Loss of Mandibular Lymph Node Integrity Is Associated with an Increase in Sensitivity to HSV-1 Infection in CD118-Deficient Mice

Conrady, Christopher D.; Thapa, Manoj; Wuest, Todd; Carr, Daniel J.J.

doi:10.4049/jimmunol.0803878

Cited by 25 publications

(58 citation statements)

References 73 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For instance, the depletion of macrophages during HSV-1 infection in mice was demonstrated previously to lead to a higher survival rate (34). On the other hand, uncontrolled virus dissemination can also lead to a fatal outcome in mice missing the type I interferon receptor (14,33). Needless to say, a balance must be struck between the host immune response and the extent of virus infection.…”

Section: Discussionmentioning

confidence: 99%

APOBEC1-Mediated Editing and Attenuation of Herpes Simplex Virus 1 DNA Indicate That Neurons Have an Antiviral Role during Herpes Simplex Encephalitis

Gee

Ando

Kitayama

et al. 2011

J Virol

View full text Add to dashboard Cite

APOBEC1 (A1) is a cytidine deaminase involved in the regulation of lipids in the small intestine. Herpes simplex virus 1 (HSV-1) is a ubiquitous pathogen that is capable of infecting neurons in the brain, causing encephalitis. Here, we show that A1 is induced during encephalitis in neurons of rats infected with HSV-1. In cells stably expressing A1, HSV-1 infection resulted in significantly reduced virus replication compared to that in control cells. Infectivity could be restored to levels comparable to those observed for control cells if A1 expression was silenced by specific A1 short hairpin RNAs (shRNA). Moreover, cytidine deaminase activity appeared to be essential for this inhibition and led to an impaired accumulation of viral mRNA transcripts and DNA copy numbers. The sequencing of viral gene UL54 DNA, extracted from infected A1-expressing cells, revealed G-to-A and C-to-T transitions, indicating that A1 associates with HSV-1 DNA. Taken together, our results demonstrate a model in which A1 induction during encephalitis in neurons may aid in thwarting HSV-1 infection.The human apolipoprotein B-editing catalytic polypeptide (ABOBEC) family is a group of zinc-dependent DNA and RNA cytidine deaminases and consists of AID, APOBEC1 (A1), APOBEC2 (A2), seven APOBEC3s (APOBEC3A [A3A] to A3H), and APOBEC4 (A4). A1, the first APOBEC to be discovered, is known to introduce a premature stop codon into host apolipoprotein B mRNA in the gastrointestinal tract, an event critical for lipid metabolism (17,40,61). The editing by A1 is highly precise and specifically converts C to U at position 6666 of the apolipoprotein B mRNA substrate (46). Along with APOBEC1 complementation factor (ACF), these two proteins constitute the minimal required components necessary for the editing of apolipoprotein B mRNA in vitro (37).Cytidine deaminases first came into the limelight as antiviral factors after A3G was identified as a cellular restriction factor capable of inhibiting HIV-1 dissemination in the absence of HIV-1 virus infectivity factor (Vif) (56). This molecule was later shown to inhibit retrovirus infection by inducing a massive hypermutation of the murine leukemia virus (MLV) genome (23). Further detailed studies revealed that APOBEC molecules are packaged into HIV-1 virions in virus producer cells via a specific interaction with Gag and viral RNA and then exert their deaminase activity in subsequent target cells on a single-stranded DNA (ssDNA) intermediate synthesized by reverse transcriptase (3, 28, 55). Editing can lead to nonsynonymous mutations, such as premature stop codons, in critical proteins (e.g., reverse transcriptase) necessary for virus replication and infectivity, severely impairing the next round of infection (54,64). Extensive studies to assess the antiviral nature of these APOBEC enzymes have been performed across a broad range of retroviruses and hepatitis B virus (HBV) (7,35,36,42,43,50,56,58).Herpes simplex virus (HSV) is an enveloped, double-stranded DNA (dsDNA) virus and a member of the genus Alphaherpe...

show abstract

Section: Discussionmentioning

confidence: 99%

APOBEC1-Mediated Editing and Attenuation of Herpes Simplex Virus 1 DNA Indicate That Neurons Have an Antiviral Role during Herpes Simplex Encephalitis

Gee

Ando

Kitayama

et al. 2011

J Virol

View full text Add to dashboard Cite

show abstract

“…Previously, we reported a massive loss of cells residing in the draining lymph node of CD118 Ϫ/Ϫ mice infected in the cornea with herpes simplex virus 1 (HSV-1), including T cells, NK cells, pDCs, and neutrophils (11). This loss corresponded to a reduction in these populations in the infected tissue as well.…”

