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PubMed1975

Adenovirus transcription. II. RNA sequences complementary to simian virus 40 and adenovirus 2DNA in AD2+ND1- and AD2+ND3-infected cells.

The genomes of the two nondefective adenovirus 2/simian virus 40 (Ad2/SV 40) hybrid viruses, nondefective Ad2/SV 40 hybrid virus 1 (Ad2+ND1) and nondefective hybrid virus 3 (Ad2+ND3), WERE FORMED BY A DELETION OF ABOUT 5% OF Ad2 DNA and insertion of part of the SV40 genome. We have compared the cytoplasmic RNA synthesized during both the early and late stages of lytic infection of human cells by these hybrid viruses to that expressed in Ad2-infected and SV40-infected cells. Separated strands of the six fragments of 32P-labeled Ad2 DNA produced by cleavage with the restriction endonuclease EcoRI (isolated from Escherichia coli) and the four fragments of 32P-labeled SV40 DNA produced by cleavage with both a restriction nuclease isolated from Haemophilus parainfluenzae, Hpa1, and EcoRI were prepared by electrophoresis of denatured DNA in agarose gels. The fraction of each fragment strand expressed as cytoplasmic RNA was determined by annealing fragmented 32P-labeled strands to an excess of cellular RNA extracted from infected cells. The segment of Ad2 DNA deleted from both hybrid virus genomes is transcribed into cytoplasmic mRNA during the early phase of Ad2 infection. Hence, we suggest that Ad2 codes for at least one "early" gene product which is nonessential for virus growth in cell culture. In both early Ad2+ND1 and Ad2+ND3-infected cells, 1,000 bases of Ad2 DNA adjacent to the integrated SV40 sequences are expressed as cytoplasmic RNA but are not similarly expressed in early Ad2-infected cells. The 3' termini of this early hybrid virus RNA maps in the vicinity of 0.18 on the conventional SV40 map and probably terminates at the same position as early lytic SV40 cytoplasmic RNA. Therefore, the base sequence in this region of SV40 DNA specifies the 3' termini of early messenger RNA present in both hybrid virus and SV40-infected cells.

Adenoviridae↗
PubMed1976

Hybridization of mRNA from adenovirus-transformed cells to segments of the adenovirus genome.

Cytoplasmic viral-specific RNA from the 8617 line of adenovirus type 2 (Ad2) transformed rat cells was hybridized to DNA fragments derived either by Eco-RI or Sma-I restriction endonucleases. Three discrete classes of viral RNA (26S, 20S, and 15S) were detected by hybridization of total cytoplasmic RNA with the fragment, and all of these RNA molecules also hybridized to the much smaller Sma-E fragment of Ad2 DNA. Poly (A)-containing RNA (exposed to 90% formamide) contained only the 20S and 15S mRNA species, suggesting that the 26S RNA might be an aggregated species. Viral RNA of the same size derived from the same regions of the genome has not been detected in lytically infected cells, suggesting some change in the pattern of transcription or RNA processing of the Ad2 DNA in the integrated state.

Adenoviridae↗
PubMed1968

Biochemical studies on adenovirus multiplication. 13. Synthesis of virus-specific ribonucleic acid during infection with human adenovirus type 12.

The transcription of virus-specific ribonucleic acid (RNA) was studied in KB cells infected with adenovirus type 12 (strain Huie). Viral deoxyribonucleic acid (DNA) synthesis began at 12 to 15 hr after infection, and virus maturation occurred between 20 and 50 hr after infection. The rate of incorporation of (3)H-uridine into RNA per infected cell was stimulated, reaching a maximum of 1.6 times that of uninfected cells at 20 hr after infection. "Early" viral messenger ribonucleic acid (mRNA) constituted 0.1% of RNA synthesized at 11 hr, and "late" viral mRNA constituted 50% of RNA synthesized at 45 hr after infection, as determined by hybridization of viral DNA with labeled RNA from infected cells pulse labeled with (3)H-uridine. The species of virus-specific RNA synthesized at 22 hr after infection (when virus maturation has just begun) and at 45 hr (when virus maturation is nearly complete) were studied further: (i) 22- and 45-hr RNA had the same average guanine plus cytosine content, 47%, (ii) 22- and 45-hr RNA contained mostly the same viral nucleotide sequences, (iii) 45-hr RNA had a five times higher concentration of virus-specific RNA molecules than did 22-hr RNA, and (iv) 22- and 45-hr RNA contained virus-specific nucleotide sequences transcribed from all, or nearly all, of the viral genome.

