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PubMed1996

Herpesvirus genes: molecular basis of viral replication and pathogenicity.

Herpesviruses possess large DNA genomes which contain from approximately 80 to 200 genes. These viral genes are divided into two groups based on whether they are essential or nonessential (dispensable) for virus growth in cell culture: the essential gene products include a set of replication proteins which accomplish the viral DNA replication, while the dispensable gene products include those important in influencing pathogenesis. This article briefly reviews the results of studies relating to the functions and roles of the gene products of human herpesviruses, particularly products associated with the herpes simplex virus.

Genes, Viral↗

PubMed1991

Herpes simplex virus origin-binding protein (UL9) loops and distorts the viral replication origin.

To investigate the role of the herpes simplex virus origin-binding protein (UL9) in the initiation of DNA replication, we have examined the effect of UL9 binding on the structure of the viral origin of replication. UL9 loops and alters the DNA helix of the origin regardless of the phasing of the binding sites. DNase I and micrococcal nuclease footprinting show that UL9 binds two sites in the origin and loops the AT-rich DNA between them independent of the topology of the DNA. KMnO4 and dimethyl sulfate footprinting further show that UL9 alters the DNA helix in the AT region. In contrast to the looping reaction, however, helical distortion requires the free energy of supercoiled DNA. UL9 also loops and distorts the origin DNA of a replication-defective mutant with a 6-bp insertion in the AT region. Because the helical distortion of this mutant DNA is different from that of functional origins, we conclude that an imperfect tertiary structure of the mutant DNA may contribute to its loss of replication function.

Animals↗

PubMed2001

Human cytomegalovirus up-regulates the phosphatidylinositol 3-kinase (PI3-K) pathway: inhibition of PI3-K activity inhibits viral replication and virus-induced signaling.

Infection of quiescent fibroblasts with human cytomegalovirus (HCMV) was found to cause a rapid activation of cellular phosphatidylinositol 3-kinase (PI3-K). Maximum PI3-K activation occurred from 15 to 30 min postinfection. This activation was transient, and by 2 h postinfection (hpi), PI3-K activity had declined to preinfection levels. However, at 4 hpi, a second tier of PI3-K activation was detected, and PI3-K activity remained elevated relative to that of mock-infected cells for the remainder of infection. The cellular kinases Akt and p70S6K and the transcription factor NF-kappaB were activated in a PI3-K-dependent manner at similar times following HCMV infection. Analysis using UV-irradiated virus indicated that no viral protein synthesis was necessary for the first phase of PI3-K activation, but viral protein expression was required for the second tier of PI3-K activation. Treatment of infected fibroblasts with LY294002, a potent and specific inhibitor of PI3-K kinase activity, caused a 4-log decrease in viral titers. LY294002 did not inhibit viral entry, but it did decrease viral immediate-early gene expression. In addition, the protein levels of two viral early genes required for DNA replication, UL84 and UL44, were significantly lower in the presence of LY294002. Furthermore, viral DNA replication was strongly inhibited by LY294002 treatment. This inhibition of viral DNA replication could be reversed by adding back the products of PI3-K activity (PI-3,4-P(2) and PI-3,4,5-P(3)), demonstrating that the effect of LY294002 on the viral life cycle was specifically due to the inhibition of PI3-K activity. These results are the first to suggest that PI3-K mediates HCMV-induced activation of host cell mitogenic pathways. They also provide strong evidence that PI3-K activation is important for initiation of viral DNA replication and completion of the viral lytic life cycle.

Cell Line↗

PubMed2003

A truncated form of Nef selected during pathogenic reversion of simian immunodeficiency virus SIVmac239Deltanef increases viral replication.

