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The Journal of Immunology, 2001, 166: 5869-5873.
Copyright © 2001 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: A NK Complex-Linked Locus Governs Acute Versus Latent Herpes Simplex Virus Infection of Neurons1

Rosemarie A. Pereira*, Anthony Scalzo{dagger} and Anthony Simmons2,*

* Pediatric Virology and Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555; and {dagger} Department of Microbiology, University of Western Australia, Queen Elizabeth II Medical Centre, Nedlands, Australia


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Herpes simplex causes latent infections that periodically reactivate. Specific immunization attempts are failing to control herpes, prompting a fresh look at which host responses predominate. We report a NK complex-linked genetic locus, Rhs1, whose alleles influence the magnitude of experimental herpes simplex. Rhs1 provided rapid control of primary infection but caused a reciprocal increase in the number of latently infected neurons. Thus, in principle, establishment of latency is a consequence of efficient front line defense against herpesvirus infection. Based on conservation between human and mouse NK complexes, the data predict the presence of a human Rhs1 orthologue on chromosome 12p12–13.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Primary HSV infection involves transport of virus to the peripheral nervous system (PNS),3 causing productive or latent infection of sensory neurons. Experimental infections in mice have suggested that innate immunity may be preeminent in limiting lethal interneuronal spread of productive infection (1), but adaptive immunity has received greater attention owing to the rapidly advancing understanding of mechanisms involved in specific Ag recognition. Nonetheless, attempts to control recurrent HSV by conventional immunization have met with limited success, prompting a fresh look at which host responses predominate. We took a genetic approach to this issue, using a model that mimics the shuttling of virus between skin and the PNS. After inoculation of mouse flanks, HSV infects thoracic sensory nerve ganglia (2). During the week-long ganglionic infection that ensues, virus spreads to previously uninvolved neurons and returns by anterograde axonal transport to skin that was not initially inoculated. The result is a zosteriform skin lesion (Fig. 1Gob, arrow) that indicates the rate of virus spread through the PNS (2). Development of zosteriform lesions is retarded in C57BL/6 (B6) mice compared with other strains such as BALB/c, reflecting delayed establishment of acute ganglionic infection. Further, spread of HSV to the CNS from peripheral sites is restricted in C57BL mice, making mortality the lowest among all inbred mouse strains so far tested (1). Here we show that a NK complex (NKC)-linked locus is responsible for the resistance of C57BL mice.



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  		FIGURE 1. The BALB.B6.Cmv1r congenic mouse strain used for identification of Cmv1 and Rhs1 was created from resistant B6 (a, no zosteriform lesion, day 5) and susceptible BALB/c mice (b, zosteriform lesion day 5, arrow). B6-like resistance to murine CMV was transferred to BALB/c by part of the distal arm of chromosome 6 encompassing the NKC. This transfer was facilitated using NKC and microsatellite markers (9 ), some of which are indicated in the left panel. Intra-NKC recombinant mouse strains (4 ) derived from the BALB.B6.Cmv1r strain were used to distinguish Cmv1 from Rhs1, a gene shown here to control acute and latent HSV infections of the nervous system. There is striking conservation of genes and their arrangement (c) on the distal arm of mouse chromosome 6 (c, top) and human chromosome 12p12–13 (c, bottom). The orientations of NKC-linked genes with respect to the chromosomal centromere (•) differs in mouse and humans, suggesting the likely position of the putative orthologue of mRhs1 is telomeric of Ly55.

 

   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Virus and inoculation of mice

HSV-1, strain SC16 (3), was used throughout. The zosteriform model is described elsewhere (2). Briefly, mice are infected with 5 x 105 PFU by scarification. Experiments were approved by the Institutional Review Board.

Intra-NKC recombinant mice and speed congenics

Mice used included intra-NKC recombinant mice created previously (4), with the aid of known microsatellite markers for the distal arm of chromosome 6 (Fig. 1Go). The B6.BALB-Cmv1s and the B6.BALB-TC1 (Rhs1r) strains were produced using a speed congenic approach, as described (4).

In vivo depletion of NK cells

Intraperitoneal injections of 100 µg of mAb PK136 (5), against the B6 NK cell surface product of Ly55c, were given every other day, commencing 2 days before infection.

Virus load and LD50 determinations

Virus titers in homogenized sensory nerve ganglia were measured as described previously (2). LD50 was determined by the method of Reed and Muench (6), following i.p. injection (100 µl) with 10-fold dilutions of virus suspension.

