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PubMed1999

A re-evaluation of the frequency of CD8+ T cells specific for EBV in healthy virus carriers.

EBV is a gammaherpesvirus that can establish both nonproductive (latent) and productive (lytic) infections within the cells of its host. Although T cell responses to EBV latent proteins have been well characterized, little is known about the importance of responses to lytic proteins in long term virus carriers. Here we have compared the frequencies of CD8+ T cells specific for EBV latent and lytic Ags in healthy virus carriers, using three techniques: limiting dilution analysis, enzyme-linked immunospot assay, and FACS staining with tetrameric MHC-peptide complexes. T cells specific for EBV lytic protein epitopes were readily detectable in all donors and were usually more abundant than those specific for latent epitopes. We infer that direct T cell control of viral replicative lesions is maintained in long term carriers of EBV and is an important component of the immune response to this virus. Estimates of CD8+ T cell frequencies varied considerably according to methodology; values obtained from MHC-peptide tetramer staining were, on the average, 4.4-fold higher than those obtained from enzyme-linked immunospot assays, which were, in turn, on the average, 5.3-fold higher than those obtained from limiting dilution analysis. Tetramer staining showed that as many as 5.5% circulating CD8+ T cells in a virus carrier were specific for a single EBV lytic protein epitope. Such values are much greater than previously imagined and illustrate how antigenic challenge from a persistent herpesvirus can influence the composition of the host's CD8+ T cell pool.

Adult↗
PubMed2006

Herpes simplex virus type I disrupts the ATR-dependent DNA-damage response during lytic infection.

Like other DNA viruses, herpes simplex virus type 1 (HSV-1) interacts with components of the cellular response to DNA damage. For example, HSV-1 sequesters endogenous, uninduced, hyperphosphorylated RPA (replication protein A) away from viral replication compartments. RPA is a ssDNA-binding protein that signals genotoxic stress through the ATR (ataxia telangiectasia-mutated and Rad3-related) pathway. The sequestration of endogenous hyperphosphorylated RPA away from replicating viral DNA suggests that HSV-1 prevents the normal ATR-signaling response. In this study we examine the spatial distribution of endogenous hyperphosphorylated RPA with respect to ATR, its recruitment factor, ATRIP, and the cellular dsDNA break marker, gammaH2AX, during HSV-1 infection. The accumulation of these repair factors at DNA lesions has previously been identified as an early event in signaling genotoxic stress. We show that HSV-1 infection disrupts the ATR pathway by a mechanism that prevents the recruitment of repair factors, spatially uncouples ATRIP from ATR and sequesters ATRIP and endogenous hyperphosphorylated RPA within virus-induced nuclear domains containing molecular chaperones and components of the ubiquitin proteasome. The HSV-1 immediate early protein ICP0 is sufficient to induce the redistribution of ATRIP. This is the first report that a virus can disrupt the usually tight colocalization of ATR and ATRIP.

Adaptor Proteins, Signal Transducing↗
PubMed1992

Epstein-Barr virus (EBV)-negative B-lymphoma cell lines for clonal isolation and replication of EBV recombinants.

