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• W1999332832 abstract "In humans, herpes simplex virus (HSV) establishes latency in sensory nerve ganglia from where it periodically reactivates, whereas in murine models, the virus efficiently establishes latency but rarely reactivates. HSV inhibits MHC class I antigen presentation to CD8 T cells efficiently in humans but poorly in mice, and whether this is a crucial determinant of HSV's ability to reactivate in humans remains uncertain. To test this, we generated a panel of recombinant HSVs that inhibit presentation by murine MHC class I mimicking the effect in humans. Antigen-specific CD8 T cells prevent the in vivo reactivation of wild-type HSV. Despite their presence in the ganglia of latently infected mice, CD8 T cells do not prevent the reactivation of recombinant HSVs that inhibit murine MHC class I in mice. These findings suggest that efficient inhibition of MHC class I by HSV is a key factor in its ability to reactivate in humans. In humans, herpes simplex virus (HSV) establishes latency in sensory nerve ganglia from where it periodically reactivates, whereas in murine models, the virus efficiently establishes latency but rarely reactivates. HSV inhibits MHC class I antigen presentation to CD8 T cells efficiently in humans but poorly in mice, and whether this is a crucial determinant of HSV's ability to reactivate in humans remains uncertain. To test this, we generated a panel of recombinant HSVs that inhibit presentation by murine MHC class I mimicking the effect in humans. Antigen-specific CD8 T cells prevent the in vivo reactivation of wild-type HSV. Despite their presence in the ganglia of latently infected mice, CD8 T cells do not prevent the reactivation of recombinant HSVs that inhibit murine MHC class I in mice. These findings suggest that efficient inhibition of MHC class I by HSV is a key factor in its ability to reactivate in humans. Herpes simplex virus (HSV) is one of the most common human pathogens, infecting 50%–70% of the world population (Smith and Robinson, 2002Smith J.S. Robinson N.J. Age-specific prevalence of infection with herpes simplex virus types 2 and 1: a global review.J. Infect. Dis. 2002; 186: S3-S28Crossref PubMed Scopus (641) Google Scholar). While HSV infection can cause serious or fatal disease in neonates and the immunocompromised, and ocular infection may lead to corneal scaring and blindness in normal hosts (Liesegang, 2001Liesegang T.J. Herpes simplex virus epidemiology and ocular importance.Cornea. 2001; 20: 1-13Crossref PubMed Scopus (396) Google Scholar, Looker and Garnett, 2005Looker K.J. Garnett G.P. A systematic review of the epidemiology and interaction of herpes simplex virus types 1 and 2.Sex. Transm. Infect. 2005; 81: 103-107Crossref PubMed Scopus (103) Google Scholar, Whitley and Roizman, 2001Whitley R.J. Roizman B. Herpes simplex virus infections.Lancet. 2001; 357: 1513-1518Abstract Full Text Full Text PDF PubMed Scopus (788) Google Scholar), it typically manifests as lesions at mucosal surfaces. These recurrent lesions occurring periodically over the lifetime of an infected individual reflect reactivation of latent HSV infection, which is established in the sensory nerve ganglia at the time of primary infection. This life-long infection results in limited morbidity but facilitates transmission to new hosts and thereby helps to sustain the high prevalence of HSV infection in the human population. The traditional model of HSV latency posits that viral protein production is halted, and the virus is maintained in a quiescent state in which only an untranslated mRNA, LAT, is produced. However careful analysis of latently infected murine ganglia has revealed infrequent, but readily detectable viral protein production, indicating