LAT) Can Compensate for Latency Reactivation and Anti-apoptotic Functions of LAT

Effect of Loss-of-function of the Herpes Simplex Virus-1 microRNA H6-5p on Virus Replication

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