Adenoviridae↗
PubMed1969

Biochemical studies on adenovirus multiplication. XVI. Transcription of the adenovirus genome during abortive infection of elevated temperatures.

The synthesis of infectious virus is reduced by 99% in adenovirus type 2-infected KB cells maintained at 42 C in suspension. Studies to delineate the steps in virus biosynthesis blocked at 42 C revealed the following. (i) The inhibition of ribosomal ribonucleic acid (RNA) synthesis and the block in the conversion of ribosomal RNA precursors to ribosomal RNA which normally occur in infected cells at 37 C was accentuated at 42 C. (ii) The same species of early and late viral messenger RNA were synthesized at 37 and 42 C. (iii) The shift from host cell deoxyribonucleic acid (DNA) synthesis to viral DNA replication occurred earlier at 42 C than at 37 C. These findings indicate that the thermosensitive block(s) in virion formation does not occur at the level of viral DNA replication or transcription of viral mRNA but probably involves the synthesis of late viral proteins or the maturation of the virion.

Adenoviridae↗
PubMed1997

Adenovirus vector-infected cells can escape adenovirus antigen-specific cytotoxic T-lymphocyte killing in vivo.

The recent findings that prolonged expression of certain adenovirus (Ad) vector-encoded proteins, including human alpha1-antitrypsin (huAAT), mouse erythropoietin (EPO), and human factor IX, can be achieved in animals that do not mount an immune response to the reporter protein were obtained with mouse strains which have been shown to be capable of mounting a cellular immune response against Ad vector antigens. This suggests either that Ad vectors expressing nonimmunogenic transgenes fail to elicit a cellular immune response or that an Ad-specific cellular immune response does develop but is ineffective against cells expressing nonimmunogenic transgenes. Here we demonstrate that an Ad vector expressing huAAT administered by intravenous injection does stimulate an Ad-specific cellular immune response but that this response fails to abolish vector-directed gene expression in vivo. Moreover, expression of huAAT remained stable in animals stimulated by concurrent and multiple administrations of different Ad vectors or viruses. We also demonstrate prolonged expression of huAAT in CD1 mice transgenic for the huAAT gene, indicating that long-term expression is not restricted to C57BL/6 mice. These results demonstrate that under some circumstances, an Ad vector can direct prolonged expression of a nonimmunogenic transgene despite the presence of a robust Ad-specific cellular immune response.

Adenoviridae↗
PubMed1998

Construction and characterization of hexon-chimeric adenoviruses: specification of adenovirus serotype.

This study has used the strategy of gene replacement to characterize the contribution of the adenovirus (Ad) capsid protein hexon to serotype definition. By replacing the Ad type 5 (Ad5) hexon gene with sequences from Ad2, we have changed the type specificity of the chimeric virus. The type-determining epitopes are primarily associated with loop 1 of hexon and, to a much lesser degree, with loop 2. In spite of the serotype distinctiveness of the chimeric hexon viruses, epitope similarity between the vectors resulted in a low level of cross-reactive neutralizing antibody, which in combination with activated cellular and innate arms of the immune system is sufficient to suppress gene transduction following readministration in vivo.

Adenoviridae Infections↗
PubMed1972

Intracellular forms of adenovirus deoxyribonucleic acid. I. Evidence for a deoxyribonucleic acid-protein complex in baby hamster kidney cells infected with adenovirus type 12.