Previous experiments have demonstrated that positive selection markers recombined into the Epstein-Barr virus (EBV) genome enable the isolation of transforming or nontransforming mutant EBV recombinants in EBV-negative B-lymphoma (BL) cell lines (A. Marchini, J. I. Cohen, and E. Kieff, J. Virol. 66:3214-3219, 1992; F. Wang, A. Marchini, and E. Kieff, J. Virol. 65:1701-1709, 1991). However, virus has been recovered from a BL cell clone (BL41) infected with an EBV recombinant in only one instance (Wang et al., J. Virol. 65:1701-1709, 1991). We now compare the utility of four EBV-negative BL lines, BJAB, BL30, BL41, and Loukes, for isolating EBV recombinants and supporting their subsequent replication. Transforming or nontransforming EBV recombinants carrying a simian virus 40 promoter-hygromycin phosphotransferase (HYG) cassette were cloned by selecting newly infected BL cells for HYG expression. Most of the infected BL clones contained EBV episomes, and EBV gene expression was largely restricted to EBNA-1. Although the BJAB cell line was a particularly good host for isolating EBV recombinants (Marchini et al., J. Virol. 66:3214-3219, 1992), it was largely nonpermissive for virus replication, even in response to heterologous expression of the BZLF1 immediate-early transactivator. In contrast, approximately 50% of infected BL41, BL30, or Loukes cell clones responded to lytic cycle induction. Frequently, a substantial fraction of infected cells expressed the late lytic infection viral protein, gp350/220, and released infectious virus. Since BL cells do not depend on EBV for growth, transforming and nontransforming EBV recombinants were isolated and passaged.

Antigens, Viral↗
PubMed2003

Marek's disease virus reactivation from latency: changes in gene expression at the origin of replication.

Marek's disease is a contagious lymphoma of chickens caused by Marek's disease virus (MDV). MDV replicates in chicken lymphocytes and establishes latency within and transforms chicken CD4+ T-cells. Transformed T-cells are seen as skin leukosis or as lymphomas in visceral organs. A major focus of our laboratory is the functional study of genes flanking the origin of replication. This origin (OriLyt) is contained within the repeats flanking the unique long (UL) region of the genome (IRL and TRL). To the left of this Ori are genes associated with MDV latent/transforming infection [1.8-kb RNA family, pp14, Meq), and to the right (UL) are genes associated with early stages of MDV lytic infection [BamHI-H-encoded protein (Hep), pp38/pp24, Mys]. During latency, MDV suppresses lytic gene expression and has evolved mechanisms for blocking the apoptosis of latently-infected CD4+ T-cells. Of the genes expressed during MDV latency and in the transformed cell, the Meq (Marek's EcoRI-Q-encoded protein) has been shown to block apoptosis and transactivate gene expression. Upon reactivation to lytic infection, we have found that splice variants of Meq predominate and that these forms lack several of the domains important to Meq trans-activation and trans-repression. We have found that rightward from the origin of replication, a family genes, including phosphoprotein 38 (pp38) are expressed during early stages of reactivation. Three separate open reading frames (Hep, Mys, and pp38) are encoded by distinct transcripts from this region. We are now determining the kinetics of expression of these transcripts and their relative abundance during reactivation.

Animals↗
PubMed1992

Carcinogen-induced activation of SV40 gene expression in a semi-permissive environment.

Carcinogen-induced expression of the integrated viral genome was examined on SV40-transformed Chinese hamster cells. Carcinogen treatment markedly increased the transcription rate and the steady state mRNA level of both early and late viral transcripts. Carcinogen-induced transcription was mediated by RNA polymerase II. The increase in viral gene expression was also detected at the protein level, although at a reduced amplitude. Enhanced transcription was apparent as early as 12 hr postexposure and was considerably elevated after 24-36 hr. The increased gene expression depended on the existence of a functional replication machinery, as indicated by two lines of evidence. First, a cell line that harbors origin-deleted SV40 failed to respond to carcinogen treatment by increasing transcription and expression of T antigen. Furthermore, carcinogen-induced overtranscription was inhibited by aphidicolin, an inhibitor of DNA polymerase alpha. The involvement of the replication apparatus in the enhanced expression points to mechanistic similarities between the carcinogen-induced viral gene expression in the drug-treated semipermissive cells and the SV40 lytic pathway under permissive conditions. It is therefore suggested that cellular permissivity to viral development is enhanced following exposure to carcinogens. The implications of these findings for the nature of cellular permissivity to viral infection and the synergistic effects of carcinogens and tumor viruses are discussed.

Amanitins↗
PubMed1994

Effects of IL-12 on the response and susceptibility to experimental viral infections.