that latency is leakier than previously thought (Feldman et al., 2002Feldman L.T. Ellison A.R. Voytek C.C. Yang L. Krause P. Margolis T.P. Spontaneous molecular reactivation of herpes simplex virus type 1 latency in mice.Proc. Natl. Acad. Sci. USA. 2002; 99: 978-983Crossref PubMed Scopus (201) Google Scholar). These proteins may be processed and presented by MHC class I to virus-specific CD8 T cells, allowing detection and repression of overt viral reactivation (Khanna et al., 2004aKhanna K.M. Lepisto A.J. Decman V. Hendricks R.L. Immune control of herpes simplex virus during latency.Curr. Opin. Immunol. 2004; 16: 463-469Crossref PubMed Scopus (107) Google Scholar). Consistent with this notion, CD8 T cells have been found to colocalize with latently infected cells in the trigeminal ganglia of both humans and mice (Hufner et al., 2006Hufner K. Derfuss T. Herberger S. Sunami K. Russell S. Sinicina I. Arbusow V. Strupp M. Brandt T. Theil D. Latency of alpha-herpes viruses is accompanied by a chronic inflammation in human trigeminal ganglia but not in dorsal root ganglia.J. Neuropathol. Exp. Neurol. 2006; 65: 1022-1030Crossref PubMed Scopus (40) Google Scholar, Khanna et al., 2003Khanna K.M. Bonneau R.H. Kinchington P.R. Hendricks R.L. Herpes simplex virus-specific memory CD8+ T cells are selectively activated and retained in latently infected sensory ganglia.Immunity. 2003; 18: 593-603Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar, Pereira and Simmons, 1999Pereira R.A. Simmons A. Cell surface expression of H2 antigens on primary sensory neurons in response to acute but not latent herpes simplex virus infection in vivo.J. Virol. 1999; 73: 6484-6489PubMed Google Scholar, Theil et al., 2003Theil D. Derfuss T. Paripovic I. Herberger S. Meinl E. Schueler O. Strupp M. Arbusow V. Brandt T. Latent herpesvirus infection in human trigeminal ganglia causes chronic immune response.Am. J. Pathol. 2003; 163: 2179-2184Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar). In humans, a substantial number of these cells are HSV specific and bear markers associated with an effector or effector memory phenotype (Verjans et al., 2007Verjans G.M. Hintzen R.Q. van Dun J.M. Poot A. Milikan J.C. Laman J.D. Langerak A.W. Kinchington P.R. Osterhaus A.D. Selective retention of herpes simplex virus-specific T cells in latently infected human trigeminal ganglia.Proc. Natl. Acad. Sci. USA. 2007; 104: 3496-3501Crossref PubMed Scopus (172) Google Scholar); many of these cells express the activation markers CD69 and granzyme B and are in close proximity to neurons expressing HSV LAT, suggesting ongoing exposure to viral antigens. In mice, these T cells are predominantly HSV specific, often have TCRs clustered at points of contact with adjacent neurons, and express CD69 and granzyme B, indicating recent antigen exposure (Khanna et al., 2003Khanna K.M. Bonneau R.H. Kinchington P.R. Hendricks R.L. Herpes simplex virus-specific memory CD8+ T cells are selectively activated and retained in latently infected sensory ganglia.Immunity. 2003; 18: 593-603Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar, van Lint et al., 2005van Lint A.L. Kleinert L. Clarke S.R. Stock A. Heath W.R. Carbone F.R. Latent infection with herpes simplex virus is associated with ongoing CD8+ T-cell stimulation by parenchymal cells within sensory ganglia.J. Virol. 2005; 79: 14843-14851Crossref PubMed Scopus (55) Google Scholar). These HSV-specific CD8 T cells prevent reactivation in vitro in a partially IFN-γ-dependent manner (Khanna et al., 2003Khanna K.M. Bonneau R.H. Kinchington P.R. Hendricks R.L. Herpes simplex virus-specific memory CD8+ T cells are selectively activated and retained in latently infected sensory ganglia.Immunity. 