Inclusion of CD80 in HSV Targets the Recombinant Virus to PD-L1 on DCs and Allows Productive Infection and Robust Immune Responses

Mott, Kevin R.; Allen, Sariah J.; Zandian, Mandana; Akbari, Omid; Hamrah, Pedram; Maazi, Hadi; Wechsler, Steven L.; Sharpe, Arlene H.; Freeman, Gordon J.; Ghiasi, Homayon

doi:10.1371/journal.pone.0087617

Cited by 23 publications

(49 citation statements)

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“…In addition, T cell exhaustion was blocked by a recombinant HSV-1 strain expressing CD80 that binds to PD-L1 on the surfaces of DCs (32). Overall, our previous and current findings suggest that CD8␣ ϩ DCs contribute to increased HSV-1 latency and T cell exhaustion (17,22,25,26,28,32). Our previously published studies with regard to the role of LAT in T cell exhaustion were done with mice.…”

Section: Fig 3 Isolation and Functionality Of Purified Cd8 ϩ T Cells supporting

confidence: 66%

“…Previously, we showed that LAT expression and increased latency correlate with T cell exhaustion (17,22,26,32). We also demonstrated that latency in PD-1 Ϫ/Ϫ mice was lower than that in their wt counterparts (17).…”

Section: Lack Of Effect Of Adoptively Transferred Cd8mentioning

confidence: 60%

“…Relative copy numbers of gB DNA and LAT RNA were calculated using standard curves generated from the plasmids pAc-gB1 and pGem5317, respectively, as we described previously (22,26,28,32). In all experiments, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used for normalization of transcripts.…”

Section: Pcr and Reverse Transcription-pcr (Rt-pcr) Analysesmentioning

confidence: 99%

“…ϩ DCs, not CD8 ϩ T cells or miRNAs, are involved in establishment and maintenance of HSV-1 latency (17,22,28,32).…”

Section: Fig 3 Isolation and Functionality Of Purified Cd8 ϩ T Cells mentioning

confidence: 99%

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CD8 ⁺ T Cells Play a Bystander Role in Mice Latently Infected with Herpes Simplex Virus 1

Mott

Gate

Matundan

et al. 2016

J Virol

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O ne of the hallmarks of herpes simplex virus (HSV) infection is the ability of the virus to establish latency in neurons of an infected host (1-4). During HSV-1 neuronal latency in mice, rabbits, and humans, the only viral gene that is consistently expressed at high levels is the latency-associated transcript (LAT) (5-8). LAT is important for wild-type (wt) levels of spontaneous and induced reactivation from latency (9-11). Experimental HSV-1 infections in mice and rabbits show that HSV-1 establishes a latent phase in sensory neurons (5,(12)(13)(14)(15). Although spontaneous reactivation occurs in rabbits in a manner similar to that in humans, spontaneous reactivation in mice occurs at extremely low rates (16,17).It has been proposed that trigeminal ganglia (TG)-resident CD8 ؉ T cells play an important role in maintaining latency (decreasing HSV-1 or HSV-2 reactivation) in mouse TG (18-21). Specifically, it was suggested that CD8 ϩ T cells infiltrate the TG at the time of latency establishment, inhibiting HSV-1 reactivation from latency. During latency establishment, a subset of CD8 ϩ T cells remain in direct contact with infected neurons. During HSV-1 reactivation from latency in ex vivo cultures of latently infected TG, it was found that addition of an antagonistic CD8 antibody decreased the time to reactivation, while addition of HSV-1-specific CD8 ؉ T cells increased this phenotype.Consistent with the notion that functional HSV-1-specific CD8 ؉ T cells in the TG decrease HSV-1 reactivation from latency, we found increased CD8 ؉ T cell exhaustion during latency with wild-type (wt; LAT ϩ ) HSV-1 compared to that with LAT Ϫ HSV-1 (17,22,23). In this context, exhaustion is synonymous with loss of function. Since LAT ϩ virus reactivates more rapidly than LAT

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Section: Fig 3 Isolation and Functionality Of Purified Cd8 ϩ T Cells supporting

confidence: 66%

Section: Lack Of Effect Of Adoptively Transferred Cd8mentioning

confidence: 60%

Section: Pcr and Reverse Transcription-pcr (Rt-pcr) Analysesmentioning

confidence: 99%

“…ϩ DCs, not CD8 ϩ T cells or miRNAs, are involved in establishment and maintenance of HSV-1 latency (17,22,28,32).…”

Section: Fig 3 Isolation and Functionality Of Purified Cd8 ϩ T Cells mentioning

confidence: 99%

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CD8 ⁺ T Cells Play a Bystander Role in Mice Latently Infected with Herpes Simplex Virus 1

Mott

Gate

Matundan

et al. 2016

J Virol

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“…We performed sitespecific mutagenesis within the gK 8mer region and inserted the complete open reading frame (ORF) of the mutated form of the gK gene into both copies of the latency-associated transcript (LAT) regions and under the LAT promoter as we described previously (34,(37)(38)(39)(40). Since suitable antibodies for detection of gK are not available, we inserted the myc epitope tag in-frame at the 3= end of the mutated gK ORF for identification of the inserted gK.…”

mentioning

confidence: 99%

Mutations within the Pathogenic Region of Herpes Simplex Virus 1 gK Signal Sequences Alter Cell Surface Expression and Neurovirulence