The live, attenuated vaccine simian immunodeficiency virus SIVmac239Deltanef efficiently protects rhesus macaques against infection with wild-type SIVmac but occasionally causes CD4(+) T-cell depletion and progression to simian AIDS (SAIDS). Virus recovered from a vaccinated macaque (Rh1490) that progressed to SAIDS had acquired an additional deletion in the nef gene, resulting in a frameshift that restored the original nef open reading frame (R. I. Connor, D. C. Montefiori, J. M. Binley, J. P. Moore, S. Bonhoeffer, A. Gettie, E. A. Fenamore, K. E. Sheridan, D. D. Ho, P. J. Dailey, and P. A. Marx, J. Virol. 72:7501-7509, 1998). Intravenous inoculation of the Rh1490 viral isolate into four naive rhesus macaques induced CD4(+) T-cell depletion and disease in three out of four animals within 2 years, indicating a restoration of virulence. A DNA fragment encompassing the truncated nef gene amplified from the Rh1490 isolate was inserted into the genetic backbone of SIVmac239. The resulting clone, SIVmac239-Delta2nef, expressed a Nef protein of approximately 23 kDa, while the original SIVmac239Deltanef clone expressed a shorter protein of 8 kDa. The revertant form of Nef did not cause downregulation of CD4, CD3, or major histocompatibility complex class I. The infectivity of SIVmac239-Delta2nef was similar to that of SIVmac239Deltanef in single-cycle assays using indicator cell lines. In contrast, SIVmac239-Delta2nef replicated more efficiently than SIVmac239Deltanef in peripheral blood mononuclear cell (PBMC) cultures infected under unstimulated conditions. The p27 Gag antigen levels in SIVmac239-Delta2nef-infected cultures were still lower than those obtained with wild-type SIVmac239, consistent with a partial recovery of Nef function. The transcriptional activity of long terminal repeat (LTR)-luciferase constructs containing the nef deletions did not differ markedly from that of wild-type LTR. Introduction of a premature stop codon within Nef-Delta2 abolished the replicative advantage in PBMCs, demonstrating that the Nef-Delta2 protein, rather than the structure of the U3 region of the LTR, was responsible for the increase in viral replication. Taken together, these results show that SIV with a deletion in the nef gene can revert to virulence and that expression of a form of nef with multiple deletions may contribute to this process by increasing viral replication.

Amino Acid Sequence↗

PubMed1986

A bovine papillomavirus type 1-encoded modulator function is dispensable for transient viral replication but is required for establishment of the stable plasmid state.

A bovine papillomavirus (BPV) type 1-encoded function (M) which is a negative regulator of viral plasmid replication has been described elsewhere (Berg et al. Cell, in press; Roberts and Weintraub, Cell, in press). We report here that expression of M, which is a repressor of transient BPV replication and is not required as a positive factor in these assays, is required for the establishment of the viral genome as a stable nuclear plasmid. This function is encoded in part by the 5' portion of the BPV E1 open reading frame, whereas the 3' part of this open reading frame encodes a positive replication function (R). The R function is required for early replication events. We used transient replication assays to define the phenotypes of mutants in both the R and M genes and complementation tests to show that R and M define two separate genes. We showed that R- and M- mutants could also complement each other in stable assays. In cotransfection experiments, M- mutants had a lethal effect on the growth of G418-resistant colonies, and in addition their morphological transformation efficiencies were reduced. The rare colonies which did appear contained the mutant DNA integrated into the cellular genome. R- mutants transformed with wild-type efficiency, and the mutant DNA was also found integrated. When cotransfected, R- and M- mutants could each be established as unrearranged plasmids.

Animals↗

PubMed2025

Detection of Orsay viral replication intermediates reveals spatial and regulatory links to Caenorhabditis elegans innate immune responses.

For a positive-strand RNA virus, the encoded viral RNA-dependent RNA polymerase (oRdRP) synthesizes complementary antigenome strand and uses it as a template for amplifying the viral genome, generating various replication intermediates. Structural proteins and viral genome are packaged into virions, but the fate of replication intermediates is underexplored. Here, we investigate Orsay Virus (OV) replication intermediates, including antigenome, oRdRP and double stranded RNA (dsRNA), using PCR and fluorescence-based imaging in C. elegans intestines. As for other positive-strand RNA viruses, we find that genome is in vast excess of antigenome. Antigenome is only visualized in cells when using denaturation protocols, indicating basepaired intermediates. OV antigenome is observed with distinct cytoplasmic and perinuclear localization patterns that depend on factors required for generation of primary, but not secondary, siRNAs. In both wildtype and RNA interference (RNAi) mutants, viral dsRNA is observed in the cytoplasm associated with oRdRP, suggesting cytoplasmic virus replication hubs. Additionally, using antibodies to oRdRP, we observed spherical structures of ~1μm in diameter defined by oRdRP at their surface; over 75% of infected wildtype animals show these structures, which associate with mitochondria and autophagosomes in an antiviral RNAi- and autophagy-dependent manner, respectively. Our study defines new features of OV replication intermediates in wildtype animals, setting the stage for understanding their connection to the viral life cycle and host antiviral pathways.