2003; 18: 593-603Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar, Liu et al., 2000Liu T. Khanna K.M. Chen X. Fink D.J. Hendricks R.L. CD8(+) T cells can block herpes simplex virus type 1 (HSV-1) reactivation from latency in sensory neurons.J. Exp. Med. 2000; 191: 1459-1466Crossref PubMed Scopus (300) Google Scholar, Liu et al., 2001Liu T. Khanna K.M. Carriere B.N. Hendricks R.L. Gamma interferon can prevent herpes simplex virus type 1 reactivation from latency in sensory neurons.J. Virol. 2001; 75: 11178-11184Crossref PubMed Scopus (175) Google Scholar). In vivo reactivation after hyperthermic stress or UV exposure is increased in IFN-γ- and IFN-γR-deficient mice (Cantin et al., 1999Cantin E. Tanamachi B. Openshaw H. Role for gamma interferon in control of herpes simplex virus type 1 reactivation.J. Virol. 1999; 73: 3418-3423PubMed Google Scholar, Minami et al., 2002Minami M. Kita M. Yan X.Q. Yamamoto T. Iida T. Sekikawa K. Iwakura Y. Imanishi J. Role of IFN-gamma and tumor necrosis factor-alpha in herpes simplex virus type 1 infection.J. Interferon Cytokine Res. 2002; 22: 671-676Crossref PubMed Scopus (53) Google Scholar). These findings indicate that antigen presentation to CD8 T cells is ongoing during latency, and that these HSV-specific CD8 T cells may limit reactivation. Accordingly, eliciting a robust CD8 T cell response is the objective of several potential therapeutic HSV vaccines (Koelle, 2006Koelle D.M. Vaccines for herpes simplex virus infections.Curr. Opin. Investig. Drugs. 2006; 7: 136-141PubMed Google Scholar). To counter the CD8 T cell response, HSV encodes multiple immune evasion strategies, including inhibition of antigen presentation by MHC class I (Tortorella et al., 2000Tortorella D. Gewurz B.E. Furman M.H. Schust D.J. Ploegh H.L. Viral subversion of the immune system.Annu. Rev. Immunol. 2000; 18: 861-926Crossref PubMed Scopus (695) Google Scholar). HSV ICP47 binds to the transporter associated with antigen presentation (TAP) 1/2 complex, preventing peptides from being loaded onto nascent MHC class I heavy chains (Hill et al., 1995Hill A. Jugovic P. York I. Russ G. Bennink J. Yewdell J. Ploegh H. Johnson D. Herpes simplex virus turns off the TAP to evade host immunity.Nature. 1995; 375: 411-415Crossref PubMed Scopus (707) Google Scholar). An ICP47-deletion virus was shown to be less neurovirulent, and this decrease was due to CD8 T cells, as depletion of these cells restored neurovirulence (Goldsmith et al., 1998Goldsmith K. Chen W. Johnson D.C. Hendricks R.L. Infected cell protein (ICP)47 enhances herpes simplex virus neurovirulence by blocking the CD8+ T cell response.J. Exp. Med. 1998; 187: 341-348Crossref PubMed Scopus (123) Google Scholar). While ICP47 effectively blocks MHC class I antigen presentation on infected human cells, inhibition of presentation by murine cells is only marginally reduced, due to the low affinity of ICP47 for murine TAP1/2 (Tomazin et al., 1996Tomazin R. Hill A.B. Jugovic P. York I. van Endert P. Ploegh H.L. Andrews D.W. Johnson D.C. Stable binding of the herpes simplex virus ICP47 protein to the peptide binding site of TAP.EMBO J. 1996; 15: 3256-3266Crossref PubMed Scopus (211) Google Scholar, Tomazin et al., 1998Tomazin R. van Schoot N.E. Goldsmith K. Jugovic P. Sempe P. Fruh K. Johnson D.C. Herpes simplex virus type 2 ICP47 inhibits human TAP but not mouse TAP.J. Virol. 1998; 72: 2560-2563Crossref PubMed Google Scholar, Jugovic et al., 1998Jugovic P. Hill A.M. Tomazin R. Ploegh H. Johnson D.C. Inhibition of major histocompatibility complex class I antigen presentation in pig and primate cells by herpes simplex virus type 1 and 2 ICP47.J. Virol. 