Effects of administered IL-12 on immune responses to viral infection were evaluated. IL-12-mediated effects during lymphocytic choriomeningitis virus (LCMV) infection in C57BL/6 mice were contrasted to those in either uninfected mice, or mice infected with a virus inducing a more modest T cell response, murine cytomegalovirus. Mice received 0, 1, 10, 100, or 1000 ng/d of IL-12 on the day prior to infection and daily on day 0 to 6 post-infection. Responses were examined on day 7. Low doses of IL-12 enhanced immunity to LCMV infection as demonstrated by increased splenic CD8+ T cell numbers and decreased LCMV replication. Low doses of IL-12 also significantly enhanced splenic CD8+ T cell numbers in murine cytomegalovirus-infected mice. In contrast, high doses of IL-12 were detrimental to resistance against LCMV infection. Higher doses of IL-12: 1) inhibited virus-specific CTL lytic capacity per spleen by > 90%; 2) inhibited virus-induced expansion of CD8+ T cells in spleen, peripheral blood, and lymph nodes by > 80%; 3) induced necrotic lesions in splenic white pulp; and 4) resulted in 2 log increases in splenic and renal viral replication. Initiation of high dose IL-12 treatment on day 0, 1, 2, or 4 post-infection had similar effects. Although serum levels of IFN-gamma and TNF were normally not detectable in LCMV-infected mice, infection acted synergistically with IL-12 for cytokine induction. The IL-12-mediated reduction in CD8+ T cell numbers and synergistic enhancement of circulating cytokines levels observed during LCMV infection were unique to this infection. These results demonstrate that IL-12-mediated effects can be either protective or detrimental, depending upon the environment in which the factor is presented.

Animals↗
PubMed1994

Patterns of Epstein-Barr virus latent and replicative gene expression in Epstein-Barr virus B cell lymphoproliferative disorders after organ transplantation.

B cell lymphoproliferative disorders arising in organ transplant recipients (B cell posttransplant lymphoproliferative disorders [PTLD]) are generally associated with EBV. In previous reports, B cell PTLD were shown to express the full pattern of EBV latent genes, as in vitro-established lymphoblastoid cell lines. Although viral linear DNA was detected in 40% of lymphoproliferative disorders from immunocompromised hosts, immunophenotypic studies failed to detect late EBV replicative antigens. The aim of this study was to investigate the relationship of EBV latent gene expression in B cell PTLD to morphology, clonality, and immunophenotype, and to examine the replicative state of EBV in malignant cells. For this purpose, 9 cases of EBV-related B cell PTLD were analyzed. Immunoglobulin gene rearrangements were detected by Southern blot analysis. The presence of EBV was assessed by Southern blot and by in situ hybridization. B cell differentiation antigens, adhesion and activation molecules, and EBV latent and replicative gene expression were studied using immunohistochemistry techniques. We demonstrated that EBV-related B cell PTLD exhibited varying patterns of latent viral gene expression. Higher levels of adhesion molecules were detected in latent membrane protein 1 (LMP1) or LMP1 plus EBV nuclear antigen 2 (EBNA2)-positive tumors than in LMP1 and EBNA2-negative tumors. In contrast, there was no relationship between CD21 and CD23 expression and latent EBV phenotype. Activation of the EBV replicative cycle was highlighted by BamHI Z left frame 1 expression in 5 of 9 cases. Less frequent expression of late viral proteins suggested that the initiation of the EBV lytic cycle might not always lead to virions production.

Adult↗
PubMed1982

Mutant of simian virus 40 large T-antigen that is defective for viral DNA synthesis, but competent for transformation of cultured rat cells.