Matundan

Mott

Akhtar

et al. 2015

J Virol

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To investigate the role of the signal sequences of herpes simplex virus 1 (HSV-1) gK on virus replication and viral pathogenesis, we constructed recombinant viruses with or without mutations within the signal sequences of gK. These recombinant viruses expressed two additional copies of the mutated (MgK) or native (NgK) form of the gK gene in place of the latency-associated transcript with a myc epitope tag to facilitate detection at their 3= ends. The replication of MgK virus was similar to that of NgK both in vitro and in vivo, as well as in the trigeminal ganglia (TG) of latently infected mice. The levels of gB and gK transcripts in the corneas, TG, and brains of infected mice on days 3 and 5 postinfection were markedly virus and time dependent, as well as tissue specific. Mutation in the signal sequence of gK in MgK virus blocked cell surface expression of gK-myc in rabbit skin cells, increased 50% lethal dose, and decreased corneal scarring in ocularly infected mice compared to the NgK or revertant (RgK) virus. MgK and NgK viruses, and not the RgK virus, showed a reduced extent of explant reactivation at the lower dose of ocular infection but not at the higher dose. However, the time of reactivation was not affected by overexpression of the different forms of gK. Taken together, these results strongly suggest that the 8mer peptide (ITAYGLVL) within the signal sequence of gK promotes cell surface expression of gK in infected cells and ocular pathogenesis in infected mice. IMPORTANCEIn this study, we show for the first time that mutations within the signal sequence of gK blocked cell surface expression of inserted recombinant gK in vitro. Furthermore, this blockage in cell surface expression was correlated with higher 50% lethal dose and less corneal scarring in vivo. Thus, these studies point to a key role for the 8mer within the signal sequence of gK in HSV-1-induced pathogenicity. Herpes simplex virus 1 (HSV-1) infections are among the most frequent serious viral eye infections in the United States and are a major cause of virus-induced blindness (1-3). It is estimated that 70 to 90% of American adults have antibodies to HSV-1 and/or HSV-2 and ca. 25% of these individuals have clinical symptoms upon routine clinical inquiry. HSV-1 is responsible for Ͼ90% of ocular HSV infections (1, 2, 4-7). HSV-1-induced corneal scarring (CS), also broadly referred to as herpes stromal keratitis (HSK), can lead to blindness. Furthermore, HSV-1 is the leading cause of corneal blindness due to an infectious agent in developed countries (1, 2, 4-7). In addition to necrotizing HSK, ocular infection with HSV-1 can cause eye disease ranging in severity from blepharitis, conjunctivitis, and dendritic keratitis to disciform stromal edema (4, 7-11). In the United States, approximately 30,000 people per year suffer recurrent ocular HSV episodes, requiring doctor visits, medication, and in severe cases, corneal transplants.Although it is well established that HSV-1-induced CS is due to immune responses to the virus, the exact...

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Herpes Simplex Vaccines: Prospects of Live-Attenuated HSV Vaccines to Combat Genital and Ocular Infections

Stanfield

Kousoulas

2015

Curr Clin Micro Rpt

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Herpes simplex virus type-1 (HSV-1) and its closely related type-2 (HSV-2) viruses cause important clinical manifestations in humans including acute ocular disease and genital infections. These viruses establish latency in the trigeminal ganglionic and dorsal root neurons, respectively. Both viruses are widespread among humans and can frequently reactivate from latency causing disease. Currently, there are no vaccines available against herpes simplex viral infections. However, a number of promising vaccine approaches are being explored in pre-clinical investigations with few progressing to early phase clinical trials. Consensus research findings suggest that robust humoral and cellular immune responses may partially control the frequency of reactivation episodes and reduce clinical symptoms. Live-attenuated viral vaccines have long been considered as a viable option for generating robust and protective immune responses against viral pathogens. Varicella zoster virus (VZV) belongs to the same alphaherpesvirus subfamily with herpes simplex viruses. A live-attenuated VZV vaccine has been extensively used in a prophylactic and therapeutic approach to combat primary and recurrent VZV infection indicating that a similar vaccine approach may be feasible for HSVs. In this review, we summarize pre-clinical approaches to HSV vaccine development and current efforts to test certain vaccine approaches in human clinical trials. Also, we discuss the potential advantages of using a safe, live-attenuated HSV-1 vaccine strain to protect against both HSV-1 and HSV-2 infections.

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Inclusion of CD80 in HSV Targets the Recombinant Virus to PD-L1 on DCs and Allows Productive Infection and Robust Immune Responses

Cited by 23 publications

References 64 publications

CD8 ⁺ T Cells Play a Bystander Role in Mice Latently Infected with Herpes Simplex Virus 1

CD8 ⁺ T Cells Play a Bystander Role in Mice Latently Infected with Herpes Simplex Virus 1

Mutations within the Pathogenic Region of Herpes Simplex Virus 1 gK Signal Sequences Alter Cell Surface Expression and Neurovirulence

Herpes Simplex Vaccines: Prospects of Live-Attenuated HSV Vaccines to Combat Genital and Ocular Infections

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Inclusion of CD80 in HSV Targets the Recombinant Virus to PD-L1 on DCs and Allows Productive Infection and Robust Immune Responses

Cited by 23 publications

References 64 publications

CD8 + T Cells Play a Bystander Role in Mice Latently Infected with Herpes Simplex Virus 1

CD8 + T Cells Play a Bystander Role in Mice Latently Infected with Herpes Simplex Virus 1

Mutations within the Pathogenic Region of Herpes Simplex Virus 1 gK Signal Sequences Alter Cell Surface Expression and Neurovirulence

Herpes Simplex Vaccines: Prospects of Live-Attenuated HSV Vaccines to Combat Genital and Ocular Infections

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Product

Resources

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CD8 ⁺ T Cells Play a Bystander Role in Mice Latently Infected with Herpes Simplex Virus 1

CD8 ⁺ T Cells Play a Bystander Role in Mice Latently Infected with Herpes Simplex Virus 1