Journal Article↗

PubMed2003

An oncolytic adenovirus selective for retinoblastoma tumor suppressor protein pathway-defective tumors: dependence on E1A, the E2F-1 promoter, and viral replication for selectivity and efficacy.

The use of oncolytic adenoviruses as a cancer therapeutic is dependent on the lytic properties of the viral life cycle, and the molecular differences between tumor cells and nontumor cells. One strategy for achieving safe and efficacious adenoviral therapies is to control expression of viral early gene(s) required for replication with tumor-selective promoter(s), particularly those active in a broad range of cancer cells. The retinoblastoma tumor suppressor protein (Rb) pathway is dysregulated in a majority of human cancers. The human E2F-1 promoter has been shown to be selectively activated/derepressed in tumor cells with a defect in the Rb pathway. Ar6pAE2fE3F and Ar6pAE2fF are oncolytic adenoviral vectors (with and without the viral E3 region, respectively) that use the tumor-selective E2F-1 promoter to limit expression of the viral E1A transcription unit, and, thus, replication, to tumor cells. We demonstrate that the antitumor activity of Ar6pAE2fF in vitro and in vivo is dependent on the E2F-1 promoter driving E1A expression in Rb pathway-defective cells, and furthermore, that its oncolytic activity is enhanced by viral replication. Selective oncolysis by Ar6pAE2fF was dependent on the presence of functional E2F binding sites in the E2F-1 promoter, thus linking antitumor viral activity to the Rb pathway. Potent antitumor efficacy was demonstrated with Ar6pAE2fF and Ar6pAE2fE3F in a xenograft model following intratumoral administration. Ar6pAE2fF and Ar6pAE2fE3F were compared with Addl1520, which is reported to be molecularly identical to an E1B-55K deleted vector currently in clinical trials. These vectors were compared in in vitro cytotoxicity and virus production assays, after systemic delivery in an in vivo E1A-related hepatotoxicity model, and in a mouse xenograft tumor model after intratumoral administration. Our results support the use of oncolytic adenoviruses using tumor-selective promoter(s) that are activated or derepressed in tumor cells by virtue of a particular defective pathway, such as the Rb pathway.

Adenoviridae↗

PubMed1999

Loss of dimerisation of the nonstructural protein NS1 of Kunjin virus delays viral replication and reduces virulence in mice, but still allows secretion of NS1.

The flavivirus nonstructural protein NS1 has been implicated in viral RNA replication, although its precise role has not been identified. In its native state NS1 exists as a heat labile homodimer that is thought to be required for NS1 function and secretion. However, we have recently identified a cDNA clone of KUN virus (FLSD) that replicates efficiently in cell culture but produces and secretes NS1 in monomeric form. Sequence analysis of the NS1 gene in FLSD revealed a single amino acid substitution (proline(250) to leucine) when compared with the parental KUN virus. When site-directed mutagenesis was used to substitute leucine(250) with proline in FLSD to produce the clone 250pro, dimerisation was fully restored. Furthermore, time course experiments revealed that 250pro replicated in Vero cells significantly faster than FLSD and produced 100-fold more infectious virus early (12-24 h) in infection. This correlated with our observations that FLSD required approximately 10-fold more infectious virus than 250pro to produce disease in weanling mice after intraperitoneal inoculation. Taken together our results indicate that mutation from proline to leucine at residue 250 in KUN NS1 ablates dimer formation, slows virus replication, and reduces virulence in mice.

Amino Acid Sequence↗

PubMed2002

Human cytomegalovirus UL84 localizes to the cell nucleus via a nuclear localization signal and is a component of viral replication compartments.

The UL84 open reading frame encodes a protein that is required for origin-dependent DNA replication and interacts with the immediate-early protein IE2 in lytically infected cells. Transfection of UL84 expression constructs showed that UL84 localized to the nucleus of transfected cells in the absence of any other viral proteins and displayed a punctate speckled fluorescent staining pattern. Cotransfection of all the human cytomegalovirus replication proteins and oriLyt, along with pUL84-EGFP, showed that UL84 colocalized with UL44 (polymerase accessory protein) in replication compartments. Experiments using infected human fibroblasts demonstrated that UL84 also colocalized with UL44 and IE2 in viral replication compartments in infected cells. A nuclear localization signal was identified using plasmid constructs expressing truncation mutants of the UL84 protein in transient transfection assays. Transfection assays showed that UL84 failed to localize to the nucleus when 200 amino acids of the N terminus were deleted. Inspection of the UL84 amino acid sequence revealed a consensus putative nuclear localization signal between amino acids 160 and 171 (PEKKKEKQEKK) of the UL84 protein.