1998; 72: 5076-5084PubMed Google Scholar, Ahn et al., 1996Ahn K. Meyer T.H. Uebel S. Sempe P. Djaballah H. Yang Y. Peterson P.A. Fruh K. Tampe R. Molecular mechanism and species specificity of TAP inhibition by herpes simplex virus ICP47.EMBO J. 1996; 15: 3247-3255Crossref PubMed Scopus (269) Google Scholar). These findings suggest that the effects of ICP47 in vivo are likely to be much greater in humans than in mice. To mimic in mice the effects of ICP47 in humans, we previously generated recombinant herpes simplex viruses (rHSVs) that also express either human cytomegalovirus (HCMV) US11 (designated 27US11) or murine CMV m152 (designated 27m152) in addition to gfp, and a control virus (designated 27gfp) that expresses gfp but not an MHC class I inhibitor (Orr et al., 2005Orr M.T. Edelmann K.H. Vieira J. Corey L. Raulet D.H. Wilson C.B. Inhibition of MHC class I is a virulence factor in herpes simplex virus infection of mice.PLoS Pathog. 2005; 1: e7https://doi.org/10.1371/journal.ppat.0010007Crossref PubMed Scopus (25) Google Scholar). Both 27US11 and 27m152 reduced surface expression of murine MHC class I, rendering infected cells less susceptible to recognition and killing by CD8 T cells, leading to a loss of CD8 T cell-mediated control and increased virulence during acute infection (Orr et al., 2005Orr M.T. Edelmann K.H. Vieira J. Corey L. Raulet D.H. Wilson C.B. Inhibition of MHC class I is a virulence factor in herpes simplex virus infection of mice.PLoS Pathog. 2005; 1: e7https://doi.org/10.1371/journal.ppat.0010007Crossref PubMed Scopus (25) Google Scholar). We now show that HSV-mediated inhibition of MHC class I antigen presentation during latency abrogated CD8 T cell control of viral reactivation using both in vitro and in vivo models of HSV reactivation. Further, in the case of m152-mediated inhibition, this immune evasion strategy also reduced the frequency and activation of HSV-specific CD8 T cells in the latently infected trigeminal ganglia. These data demonstrate that latent HSV is under immune surveillance, and that the virus is able to counteract this surveillance and to reactivate in the presence of HSV-specific CD8 T cells. We previously demonstrated that viral inhibition of MHC class I resulted in increased viral titers during primary infection of mice inoculated in the footpad (Orr et al., 2005Orr M.T. Edelmann K.H. Vieira J. Corey L. Raulet D.H. Wilson C.B. Inhibition of MHC class I is a virulence factor in herpes simplex virus infection of mice.PLoS Pathog. 2005; 1: e7https://doi.org/10.1371/journal.ppat.0010007Crossref PubMed Scopus (25) Google Scholar). To determine whether viral inhibition of MHC class I affected the course of primary ocular infection, we analyzed viral shedding by sequentially swabbing both eyes of infected mice over a 10 day period and measured viral titers in homogenates of eyes and trigeminal ganglia from additional mice sacrificed at intervals over the first 14 days of infection. The amounts of virus shed from the eyes were similar for 27gfp, 27US11, and 27m152 through day 7, and shedding ceased by day 10 postinfection (Figure 1A). Viral abundance in eye homogenates followed a similar pattern, with the greatest amounts at day one and clearance by day 14 (Figure 1B). Whereas peak titers in the trigeminal ganglia were observed on day 3, virus was also cleared from this site by day 14 (Figure 1C). 27m152 demonstrated a replication advantage over 27gfp in both tissues by day 3 postinfection, while 27US11 demonstrated a similar advantage in the trigeminal ganglia but not in eye homogenates. Nonetheless, by 14 days postinfection these viruses were uniformly cleared, irrespective of their ability to inhibit MHC class I. Previous reports have demonstrated that the amount of latent virus correlates with the amount of virus in the initial inoculum (Lekstrom-Himes et al., 1998Lekstrom-Himes J.A. Pesnicak L. Straus S.E. The quantity of latent viral DNA correlates with the relative rates at which herpes simplex virus types 1 and 2 cause recurrent genital herpes outbreaks.J. Virol. 