A mutant was isolated which demonstrates that the transforming activity of simian virus 40 large T-antigen is separable from its function in viral DNA replication. The mutant, SVR9D, is nonconditionally defective for viral DNA synthesis, but competent at wild-type level for morphological transformation of cultured rat cells. The lytic growth defect in SVR9D is complemented by the simian virus 40 A gene product present in the transformed CV1 cell line, COS1. The lesion in SVR9D DNA was mapped genetically by marker rescue of plaque formation and localized to a 214-base-pair segment of the viral genome bounded by nucleotide numbers 4100 and 4314. DNA sequence analysis showed the mutation to be an adenine-to-guanine transition at nucleotide number 4178. This change predicts a lysine-to-glutamic acid amino acid change at residue number 214 of the mutant large T-antigen polypeptide.

Animals↗
PubMed2004

Role of an arbovirus nonstructural protein in cellular pathogenesis and virus release.

The insect-borne Bluetongue virus (BTV) is considered the prototypic Orbivirus, a member of the Reovirus family. One of the hallmarks of Orbivirus infection is the production of large numbers of intracellular tubular structures of unknown function. For BTV these structures are formed as the polymerization product of a single 64-kDa nonstructural protein, NS1, encoded by the viral double-stranded RNA genome segment 6. Although the NS1 protein is the most abundant viral protein synthesized in infected cells, its function has yet to be determined. One possibility is that NS1 tubules may be involved in the translocation of newly formed viral particles to the plasma membrane, and NS1-specific monoclonal antibodies have been shown to react with viral particles leaving infected cells. In the present study we generated a mammalian cell line that expresses a recombinant single-chain antibody fragment (scFv) derived from an NS1-specific monoclonal antibody (10B1) and analyzed the effect that this intracellular antibody has on BTV replication. Normally, BTV infection of mammalian cells in culture results in a severe cytopathic effect within 24 to 48 h postinfection manifested by cell rounding, apoptosis, and lytic release of virions into the culture medium. However, infection of scFv-expressing cells results in a marked reduction in the stability of NS1 and formation of NS1 tubules, a decrease in cytopathic effect, an increased release of infectious virus into the culture medium, and budding of virions from the plasma membrane. These results suggest that NS1 tubules play a direct role in the cellular pathogenesis and morphogenesis of BTV.

Animals↗
PubMed1998

Acute infection of Sindbis virus induces phosphorylation and intracellular translocation of small heat shock protein HSP27 and activation of p38 MAP kinase signaling pathway.

In general, viral infection is supposed to induce stress responses in the host cell. However, very few detailed observations about virus-induced stress responses have been reported. Here we investigated specific stress responses in Vero cells infected with Sindbis virus (SV), a single-stranded RNA virus, acute infection with which is known to cause apoptotic cell death in the host cells. Prior to the onset of apoptosis, p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinases (JNKs) were activated. Subsequently, a 27-kDa heat shock protein (HSP27) became phosphorylated, and intracellular distribution of HSP27 was changed from the cytoplasm to the perinuclear region. These results indicate that the cellular signaling cascades activated by pro-inflammatory cytokines and environmental stresses are also activated as a result of lytic infection with SV. These responses may contribute to the delayed onset of apoptosis in the host cells and the facilitation of viral replication.

Animals↗
PubMed1963

EFFECT OF SODIUM CHLORIDE ON STAPHYLOCOCCUS-PHAGE RELATIONSHIPS.