Animals↗

PubMed2003

The hepatitis B virus polymerase mutation rtV173L is selected during lamivudine therapy and enhances viral replication in vitro.

Therapy of chronic hepatitis B virus (HBV) infection with the polymerase inhibitor lamivudine frequently is associated with the emergence of viral resistance. Genotypic changes in the YMDD motif (reverse transcriptase [rt] mutations rtM204V/I) conferred resistance to lamivudine as well as reducing the in vitro replication efficiency of HBV. A second mutation, rtL180M, was previously reported to partially restore replication fitness as well as to augment drug resistance in vitro. Here we report the functional characterization of a third polymerase mutation (rtV173L) associated with resistance to lamivudine and famciclovir. rtV173L was observed at baseline in 9 to 22% of patients who entered clinical trials of adefovir dipivoxil for the treatment of lamivudine-resistant HBV. In these patients, rtV173L was invariably found as a third mutation in conjunction with rtL180M and rtM204V. In vitro analyses indicated that rtV173L did not alter the sensitivity of wild-type or lamivudine-resistant HBV to lamivudine, penciclovir, or adefovir but instead enhanced viral replication efficiency. A molecular model of HBV polymerase indicated that residue rtV173 is located beneath the template strand of HBV nucleic acid near the active site of the reverse transcriptase. Substitution of leucine for valine at this residue may enhance polymerization either by repositioning the template strand of nucleic acid or by affecting other residues involved in the polymerization reaction. Together, these results suggest that rtV173L is a compensatory mutation that is selected in lamivudine-resistant patients due to an enhanced replication phenotype.

2-Aminopurine↗

PubMed2000

Viral replication and the coactivators p300 and CBP.

Productive viral infection requires coordinate regulation of viral and cellular gene expression. Viruses of different classes have evolved different mechanisms to conform to, adapt to and exploit programs of cellular gene expression. Many viral gene products influence and respond to cellular signals that control differentiation and proliferation Transcriptional coactivators are central to the regulation of the expression of genes controlling these events. p300 and CBP are closely related coactivators that regulate the transcription of specific genes, modify chromatin structure and influence cell cycle progression. In this review, the different molecular interactions of proteins encoded by DNA tumor viruses and lentiviruses with these transcriptional coactivators and related cellular proteins are summarized.

Animals↗

PubMed2002

Viable human cytomegalovirus recombinant virus with an internal deletion of the IE2 86 gene affects late stages of viral replication.

Using bacterial artificial chromosome (BAC) technology, we have constructed and characterized a human cytomegalovirus recombinant virus with a mutation in the exon specific for the major immediate-early region 2 (IE2) gene product. The resulting IE2 86-kDa protein (IE2 86) has an internal deletion of amino acids 136 to 290 and is fused at the carboxy terminus to enhanced green fluorescent protein (EGFP). The deletion also removes the promoter and initiator methionine for the p40 form of IE2 and initiator methionine for the p60 form of the protein, and therefore, these late gene products are not produced. The mutant virus IE2 86 Delta SX-EGFP is viable but exhibits altered growth characteristics in tissue culture compared with a full-length wild-type (wt) IE2 86-EGFP virus or a revertant virus. When cells are infected with the mutant virus at a low multiplicity of infection (MOI), there is a marked delay in the production of infectious virus. This is associated with slower cell-to-cell spread of the virus. By immunofluorescence and Western blot analyses, we show that the early steps in the replication of the mutant virus are comparable to those for the wt. Although there is significantly less IE2 protein in the cells infected with the mutant, there is only a modest lag in the initial accumulation of IE1 72 and viral early proteins, and viral DNA replication proceeds normally. The mutation also has only a small effect on the synthesis of the viral major capsid protein. The most notable molecular defect in the mutant virus infection is that the steady-state levels of the pp65 (UL83) and pp28 (UL99) matrix proteins are greatly reduced. In the case of UL83, but not UL99, there is also a corresponding decrease in the amount of mRNA present in cells infected with the mutant virus.