Section: Severity Of Infection In the Hsv-2-infected Cd118mentioning

confidence: 99%

Loss of the Type I Interferon Pathway Increases Vulnerability of Mice to Genital Herpes Simplex Virus 2 Infection

Conrady

Halford

Carr

2011

J Virol

Self Cite

View full text Add to dashboard Cite

The mouse model of genital herpes relies on medoxyprogesterone treatment of female mice to render the vaginal lumen susceptible to inoculation with herpes simplex virus 2 (HSV-2). In the present study, we report that mice deficient in the A1 chain of the type I interferon receptor (CD118 ؊/؊ ) are susceptible to HSV-2 in the absence of medroxyprogesterone preconditioning. In the absence of hormone pretreatment, 2,000 PFU of a clinical isolate of HSV-2 was sufficient to establish a productive infection in the vagina of 75% ؎ 17% and in the spinal cord of 71% ؎ 14% of CD118 ؊/؊ mice, whereas the same dose of HSV-2 replicated to detectable levels in only 13% ؎ 13% of vaginal samples and 0% of spinal cord samples from wild-type mice, as determined at day 5 postinfection. The susceptibility to HSV-2 infection in the CD118 ؊/؊ mice was associated with a significant reduction in the infiltration of HSV-specific cytotoxic T lymphocytes into the vaginal tissue, the local production of gamma interferon (IFN-␥), and the expression of T cell-recruiting chemokines CCL5, CXCL9, and CXCL10. Collectively, the results underscore the significant contribution of type I IFNs in resistance to genital HSV-2 infection.

show abstract

“…Approximately 90% of the human population is seropositive for this virus (1)(2)(3)(4). Although HSV-1 usually causes mild lesions on the lips (cold sores), it also causes blinding infection in eyes and fatal encephalitis in the brain (1,2,(5)(6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

The Herpes Simplex Virus Type 1 Latency-Associated Transcript Inhibits Phenotypic and Functional Maturation of Dendritic Cells

et al. 2012

View full text Add to dashboard Cite

We recently found that the herpes simplex virus-1 (HSV-1) latency-associated transcript (LAT) results in exhaustion of virus-specific CD8+ T cells in latently-infected trigeminal ganglia (TG). In this study we sought to determine if this impairment may involve LAT directly and/or indirectly interfering with DC maturation. We found that a small number of HSV-1 antigen-positive DCs are present in the TG of latently-infected CD11c/eYFP mice; however, this does not imply that these DCs are acutely or latently infected. Some CD8 + T cells are adjacent to DCs, suggesting possible interactions. It has previously been shown that wild-type HSV-1 interferes with DC maturation. Here we show for the first time that this is associated with LAT expression, since compared to LAT ( -) virus: (1) LAT ( + ) virus interfered with expression of MHC class I and the co-stimulatory molecules CD80 and CD86 on the surface of DCs; (2) LAT ( + ) virus impaired DC production of the proinflammatory cytokines IL-6, IL-12, and TNF-a; and (3) DCs infected in vitro with LAT ( + ) virus had significantly reduced the ability to stimulate HSV-specific CD8 + T cells. While a similar number of DCs was found in LAT ( + ) and LAT ( -) latently-infected TG of CD11c/eYFP transgenic mice, more HSV-1 Ag-positive DCs and more exhausted CD8 T cells were seen with LAT ( + ) virus. Consistent with these findings, HSV-specific cytotoxic CD8 + T cells in the TG of mice latently-infected with LAT ( + ) virus produced less IFN-c and TNF-a than those from TG of LAT ( -) infected mice. Together, these results suggest a novel immune-evasion mechanism whereby the HSV-1 LAT increases the number of HSV-1 Ag-positive DCs in latently-infected TG, and interferes with DC phenotypic and functional maturation. The effect of LAT on TG-resident DCs may contribute to the reduced function of HSVspecific CD8 + T cells in the TG of mice latently infected with LAT ( + ) virus.

show abstract

Loss of Mandibular Lymph Node Integrity Is Associated with an Increase in Sensitivity to HSV-1 Infection in CD118-Deficient Mice

Cited by 25 publications

References 73 publications

APOBEC1-Mediated Editing and Attenuation of Herpes Simplex Virus 1 DNA Indicate That Neurons Have an Antiviral Role during Herpes Simplex Encephalitis

APOBEC1-Mediated Editing and Attenuation of Herpes Simplex Virus 1 DNA Indicate That Neurons Have an Antiviral Role during Herpes Simplex Encephalitis

Loss of the Type I Interferon Pathway Increases Vulnerability of Mice to Genital Herpes Simplex Virus 2 Infection

The Herpes Simplex Virus Type 1 Latency-Associated Transcript Inhibits Phenotypic and Functional Maturation of Dendritic Cells

Contact Info

Product

Resources

About