1998; 72: 2760-2764PubMed Google Scholar, Maggioncalda et al., 1996Maggioncalda J. Mehta A. Su Y.H. Fraser N.W. Block T.M. Correlation between herpes simplex virus type 1 rate of reactivation from latent infection and the number of infected neurons in trigeminal ganglia.Virology. 1996; 225: 72-81Crossref PubMed Scopus (91) Google Scholar, Sawtell, 1998Sawtell N.M. The probability of in vivo reactivation of herpes simplex virus type 1 increases with the number of latently infected neurons in the ganglia.J. Virol. 1998; 72: 6888-6892PubMed Google Scholar). Since 27US11 and 27m152 both replicated to higher titers than 27gfp in the trigeminal ganglia by day 3 and maintained this advantage until all viruses were cleared, we hypothesized that viral inhibition of MHC class I would result in an increased amount of latent virus. Surprisingly, at 2 weeks postinfection the numbers of latent viral copies in the trigeminal ganglia were slightly reduced in 27US11 or 27m152-infected mice, as compared to 27gfp-infected animals; however, these differences were not statistically significant (Figure 2). Thus, viral inhibition of MHC class I favored replication during acute infection but did not prevent viral clearance or increase the amount of latent virus. As previously reported with wild-type HSV (Khanna et al., 2003Khanna K.M. Bonneau R.H. Kinchington P.R. Hendricks R.L. Herpes simplex virus-specific memory CD8+ T cells are selectively activated and retained in latently infected sensory ganglia.Immunity. 2003; 18: 593-603Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar), 2 weeks after primary infection with 27gfp HSV-specific CD8 T cells were readily found within latently infected trigeminal ganglia as detected by staining with H-2Kb dimer loaded with the immunodominant HSV peptide gB498-505 (Wallace et al., 1999Wallace M.E. Keating R. Heath W.R. Carbone F.R. The cytotoxic T-cell response to herpes simplex virus type 1 infection of C57BL/6 mice is almost entirely directed against a single immunodominant determinant.J. Virol. 1999; 73: 7619-7626PubMed Google Scholar) (Figure 3A). Whereas mice latently infected with 27US11 and 27gfp had a similar frequency of HSV-specific CD8 T cells in the trigeminal ganglia at this time point, there were significantly fewer HSV-specific cells in ganglia latently infected with 27m152 (Figure 3A). The frequencies of HSV-specific CD8 T cells did not change from 2 (Figure 3A) to 5 (Figure 3B) weeks postinfection, indicating that this number is set by 2 weeks postinfection. A similar decrease in the frequency of HSV-specific CD8 T cells in 27m152-infected mice was observed by intracellular staining for IFN-γ after restimulation with the gB peptide; this finding corroborates the results obtained by H-2Kb-gB dimer staining and indicates that the fraction of HSV gB-specific CD8 T cells capable of producing IFN-γ directly ex vivo was similar for the three viruses (Figure 3C). By 5 weeks postinfection, the majority of the gB-specific CD8 T cells in the trigeminal ganglia of 27gfp-infected mice expressed granzyme B. In 27m152-infected mice, we observed a subtle though reproducible and statistically significant (p < 0.001) reduction in the fraction of gB-specific CD8 T cells expressing granzyme B ex vivo, as compared to 27gfp-infected mice, suggesting that fewer of these antigen-specific CD8 T cells had recently encountered cognate peptide-MHC (van Lint et al., 2005van Lint A.L. Kleinert L. Clarke S.R. Stock A. Heath W.R. Carbone F.R. Latent infection with herpes simplex virus is associated with ongoing CD8+ T-cell stimulation by parenchymal cells within sensory ganglia.J. Virol. 