Cells, Cultured↗

PubMed2002

Inhibition of herpes simplex virus type 2 (HSV-2) viral replication by the dominant negative mutant polypeptide of HSV-1 origin binding protein.

UL9-C535C, the trans-dominant negative mutant polypeptide of herpes simplex virus type 1 (HSV-1) UL9 origin binding protein, is a potent inhibitor of HSV-1 viral DNA replication. This study focused on testing whether HSV-1 UL9-C535C and a genetically engineered UL9-C535C-encoding HSV-1 recombinant virus CJ83193 could inhibit herpes simplex virus type 2 (HSV-2) infection. First, a stable cell line, R-C535C, expressing a high level of UL9-C535C in the presence of tetracycline and little or no UL9-C535C in the absence of tetracycline was established. The single step growth experiment showed that like HSV-1, the de novo synthesis of HSV-2 could be suppressed approximately 1000-fold by UL9-C535C expressed in R-C535C cells in the presence of tetracycline. Secondly, compared with cells singly infected with HSV-2, co-infection of Vero cells with HSV-2 and CJ83193 reduced the replication efficiency of HSV-2 in co-infected cells by 30-40 fold in a single-step growth assay, which coincided with marked reduction in viral late gene expression, but not the expression of viral immediate-early genes. Taken together, in view of our recent demonstration that CJ83193 can serve as an effective vaccine in preventing HSV-1 infection in mice, one can generate a CJ83193-like HSV-2 recombinant virus that could potentially function as a new therapeutic class of recombinant viral vaccine against HSV-2 infection.

Animals↗

PubMed2005

Overexpression of the M2-2 protein of respiratory syncytial virus inhibits viral replication.

The M2-2 protein of respiratory syncytial virus (RSV) is involved in regulation of viral RNA transcription and replication. Encoded by the next-to-last gene of RSV, the M2-2 open reading frame (ORF) overlaps with the upstream M2-1 ORF, suggesting that the production of the M2-2 protein might be tightly regulated during virus replication. To evaluate the effect of M2-2 overexpression on RSV replication, the M2-2 gene was separated from M2-1 by leaving it at the position prior to the M2-1 or moving it to the promoter proximal position as an independent transcriptional unit in the RSV A2 genome. Although recombinant viruses bearing the shuffled M2-2 gene were recovered and expressed higher levels of M2-2, most of these viruses grew poorly in HEp-2 cells. Sequence analysis revealed that various mutations (substitution, insertion, and deletion) occurred in the M2-2 gene, resulting in reduced M2-2 activity as measured by the RSV minigenome system. Further examination of the M2-2 sequence and its function showed that either one of the first two AUG codons located at the 5' end of M2-2 could be used to produce a functional M2-2 protein and that deletion of the first six amino acids from its N terminus or four amino acids from its C terminus greatly reduced its function. The effect of M2-2 protein on RSV replication was also studied by examining RSV replication in cells transiently expressing M2-2. The M2-2 protein expressed at a high level completely inhibited RSV replication. These results strongly suggested that the level of the M2-2 protein produced in the infected cells is critical to RSV replication.

Animals↗

PubMed1983

Simian virus 40 large tumor antigen on replicating viral chromatin: tight binding and localization on the viral genome.

Pulse-labeled simian virus 40 (SV40) chromatin as well as uniformly labeled viral chromatin are immunoprecipitable by an SV40-specific tumor antiserum and therefore contain bound tumor antigen (T antigen). Single-stranded calf thymus DNA, immobilized on cellulose, competes effectively for T antigen binding with uniformly labeled nonreplicating, but not with pulse-labeled replicating, chromatin. Furthermore, T antigen dissociates in 0.5 M NaCl from nonreplicating chromatin and from purified SV40 DNA, whereas most T antigen remains associated with replicating chromatin even in the presence of 1.2 to 1.5 M NaCl. We used filtration through DNA-cellulose columns and treatment with high salt to prepare pulse-labeled immunoreactive viral chromatin. The viral DNA was digested before, and in other experiments after, immunoprecipitation with the restriction endonuclease HindIII. We found that SV40 DNA sequences, most probably representing the entire genome, remain in the immunoprecipitate after HindIII digestion, indicating an association of T antigen with origin-distal sections of replicating viral DNA. The results suggest that T antigen in replicating chromatin may be bound to regions close to replicating points. We performed control experiments with in vitro-formed complexes of T antigen and SV40 DNA. When these complexes were immunoprecipitated and HindIII digested we found, in agreement with previous studies, that only the origin containing the HindIII C fragment carried bound T antigen.