West, B. (University of Oklahoma Medical Center, Oklahoma City), Florene C. Kelly, and Doris A. Shields. Effect of sodium chloride on staphylococcus-phage relationships. J. Bacteriol. 86:773-780. 1963.-Phage patterns of 21 phage-propagating strains of staphylococci on medium with high NaCl content appeared to be an expression of the staphylococcal cells, as well as of the salt tolerance of the phages. Serological group A phages, previously found to be NaCl-tolerant in the free state, were capable of lysing susceptible staphylococci on 3, 7.5, and 10% NaCl Trypticase Soy Agar. None of the other phages tested was active when the medium contained 7.5 and 10% NaCl. Increasing the NaCl content of the medium rarely resulted in nonspecific reactions; rather the effect was, generally, a narrowing of the phage spectrum of the cells, with persistence in the phage pattern of the phage, or phages, which were propagated on the cells being tested. Although NaCl tolerance of the phages was the chief limiting factor of phage activity in the presence of 7.5 and 10% NaCl, reactions on salt medium also depended on the degree of susceptibility of cells to phage on routine typing medium and to certain other unexplained factors. In some instances, under the influence of increased NaCl, significant lysis at 1000 RTD was replaced by thinning of growth (inhibition), with or without the presence of plaques. Conversely, certain phage-cell combinations, which gave inhibition at 1000 RTD on standard medium produced some degree of lysis when the NaCl concentration was increased. Studies of phage 81 and its propagating strain showed that replication of phage occurred in 10% NaCl medium, although adsorption diminished as salt concentration was increased, and the time required to reach maximal lytic activity was delayed.

Bacteriophages↗
PubMed1986

Identification of the trans-acting Rep proteins of adeno-associated virus by antibodies to a synthetic oligopeptide.

Prior genetic analysis provided evidence for trans-acting regulatory proteins (Rep) coded by the left-hand open reading frame (orf-1) of adeno-associated virus (AAV). We have used immunoblotting analysis to identify four protein products of orf-1. Antibodies elicited against an oligopeptide encoded by orf-1 were reacted with extracts of cells that were infected with AAV or transfected with AAV recombinant vectors in the presence or absence of helper adenovirus. The antibody recognized four polypeptides with apparent molecular weights of 78,000, 68,000, 52,000, and 40,000. The 78,000-dalton (78K) (Rep78) and 68K (Rep68) proteins appear to be encoded by the unspliced 4.2-kilobase (kb) and spliced 3.9-kb mRNAs, respectively, transcribed from the p5 promoter. The 52K (Rep52) and 40K (Rep40) proteins appear to be the products of the unspliced 3.6-kb and the spliced 3.3-kb mRNAs, respectively, transcribed from the p19 promoter. Rigorous identification of Rep68 as an AAV-coded protein is compromised by a cross-reacting cellular protein of similar size. All four proteins were expressed in the human cell lines 293, HeLa, HT29, and A549 infected with AAV together with adenovirus. Rep78 and Rep52 were detected at lower levels in cells infected with AAV at high multiplicity in the absence of adenovirus. Human 293 cells transfected with a recombinant AAV vector (pAV2) also expressed Rep proteins in the presence or absence of adenovirus. Mutations introduced into the Rep region of pAV2 further identified the Rep proteins. The amount of each Rep protein varied between nuclear and cytoplasmic extracts, but all four proteins accumulated during the lytic cycle of the viral infection. Other studies have indicated that the Rep proteins have independent trans-acting functions in viral DNA replication and negative and positive regulation of gene expression. Correlation of each trans-acting function with individual Rep proteins will be facilitated with the antibodies described herein.

Amino Acid Sequence↗
PubMed1988

Genetic structure and function of an early transcript of visna virus.

During the early step of the lytic cycle, visna provirus is first transcribed into two small multispliced mRNAs of 1.6 and 1.2 kilobases which may encode factors regulating the replication of visna virus (R. Vigne, V. Barban, G. Quérat, V. Mazarin, I. Gourdou, and N. Sauze, Virology 161:218-227, 1987). By cDNA cloning and nucleotide sequencing, we determined that the 1.2-kilobase mRNA is 1,174 nucleotides long without the 3'-polyadenylated tail and is composed of four exons, two of which originated from the 5' and 3' ends, respectively, of the env gene region. Two overlapping open reading frames are present in each of these two exons. They were translated in vitro and gave rise to three proteins, two of 19 and 17 kilodaltons, termed VEP1, and one of 16.5 kilodaltons, termed STM. Only the VEP1 proteins were recognized by a hyperimmune anti-visna virus serum of infected sheep. Transient-expression assays performed in eucaryotic cells demonstrated that the cDNA clone described here has a trans-acting effect on transcription of the visna virus genes.