2005; 79: 14843-14851Crossref PubMed Scopus (55) Google Scholar) (Figure 3D). Together, these data indicate that inhibition of MHC class I by 27m152, but not by 27US11, reduced the number and degree of activation of gB-specific CD8 T cells within the latently infected ganglia. The greater impact of m152 compared to US11 on HSV-specific CD8 T cells may be due to the more efficient blockade by m152 of antigen presentation by cells expressing H-2b (Orr et al., 2005Orr M.T. Edelmann K.H. Vieira J. Corey L. Raulet D.H. Wilson C.B. Inhibition of MHC class I is a virulence factor in herpes simplex virus infection of mice.PLoS Pathog. 2005; 1: e7https://doi.org/10.1371/journal.ppat.0010007Crossref PubMed Scopus (25) Google Scholar). HSV-specific CD8 T cells can prevent in vitro reactivation of wild-type HSV from explanted latently infected ganglia (Khanna et al., 2003Khanna K.M. Bonneau R.H. Kinchington P.R. Hendricks R.L. Herpes simplex virus-specific memory CD8+ T cells are selectively activated and retained in latently infected sensory ganglia.Immunity. 2003; 18: 593-603Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar, Liu et al., 2000Liu T. Khanna K.M. Chen X. Fink D.J. Hendricks R.L. CD8(+) T cells can block herpes simplex virus type 1 (HSV-1) reactivation from latency in sensory neurons.J. Exp. Med. 2000; 191: 1459-1466Crossref PubMed Scopus (300) Google Scholar). In good agreement with these reports, we found that HSV-specific CD8 T cells efficiently prevented reactivation of 27gfp from cultures of dissociated, latently infected ganglia that were explanted 14 days postinfection (Figure 4A). Reactivation was prevented by CD8 T cells, as addition of blocking CD8 antibody resulted in 100% reactivation by all three viruses (Figure 4B). However, 27m152 and 27US11 reactivated much more readily from latently infected ganglia in the presence of HSV-specific CD8 T cells (Figure 4A). Thus, by limiting antigen presentation by MHC class I, 27m152, and to a lesser extent, 27US11 were able to reactivate more efficiently in the presence of virus-specific CD8 T cells. Although spontaneous reactivation is rare in mice, reactivation can be induced by hyperthermia or exposure to UV light (Laycock et al., 1991Laycock K.A. Lee S.F. Brady R.H. Pepose J.S. Characterization of a murine model of recurrent herpes simplex viral keratitis induced by ultraviolet B radiation.Invest. Ophthalmol. Vis. Sci. 1991; 32: 2741-2746PubMed Google Scholar, Sawtell and Thompson, 1992Sawtell N.M. Thompson R.L. Rapid in vivo reactivation of herpes simplex virus in latently infected murine ganglionic neurons after transient hyperthermia.J. Virol. 1992; 66: 2150-2156PubMed Google Scholar). Since the latter is a known cause of HSV reactivation in humans (Rooney et al., 1991Rooney J.F. Bryson Y. Mannix M.L. Dillon M. Wohlenberg C.R. Banks S. Wallington C.J. Notkins A.L. Straus S.E. Prevention of ultraviolet-light-induced herpes labialis by sunscreen.Lancet. 1991; 338: 1419-1422Abstract PubMed Scopus (114) Google Scholar), we examined the impact of MHC class I inhibition on reactivation in vivo as determined by the recovery of lytic virus from the eyes and trigeminal ganglia following exposure of latently infected mice to UV irradiation. These rHSVs were made in the KOS strain of HSV-1 that reactivates less frequently than many other HSV strains (Sawtell et al., 1998Sawtell N.M. Poon D.K. Tansky C.S. Thompson R.L. The latent herpes simplex virus type 1 genome copy number in individual neurons is virus strain specific and correlates with reactivation.J. Virol. 