The total intracellular deoxyribonucleic acid (DNA) from baby hamster kidney cells abortively infected with (3)H-adenovirus type 12 was analyzed in dye-buoyant density gradients. Between 10 and 20% of the cell-associated radioactivity derived from viral DNA bands in a density position which is 0.043 to 0.085 g/cm(3) higher than that of viral DNA extracted from purified virions. The DNA in the high-density region (HP-fraction) is almost completely absent when DNA, ribonucleic acid (RNA) or protein synthesis is chemically inhibited in separate experiments. The HP-fraction is not found when the virus does not adsorb to and enter the cell. The DNA in the HP-fraction appears as early as 2 hr after inoculation. At 2 hr after infection, the HP-fraction is present both in the nucleus and the cytoplasm. This DNA hybridizes exclusively with viral DNA and sediments at approximately the same rate in both neutral and alkaline sucrose density gradients. Electron microscopy has revealed no circular DNA molecules in this fraction. Evidence indicates that the viral DNA in the HP-fraction exists in a complex with protein and possibly RNA. The protein component of the complex is resistant to enzymatic digestion, whereas the complex is susceptible to ribonuclease treatment. Digestion with deoxyribonuclease reduces the amount of DNA found in the HP-fraction. The structure and biological function of this complex are currently being investigated.

Adenoviridae↗
PubMed1999

Adenovirus-mediated expression of interleukin-12 induces natural killer cell activity and complements adenovirus-directed gp75 treatment of melanoma lung metastases.

Based on the knowledge that adenovirus (Ad)-mediated expression of the murine gp75 melanoma antigen (Adgp75) will effectively immunize mice against H2-matched B16 melanoma cells, probably via cell- mediated immune mechanisms, we hypothesized that Ad-mediated delivery of the murine interleukin-12 (IL-12) complementary DNA heterodimer would have independent therapeutic effects on tumor growth, and that the combination of the two vectors would work synergistically to augment the antitumor response. We evaluated the therapeutic effect of each vector alone and in combination for efficacy in C57BL/6 mice with preestablished (2 d) B16 melanoma-derived pulmonary metastases, using the number of lung metastases as the efficacy parameter. Intraperitoneal administration of Adgp75 (10(8) PFU) reduced tumor burden to 45 +/- 7% of controls (P < 0.01), and AdIL12 administration (10(8) PFU, intraperitoneally) reduced the number of metastases to 43 +/- 7% of controls (P < 0.01). The combination of Adgp75 (10(8) PFU, intraperitoneally) and AdIL12 (10(8) PFU, intraperitoneally) provided further protection (15 +/- 3%; P < 0.01 as compared with naive control; P < 0.01 compared with Adgp75 or AdIL12 alone). Mice receiving AdIL12 showed increased natural killer cell (NK cell) function in an in vitro cytotoxicity assay, with a dose- dependent lysis of YAC-1 cells and, to a lesser extent, lysis of B16 cells. To assess the relative contribution of major histocompatibility complex I (MHC I) Dependent and Independent activity in combination therapy with Adgp75 plus AdIL12, we performed adoptive transfer experiments, using splenocytes from mice receiving Adgp75, AdIL12, or Adgp75 + AdIL12, from among which NK cells had been selectively depleted in vitro prior to adoptive transfer. Each group showed significant decreases in tumor burden resembling those with primary treatment. Interestingly, NK-cell depletion from among cells derived from the Adgp75- and AdIL12-treated mice significantly altered the therapeutic response (P < 0.01 compared with the Adgp75 + AdIL12 group), suggesting a significant role of NK-cell-mediated cytolysis in vivo, although there was still a significantly reduced tumor burden (P < 0.01 compared with that of naive controls). Collectively, these data support the concept that the combination of AdIL12 and Adgp75 provides additive effects against pulmonary metastases of B16 melanoma by MHC-independent (NK cell) means as well as MHC-dependent cytotoxic lymphocyte means, suggesting that this therapy may be a useful adjuvant in the treatment of metastatic melanoma.

Adenoviridae↗
PubMed2003

Fiber-modified adenoviruses generate subgroup cross-reactive, adenovirus-specific cytotoxic T lymphocytes for therapeutic applications.