Animals↗

PubMed2002

Novel oncolytic adenoviruses targeted to melanoma: specific viral replication and cytolysis by expression of E1A mutants from the tyrosinase enhancer/promoter.

Malignant melanoma is characterized by growing incidence, early metastasis, and a lack of effective treatment for advanced disease, suggesting a pressing need for novel therapeutic approaches. Conditionally replicative adenoviruses (CRAds) constitute a new and promising strategy for cancer treatment that has been rapidly translated into clinical trials. We engineered novel melanoma-targeted CRAds, AdTyrdelta24 and AdTyrdelta2delta24, by replacing the adenoviral E1A promoter with a cassette containing a polyA sequence and a human tyrosinase enhancer/promoter construct (hTyr2E/P). The small size of this cassette allows retention of the E3 region within these CRAds, which was shown to enhance viral spread and oncolysis. In addition, we introduced mutations (delta24 and delta2delta24) into the viral E1A gene, which attenuate adenoviral replication in quiescent cells. The cell cycle pathways mediating this attenuation are defective in melanoma cells. By analysis of E1A expression, we prove fidelity of hTyr2E/P in the adenoviral genome and in the context of viral replication when an upstream polyA was included. We further show efficient cytotoxicity of AdTyrdelta24 and AdTyrdelta2delta24 in melanoma cell lines and a 100-1000-fold attenuation in cell lines derived from various nonmelanocytic tissues. Virus replication and progeny production of these viruses were similarly selective, resulting in 200-800-fold higher virus yields in melanoma cells versus control cells, thus establishing viral cytolysis and spread as the cause of the observed cell killing. Cytotoxicity of AdTyrdelta24 for normal fibroblasts and keratinocytes was strongly attenuated, and this virus caused selective killing of melanoma cells but not surrounding keratinocytes in a coculture system. Progeny production and cytotoxicity of AdTyrdelta24 in melanoma cells were similar to matching viruses containing the stronger cytomegalovirus enhancer/promoter instead of hTyr2E/P. Furthermore, AdTyrdelta24 showed a cytopathic effect similar to the wild-type E1A containing AdTyrwt and only minimally reduced compared with wild-type adenovirus. We conclude that the generated CRAds AdTyrdelta24 and AdTyrdelta2delta24 constitute novel targeted agents for gene therapy and viral oncolysis of metastatic melanoma.

Adenovirus E1A Proteins↗

PubMed1998

Varicella-zoster virus ORF57, unlike its pseudorabies virus UL3.5 homolog, is dispensable for viral replication in cell culture.

Varicella zoster virus (VZV) encodes five genes that do not have homologs in herpes simplex virus. One of these genes, VZV ORF57, is predicted to encode a protein containing 71 amino acids. Antibody to ORF57 protein immunoprecipitated a 6-kDa protein in the cytosol of VZV-infected cells. Although the homolog of VZV ORF57 in pseudorabies virus, UL3.5, is critical for viral egress and growth in cell culture, VZV unable to express ORF57 replicated to titers similar to those seen with parental virus. Thus VZV ORF57 has a different role in viral replication than its pseudorabies virus homolog.

Cytosol↗

PubMed2006

Increased surveillance of cells in mitosis by human NK cells suggests a novel strategy for limiting tumor growth and viral replication.

The threat from cancer cells is inherently linked to cell-cycle progression, and viral genomes commonly replicate, for example, within episomes or proviruses, during mitosis. We report here that human natural killer (NK) cells bound cells in mitosis and attacked pathogenic cells in mitosis more effectively than the same cells in other stages of the cell cycle. Thus, cells in mitosis warrant and undergo heightened surveillance, a novel strategy for immunologic assessment of danger. Recognition of cells in mitosis involved ligation of activating NK-cell receptors and binding to target-cell hyaluronan, a component of the pericellular matrix known to be increased during mitosis. Direct interaction between activating NK-cell receptors and hyaluronan is possible, but other mechanisms consistent with our data are also discussed.

Cell Cycle↗