1998; 72: 5343-5350PubMed Google Scholar), allowing us to determine more readily whether viral inhibition of MHC class I increases the reactivation frequency in vivo. The frequency of reactivation 5 weeks after infection was significantly higher for mice infected with 27US11 or 27m152 compared to mice infected with 27gfp (Figure 5B). In a portion of the mice, we quantified the amount of virus in the homogenates from the trigeminal ganglia and eyes separately (Figure 5A). Although the absolute numbers of plaque-forming units recovered were low, in the few mice in which 27gfp reactivated, virus was recovered only from the trigeminal ganglia. Conversely, a subset of the animals infected with 27US11 and 27m152 had virus recovered from their eyes in addition to their trigeminal ganglia. In no case was virus recovered from eye but not trigeminal ganglia homogenates. Consistent with the low levels of virus detected in these tissue homogenates, we rarely detected viral shedding in the swabbed eyes with any of these viruses (data not shown). The increased rate of reactivation in mice infected with 27US11 and 27m152 was not simply due to decreased numbers of HSV-specific CD8 T cells, as 27US11 reactivated more frequently than 27gfp even though the number and activation status of these cells in the trigeminal ganglia of 27US11-infected mice were similar to 27gfp-infected mice (Figure 3). To test directly whether the increased rate of reactivation of 27US11 and 27m152 was due to the ability of these viruses, but not 27gfp, to efficiently evade control by CD8 T cells, we depleted these cells in latently infected mice prior to UV exposure. CD8 depletion, but not treatment with an IgG2b isotype control antibody, led to a markedly increased frequency of 27gfp reactivation that was similar to the frequency of reactivation of 27US11 and 27m152 (Figure 6). Conversely, depletion of CD8 T cells had little impact on the already high reactivation frequency of 27US11 and 27m152. These results indicate that inhibition of MHC class I antigen presentation by 27US11 and 27m152 increased the probability of reactivation by limiting the efficacy of CD8 T cells in preventing reactivation. Previous studies have shown that HSV-specific CD8 T cells are in close association with latently infected murine ganglia, and that these cells prevent HSV reactivation in vitro (Khanna et al., 2003Khanna K.M. Bonneau R.H. Kinchington P.R. Hendricks R.L. Herpes simplex virus-specific memory CD8+ T cells are selectively activated and retained in latently infected sensory ganglia.Immunity. 2003; 18: 593-603Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar, Liu et al., 2000Liu T. Khanna K.M. Chen X. Fink D.J. Hendricks R.L. CD8(+) T cells can block herpes simplex virus type 1 (HSV-1) reactivation from latency in sensory neurons.J. Exp. Med. 2000; 191: 1459-1466Crossref PubMed Scopus (300) Google Scholar). However, a caveat regarding the applicability of these studies to HSV infection in humans is the ability of HSV to efficiently inhibit human but not murine MHC class I antigen presentation to CD8 T cells (Ahn et al., 1996Ahn K. Meyer T.H. Uebel S. Sempe P. Djaballah H. Yang Y. Peterson P.A. Fruh K. Tampe R. Molecular mechanism and species specificity of TAP inhibition by herpes simplex virus ICP47.EMBO J. 1996; 15: 3247-3255Crossref PubMed Scopus (269) Google Scholar, Jugovic et al., 1998Jugovic P. Hill A.M. Tomazin R. Ploegh H. Johnson D.C. Inhibition of major histocompatibility complex class I antigen presentation in pig and primate cells by herpes simplex virus type 1 and 2 ICP47.J. Virol. 1998; 72: 5076-5084PubMed Google Scholar, Tomazin et al., 1996Tomazin R. Hill A.B. Jugovic P. York I. van Endert P. Ploegh H.L. Andrews D.W. Johnson D.C. Stable binding of the herpes simplex virus ICP47 protein to the peptide binding site of TAP.EMBO J. 1996; 15: 3256-3266Crossref PubMed Scopus (211) Google Scholar, Tomazin et al., 1998Tomazin R. van Schoot N.E. Goldsmith K. Jugovic P. Sempe P. Fruh K. Johnson D.C. Herpes simplex virus type 2 ICP47 inhibits human TAP but not mouse TAP.J. Virol. 