Amino Acid Sequence↗
PubMed1973

Gene expression during the development of Bacillus subtilis bacteriophage phi 29. I. Analysis of viral-specific transcription by deoxyribonucleic acid-ribonucleic acid competition hybridization.

The ribonucleic acid (RNA) specified by bacteriophage phi29 was analyzed to determine its composition at various times in the viral lytic cycle. Although viral-specific RNA was detected immediately after infection, a large increase in the rate was observed at 10 min when DNA synthesis began. phi29 was found to resemble other viruses in that gene expression occurred in two stages which could be defined temporally as "early" and "late." Early RNA appeared before the onset of viral deoxyribonucleic acid (DNA) replication and accounted for approximately 40% of the viral genetic potential. This RNA was also present late in the infectious cycle because of the slow turnover rate of phi29-specific RNA (approximately 10 min half-life) and the continued synthesis of much early viral RNA throughout infection. Late RNA was first detected at approximately the same time as viral DNA replication, although late transcription was not dependent upon DNA synthesis. This RNA was only partially displaced by early RNA in the appropriate competition experiments, suggesting that it contained sequences not present in the early class. Expression of viral genes was sensitive to rifamycin throughout the lytic cycle, the sensitivity resulting from a dependence upon the rifamycin phenotype of the host RNA polymerase.

Bacillus subtilis↗
PubMed2000

An explosive antisense RNA strategy for inhibition of a lactococcal bacteriophage.

The coding regions of six putative open reading frames (ORFs) identified near the phage phi31 late promoter and the right cohesive end (cos) of lactococcal bacteriophage phi31 were used to develop antisense constructs to inhibit the proliferation of phage phi31. Two middle-expressed ORFs (ORF 1 and ORF 2) and four late-expressed ORFs (ORF 3 through ORF 6) were cloned individually between the strong Lactobacillus P6 promoter and the T7 terminator (T(T7)) to yield a series of antisense RNA transcripts. When expressed on a high-copy-number vector from a strong promoter, the constructs had no effect on the efficiency of plaquing (EOP) or the plaque size of phage phi31. To increase the ratio of antisense RNA to the targeted sense mRNA appearing during a phage infection, the antisense cassettes containing the late-expressed ORFs (ORF 3 through ORF 6) were subcloned to pTRK360, a low-copy-number vector containing the phage phi31 origin of replication, ori31. ori31 allows for explosive amplification of the low-copy-number vector upon phage infection, thereby increasing levels of antisense RNA transcripts later in the lytic cycle. In addition, the presence of ori31 also lowers the burst size of phage phi31 fourfold, resulting in fewer sense, target mRNAs being expressed from the phage genome. The combination of ori31 and P6::anti-ORF 4H::T(T7) resulted in a threefold decrease in the EOP of phage phi31 (EOP = 0.11 +/- 0.03 [mean +/- standard deviation]) compared to the presence of ori31 alone (EOP = 0.36). One-step growth curves showed that expression of anti-ORF 4H RNA decreased the percentage of successful centers of infection (75 to 80% for ori31 compared to 35 to 45% for ori31 plus anti-ORF 4H), with no further reduction in burst size. Growth curves performed in the presence of varying levels of phage phi31 showed that ori31 plus anti-ORF 4H offered significant protection to Lactococcus lactis, even at multiplicities of infection of 0.01 and 0.1. These results illustrate a successful application of an antisense strategy to inhibit phage replication in the wake of recent unsuccessful reports.

Bacteriophages↗
PubMed1992

Prevention of the spread of HIV-1 infection with nonnucleoside reverse transcriptase inhibitors.