Detection of latently infected neurons

The proportion of neurons expressing HSV latency associated transcripts (LATs) was determined by in situ hybridization, using a digoxigenin-labeled riboprobe as described elsewhere (7).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
BALB.B6.Cmv1r congenic mice retard development of zosteriform skin lesions

The genetic basis for retardation of zosteriform spread of HSV by B6 mice (compared with BALB/c) was used as a clinical correlate of delayed onset of ganglionic infection. The phenotype of delayed zosteriform rash was defined by absence of a zosteriform skin lesion 5 days after inoculation on the upper flank. F1, F2, and F2 back-cross analysis indicated that retardation of zosteriform spread is a dominant trait controlled by multiple genes (Table IGo), supporting prior data using B6 and A/J parental strains. Our observations highlight the difficulties of studying genetic resistance to a complex multisystem disease and greatly increase the complexity of further analysis.


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  		Table I. Mendelian analysis of delayed zosteriform rash after cutaneous inoculation of HSV1

 
These results indicated that a different and more direct approach would be necessary to isolate loci responsible for controlling virus load in sensory ganglia. Previously, a similar problem with murine CMV was simplified by focussing on virus load in a single target organ, the spleen (8). This led to the identification of Cmv1, a locus that contributes to the overall resistance of B6 mice to murine CMV by limiting splenic viral replication (8). A congenic mouse strain was constructed (Ref. 9 , Fig. 1Go) in which B6 Cmv1-linked alleles, which are linked to the NKC (10, 11), were introduced onto the BALB/c background (BALB.B6.Cmv1r). The NKC is a region that encodes numerous surface receptors on NK cells, which are large granular lymphocytes that are known to play a pivotal role in the body’s early defenses against several viral infections (12). Whether NK cells mediate resistance to HSV has been an object of controversy for many years, owing to conflicting results in different experimental models (13, 14). However, the generation of a BALB/c mouse strain that is congenic with B6 in the NKC region made it possible to clarify the effect of NKC-linked genes and NK (or NK/T) cells on genetically determined resistance to HSV.

We tested the ability of the congenic mice to retard zosteriform spread of HSV. Five days after flank inoculation, 11/11 BALB/c mice had zosteriform rashes compared with only 2/9 BALB.B6.Cmv1r (p < 0.01). From these data we concluded that the region of chromosome 6 transferred from B6 to BALB/c mice in the congenic strain is responsible for a substantial part of the ability of B6 mice to retard zosteriform spread.

BALB.B6.Cmv1r mice are resistant to lethal HSV challenge

Congenic mice were next used to study the effect of NK-linked genes on the potentially lethal encephalitis following i.p. inoculation of HSV-1 (1). The previously established difference of >1000-fold between B6 and BALB/c animals (1) was manifest early after infection such that, 7 days after inoculation, B6 and BALB.B6 congenic mice were found to survive a challenge with >107 PFU, in contrast with BALB/c, which had an LD50 of <104. Hence, resistance to lethal HSV challenge is encoded primarily by the B6 region transferred to BALB/c during construction of the congenic strain. According to convention, we have provisionally named the locus responsible for resistance Rhs1 and the B6 allele of the responsible gene Rhs1r.

Mapping of Rhs1

To determine the location of Rhs1, HSV LD50 values were determined for a B6 background strain, BALB.B6.Cmv1s, and a series of B6 and BALB/c background intra-NKC recombinant mice (Ref. 4 , Table IIGo). BALB.B6.TC1 and BALB.B6.Cmv1s were both resistant to HSV (LD50 > 107), whereas BALB.B6.CT13 were susceptible (LD50 << 104), which clearly distinguishes Rhs1 from Cmv1. A full strain distribution pattern of HSV resistance in the intra-NKC recombinant strains showed BALB/c-like susceptibility in BALB.B6.CT13 and .CT11 that, together with B6-like resistance of BALB.B6.Cmv1r, places Rhs1 between Ly55a (mNkrp1a) and D6Mit108.


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  		Table II. Phenotypes and genotypes of parental and recombinant mice1

 
Viral loads in sensory nerve ganglia are reduced in BALB.B6 NKC congenic mice

Resistance was assessed by virus load in ganglia of groups of nine mice 5 days after flank inoculation (Fig. 2Go). Significantly less HSV was recovered from B6 (1.5 x 104 PFU) than from BALB/c mice (3 x 105 PFU). Virus load in Cmv1r congenic mice (1.9 x 104 PFU) was similar to B6 (p < 0.01, ANOVA, Tukey’s procedure). In contrast with spinal ganglia, no consistent difference in viral loads was detected in skin at the site of inoculation (not shown), leading us to conclude that NKC-linked resistance is active primarily at the level of the PNS.



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  		FIGURE 2. Reduced virus load in spinal ganglia of B6 and BALB.B6 congenic mice 5 days after flank inoculation with HSV, compared with BALB/c. Points indicate titers in individual animals, and horizontal bars indicate mean titers recovered from each strain.