1998; 72: 2560-2563Crossref PubMed Google Scholar). Using rHSVs that express either HCMV US11 or MCMV m152, both of which inhibit murine MHC class I antigen presentation (Orr et al., 2005Orr M.T. Edelmann K.H. Vieira J. Corey L. Raulet D.H. Wilson C.B. Inhibition of MHC class I is a virulence factor in herpes simplex virus infection of mice.PLoS Pathog. 2005; 1: e7https://doi.org/10.1371/journal.ppat.0010007Crossref PubMed Scopus (25) Google Scholar), we found that CD8 T cell control of reactivation is muted by this immune evasion strategy. Although viral inhibition of MHC class I increased the viral burden during primary infection, it neither prevented the clearance of primary infection nor increased the number of viral genomes in the latently infected trigeminal ganglia. Although the establishment of latency was not altered, the numbers of HSV-specific CD8 T cells residing in the latently infected ganglia were diminished in mice infected with 27m152. This decrease in cell numbers coincided with a decreased activation state of these cells, suggesting that ongoing antigen presentation is required to maintain HSV-specific CD8 T cells in latently infected ganglia. Independent of the alteration of CD8 T cell numbers, both 27US11 and 27m152 reactivated efficiently in the presence of HSV-specific CD8 T cells in vitro, whereas the control virus, 27gfp, did not. Using an UV-induced model of reactivation, we found that viral inhibition of MHC class I enhanced the rate of viral reactivation in vivo. This enhancement reflected the ability of 27US11 and 27m152 to evade CD8 T cell-mediated control, as depletion of CD8 T cells resulted in efficient reactivation by 27gfp and comparable rates of reactivation by all three viruses. These results demonstrate that HSV reactivation is under immunological surveillance by CD8 T cells, but that CD8 T cell-mediated control is subverted by efficient viral inhibition of MHC class I. Although 27US11 and 27m152 both demonstrated an increased frequency of reactivation in vitro and in vivo, the effects of m152 were consistently stronger than US11. Additionally, expression of 27m152, but not 27US11, reduced the frequency and activation status of HSV-specific CD8 T cells within the latently infected trigeminal ganglia. This difference may be due to a greater inhibition of MHC class I in cells infected with 27m152 than in cells infected with 27US11, as we previously reported (Orr et al., 2005Orr M.T. Edelmann K.H. Vieira J. Corey L. Raulet D.H. Wilson C.B. Inhibition of MHC class I is a virulence factor in herpes simplex virus infection of mice.PLoS Pathog. 2005; 1: e7https://doi.org/10.1371/journal.ppat.0010007Crossref PubMed Scopus (25) Google Scholar). However, we cannot exclude the possibility that additional functions of m152, including inhibition of NKG2D ligand expression on the surface of infected cells, may contribute to the greater effects observed with this virus (Ehrlich et al., 2005Ehrlich L.I. Ogasawara K. Hamerman J.A. Takaki R. Zingoni A. Allison J.P. Lanier L.L. Engagement of NKG2D by cognate ligand or antibody alone is insufficient to mediate costimulation of human and mouse CD8+ T cells.J. Immunol. 2005; 174: 1922-1931PubMed Google Scholar, Krmpotic et al., 2002Krmpotic A. Busch D.H. Bubic I. Gebhardt F. H" @default.
• W1999332832 created "2016-06-24" @default.
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• W1999332832 date "2007-09-01" @default.
• W1999332832 modified "2023-09-27" @default.
• W1999332832 title "CD8 T Cell Control of HSV Reactivation from Latency Is Abrogated by Viral Inhibition of MHC Class I" @default.
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