Certain bisheteroarylpiperazines (BHAPs) directly inhibit the replication of human immunodeficiency virus type 1 (HIV-1) and block the spread of infection to susceptible populations of cells. At a 1 microM concentration three analogs, U-87201, U-88204, and U-89674, inhibited the replication of HIV-1 in MT-2 cells by 83, 100, and 93%, respectively. At the same concentration, U-88204 completely inhibited replication of primary HIV-1 isolates in peripheral blood mononuclear cells. Replication of 3'-azido-2',3'-dideoxythymidine (AZT)-resistant strains of HIV-1 was also inhibited by U-88204. When MT-2 cells that were lytically infected with HIV-1 were mixed with uninfected MT-2 cells, U-88204 provided complete protection to the uninfected cells. Integrated proviral DNA sequences were not detected by the polymerase chain reaction technique in this culture after 15 days in the presence of drug. The resultant healthy cell culture was subsequently maintained without drug with no evidence of latent proviral DNA. Serial passage of a laboratory strain and a primary isolate of HIV-1 in cell culture in the presence of increasing concentrations of U-88204 yielded virus populations which were at least 100-fold resistant to the drug. These resistant viruses also showed cross-resistance to the pyridinone class of nonnucleoside inhibitors but were sensitive to AZT. Analysis of the nucleotide sequence of resistant viruses revealed mutations at conserved regions of the reverse transcriptase (RT) gene. The results presented here suggest the therapeutic potential of U-88204 in the combination therapy for HIV-1 infection.

Cell Line↗
PubMed1994

Mechanism of virus-induced Ig subclass shifts.

Infection of mice with live viruses leads to a dramatic increase in the amount of IgG2a Ig with a consequent shift in the ratio of IgG1/IgG2a. To examine the Ig subclass shift induced by viral infection, we challenged mice with live virus, inactivated virus, or replication-defective mutant viruses that were able to infect cells and produce some viral proteins but were not able to complete a replicative cycle. While killed (or inactivated) virus was capable of inducing HSV-specific antibody, it did not stimulate a shift in the subclass of the total Ig. Replication-defective mutant viruses that fail to express a functional ICP8 or ICP27 protein, but not a mutant expressing a defective ICP4 protein, were able to stimulate the shift. Thus, only a portion of the lytic cycle is sufficient to induce the shift. At least part of the effect is mediated by IFN-gamma.

Animals↗
PubMed1987

Aberrant T cells in beige mutant mice.

Cytotoxic T lymphocyte (CTL) morphology and function was examined in beige (bg/bg) mutant mice during infection with lymphocytic choriomeningitis virus (LCMV). Virus-specific, class I-restricted CTL activity mediated by total spleen leukocytes isolated from bg/+ or +/+ mice on days 7 or 9 postinfection with LCMV was moderately higher than that mediated by spleen cells isolated from bg/bg mice. The CTL generated in bg/bg mice had aberrant morphology. Lyt-2+ cells isolated from bg/+ or +/+ mice had typical large granular lymphocyte (LGL) morphology and contained numerous small azurophilic granules, whereas Lyt-2+ cells isolated from bg/bg mice contained only one or two large atypical granules in their cytoplasm. Aberrant LGL morphology correlated with reduced lytic capacity. The bg/bg CTL were inefficient killer cells mediating, on a per cell basis, only one fourth of the lysis mediated by bg/+ CTL. The bg/bg mice appeared to mount a compensatory response to regulate virus replication, because frequencies of Lyt-2+ cells and cells that specifically bound to virus-infected target cells were elevated as compared with their frequencies in bg/+ mice. The higher proportion of the CTL phenotype cells appeared to be a consequence of expanded proliferation of Lyt-2+ cells. These results demonstrate that, in comparison with bg/+ and +/+ mice, bg/bg mice have CTL with reduced lytic capacities, but may compensate during virus infection by expanding the number of these cells. Furthermore, these data suggest that the depressed lytic activity may be a consequence of aberrant granule formation.

Animals↗