 
Virus load in the PNS is controlled by NK1.1+ cells

BALB.B6.Cmv1r mice were next used to determine whether the effect of Rhs1 might be mediated by NK1.1+ (NK or NK/T) cells. We compared virus loads in ganglia of 10 BALB.B6.Cmv1r and BALB/c (Rhs1s) mice, either with or without treatment with a mAb (PK136) against the product of the B6 allele of Ly55 (NK1.1; Fig. 1Go), a molecule expressed exclusively by NK and NK/T cells. Four days after inoculation, mean virus recovery from untreated BALB.B6.Cmv1r mice was 3 x 102 PFU, whereas PK136 treatment (5) increased mean virus load in congenic animals (2 x 103 PFU) to the same level as BALB/c controls (2 x 103 PFU) (Fig. 3Go; p < 0.01, ANOVA, Tukey’s procedure). In contrast, treatment of BALB/c animals with PK136 had no effect. These data strongly implicate NK or NK/T cells as mediators of the effects of Rhs1r.



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  		FIGURE 3. Abrogation of the Cmv1r phenotype by PK136 immunotherapy, which depletes NK1.1+ cells. Points indicate virus loads in spinal ganglia of individual mice, 4 days after flank inoculation with HSV. Horizontal bars indicate mean virus recovery from each group.

 
Latency is a consequence of Rhs1-mediated rapid control of productive infection

After recovery from primary infection, HSV DNA persists in a proportion of neurons in a latent state, forming a reservoir of infection that can periodically reactivate. A limited region of the viral genome is transcribed in latently infected neurons (15). The LATs are retained in neuronal nuclei, providing a means of quantifying sites of latency in situ. To determine whether Rhs1 influences the magnitude of latent infection, LAT+ neurons were quantified by in situ hybridization (7) in ganglia of BALB/c and congenic BALB.B6.Cmv1r/Rhs1r mice 1 mo after flank inoculation. The proportion of LAT+ neurons was five times greater in Rhs1r mice than BALB/c (Fig. 4Go), indicating that rapid innate suppression of productive infection in the PNS encourages the establishment of latency.



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  		FIGURE 4. Quantification of LAT+ neurons (black nuclei) by in situ hybridization. Sensory nerve ganglia (8th–13th thoracic) that potentially innervate inoculated skin of each mouse were pooled for analysis. LAT+ neurons were abundant in ganglia from BALB.B6.Cmv1r mice (6/6 sections, each containing at least five ganglionic profiles, had >10 LAT+ neurons), compared with 0/7 BALB/c sections (p < 0.001, ANOVA, Tukey’s procedure). Representative photomicrographs from BALB/c (a) and BALB.B6.Cmv1r (b) show that at least five times more LAT+ neurons were present in the congenic strain.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The precise mode of action of Rhs1 in the PNS remains unknown. Within the Rhs1 congenic region are genes belonging to the Tnfr-1 superfamily, which have been implicated as mediators of herpesvirus entry into cells (16). However, it is unlikely that this explains Rhs1-mediated resistance because first, resistance of Rhs1 congenic mice was dependent on NK or NK/T cells and second, resistance caused by lack of an efficient entry mediator is not readily compatible with dominant inheritance. Direct involvement of TNF-{alpha} cannot be excluded because NK cells can produce this molecule. We speculate that NK or NK/T cells recognize HSV-infected neurons before expression of productive cycle genes and deliver a signal that inhibits initiation of virus replication. Type 1 IFNs, which can be made by NK and NK/T cells, have been linked with HSV innate resistance (13), raising the possibility that Rhs1 could be a previously unrecognized IFN regulatory locus. Interestingly, an immediate early gene product of HSV has the capacity to shut off cell surface expression of class I MHC molecules in infected cells (17), perhaps hindering their immunologic destruction and allowing their recognition by IFN-producing NK cells. In addition, HSV can up-regulate class I MHC expression in neighboring uninfected neurons (18), potentially enabling rapid presentation of virion structural proteins at the cell surface for perusal by cells bearing TCRs (T or NK/T cells) before the onset of viral gene expression.

In summary, a genetic locus, Rhs1r, was responsible for minimizing the magnitude of productive HSV infection in the sensory nervous system. A consequence of Rhs1r activity was increased establishment of neuronal latency. To our knowledge, this is the first description of a genetic locus influencing the magnitude of latent infection with any virus. The data predict the location of a human locus syntenic with Rhs1, on human chromosome 12 (Fig. 1Goc). Finally, we have established an important role for NK or NK/T cells in the nervous system. Their role in controlling HSV infection in sensory ganglia of Rhs1 congenic mice strongly suggests that the effects of Rhs1 are mediated by one or both of these cell types.


   Footnotes
 
1 This work was supported in part by the National Health and Medical Research Council. Back

2 Address correspondence and reprint requests to Dr. Anthony Simmons, Department of Pediatrics, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0373. Back

3 Abbreviations used in this paper: PNS, peripheral nervous system; NKC, NK complex; LAT, latency associated transcripts. Back

Received for publication February 21, 2001. Accepted for publication March 26, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Lopez, C.. 1975. Genetics of natural resistance to herpesvirus infections in mice. Nature 258:152.[Medline]
  2. Simmons, A., A. A. Nash. 1984. Zosteriform spread of herpes simplex virus as a model of recrudescence and its use to investigate the role of immune cells in prevention of recurrent disease. J. Virol. 52:816.[Abstract/Free Full Text]
  3. Hill, T. J., H. J. Field, W. A. Blyth. 1975. Acute and recurrent infection with herpes simplex virus in the mouse: a model for studying latency and recurrent disease. J. Gen. Virol. 28:841.
  4. Scalzo, A. A., M. G. Brown, D. T. Chu, J. W. Heusel, W. M. Yokoyama, C. A. Forbes. 1999. Development of intra-natural killer complex (NKC) recombinant and congenic mouse strains for mapping and functional analysis of NK cell regulatory loci. Immunogenetics 49:238.[Medline]
  5. Smart, Y. C., K. L. Stevenson, R. F. Thorne, W. D. Thomas, L. Hsu. 1989. Expression of natural killer (NK) cell-specific alloantigens on a mouse NK-like cell line. Immunol. Cell Biol. 67:239.
  6. Reed, L. J., H. Muench. 1938. A. simple method of estimating fifty percent endpoints. Am. J. Hyg. 27:493.
  7. Slobedman, B., S. Efstathiou, A. Simmons. 1994. Quantitative analysis of herpes simplex virus DNA and transcriptional activity in ganglia of mice latently infected with wild type- and thymidine kinase deficient-viral strains. J. Gen. Virol. 75:2469.[Abstract/Free Full Text]
  8. Scalzo, A. A., N. A. Fitzgerald, A. Simmons, A. B. La Vista, G. R. Shellam. 1990. Cmv-1, a genetic locus that controls murine cytomegalovirus replication in the spleen. J. Exp. Med. 171:1469.[Abstract/Free Full Text]
  9. Scalzo, A. A., P. A. Lyons, N. A. Fitzgerald, C. A. Forbes, G. R. Shellam. 1995. The BALB.B6-Cmv1 mouse—a strain congenic for Cmv1 and the NK gene complex. Immunogenetics 41:148.[Medline]
  10. Scalzo, A. A., P. A. Lyons, N. A. Fitzgerald, C. A. Forbes, W. M. Yokoyama, G. R. Shellam. 1995. Genetic mapping of Cmv1 in the region of mouse chromosome 6 encoding the NK gene complex-associated loci Ly49 and musNKR-P1. Genomics 27:435.[Medline]
  11. Forbes, C. A., M. G. Brown, R. Cho, G. R. Shellam, W. M. Yokoyama, A. A. Scalzo. 1997. The Cmv1 host resistance locus is closely linked to the Ly49 multigene family within the natural killer cell gene complex on mouse chromosome 6. Genomics 41:406.[Medline]
  12. Bancroft, G. J.. 1993. The role of natural killer cells in innate resistance to infection. Curr. Opin. Immunol. 5:503.[Medline]
  13. Bukowski, J. F., R. M. Welsh. 1986. The role of natural killer cells and interferon in resistance to acute infection of mice with herpes simplex virus type 1. J. Immunol. 136:3481.[Abstract]
  14. Rager-Zisman, B., P. C. Quan, M. Rosner, J. R. Moller, B. R. Bloom. 1987. Role of NK cells in protection of mice against herpes simplex type 1 infection. J. Immunol. 138:884.[Abstract]
  15. Stevens, J. G., E. K. Wagner, G. B. Devi-Rao, M. L. Cook, L. T. Feldman. 1987. RNA complementary to a herpesvirus {alpha} gene mRNA is prominent in latently infected neurons. Science 235:1056.[Abstract/Free Full Text]
  16. Whitbeck, J. C., C. Peng, H. Lou, R. Xu, S. H. Willis, M. Ponce de Leon, T. Peng, A. V. Nicola, R. I. Montgomery, M. S. Warner, et al 1997. Glycoprotein D of herpes simplex virus (HSV) binds directly to HVEM, a member of the tumor necrosis factor receptor superfamily and a mediator of HSV entry. J. Virol. 71:6083.[Abstract]
  17. Hill, A., P. Jogovic, I. York, G. Russ, J. Bennink, J. Yewdell, H. Ploegh, D. Johnson. 1995. Herpes simplex virus turns off the TAP to evade host immunity. Nature 375:411.[Medline]
  18. Pereira, R. A., D. C. Tscharke, A. Simmons. 1994. Up-regulation of class I MHC gene expression in primary sensory neurons, satellite cells and Schwann cells of mice in response to acute but not latent HSV infection in vivo. J. Exp. Med. 180:841.[Abstract/Free Full Text]



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