Adenovirus (Ad) infections are responsible for considerable morbidity and mortality, particularly in pediatric hematopoietic stem cell transplant (HSCT) recipients. To date there is no therapy. The present study was motivated by the potential for using adoptive immunotherapy as either prophylaxis or treatment for Ad infections and associated diseases. The authors have developed a protocol to reactivate Ad-specific memory T cells from peripheral blood mononuclear cells (PBMCs) using a clinical-grade adenoviral vector. Such lines contain a specific CD4 and CD8 T-cell component and are capable of recognizing and lysing target cells infected with wild-type Ad serotypes from different Ad groups. Furthermore, the frequency of Ad-specific precursors can be determined in PBMCs ex vivo and used as a means to assess changes in Ad-specific T-cell memory responses after infusion. This is the first report of a simple and reproducible method to activate and expand Ad-specific cytotoxic T lymphocytes (CTLs), which should be protective against the range of different Ad subtypes that affect transplant recipients.

Adenoviridae↗
PubMed2001

An adenovirus expressing mutant p27 showed more potent antitumor effects than adenovirus-p27 wild type.

The main inhibitory action of p27, a cyclin-dependent kinase inhibitor (CDKI), arises from its binding with the cyclin E/cyclin-dependent kinase 2 (Cdk2) complex that results in G(1)-S arrest. Degradation of p27 is mediated by phosphorylation of Thr-187 of p27, which follows ubiquitination. In this study, we generated two adenoviruses expressing wild-type p27 (ad-p27wt) and mutant p27 (ad-p27mt), with mutation of Thr-187/Pro-188 (ACGCCC) to Met-187/Ile-188 (ATGATC), which was produced with the belief that mutant p27 would bind cyclin E/CDK2 more stably and show more potent antitumor effects. Ad-p27wt and ad-p27mt expressed p27 proteins that were indistinguishable by anti-p27 antibody. A pulse chase experiment showed that p27mt was more resistant to degradation than p27wt. In human lung cancer cell lines, ad-p27mt showed stronger growth inhibition than ad-p27wt. Both types of ad-p27 induced G(1)-S arrest and apoptosis; however, ad-p27mt induced stronger G(1)-S arrest and apoptosis. Intratumoral injection of ad-p27mt induced partial regression of established tumors and inhibited the growth of human lung cancer xenografts more strongly than ad-p27wt. From these results, we conclude that ad-p27mt has the potential to become a novel and powerful gene therapy tool.

Adenoviridae↗
PubMed2002

[Experimental study on adenovirus-mediated transfer of p53 or adenovirus- mediated transfer of p53 combined with radiotherapy for human cervical cancer cell line HeLa cells].

OBJECTIVE: To evaluate the therapeutic efficiency of adenovirus-mediated transfer of p53(Ad-p53) or Ad-p53 combined with radiotherapy for human cervical cancer cell line HeLa cells. METHODS: HeLa cells were either transfected with Ad-p53 alone or with Ad-p53 combining with radiotherapy. Reverse transcription polymerase chain reaction(RT-PCR), the cell growth, morphological changes, cell cycle, apoptosis and molecular changes were measured using cell counting, microscopy, flow cytometry, DNA ladder, and in vivo therapy experiments to evaluate the therapeutic efficiency of the regimens. RESULTS: Ad-p53 could be transfected into HeLa cells and p53 mRNA could be expressed more in the targeted HeLa cells. Ad-p53 transfer had strong therapeutic effects to HeLa cells in vitro and in vivo (the inhibition rates were 61.8% and 54.8%, respectively), moreover, the combined administration of Ad-p53 and radiotherapy had stronger therapeutic effects in vitro and in vivo (the inhibition rate was 85.5% in vitro, and the inhibition rate was 77.4% in vivo). The inhibition rate by radiotherapy alone was 44.6% in vitro and 58.4% in vivo. Massive apoptosis of HeLa cells was induced by these regimens. Cell cycle analysis demonstrated that all these regimens could arrested HeLa cells in G(2)-M. CONCLUSIONS: After introduced into HeLa cells, Ad-p53 shows therapeutic efficiency for HeLa cells both in vitro and in vivo. Moreover, Ad-p53 could enhance therapeutic efficiency for HeLa cells when combined with radiotherapy.

Adenoviridae↗
PubMed1975

In vitro studies on target cells of oncogenic adenoviruses in hamster brain. II. In vitro transformation of brain cells of hamsters at various ages by human adenovirus type 12.

In vitro transformations of brain cells of hamsters of various ages were examined after the administration of human adenovirus type 12 (Ad 12) to determine the type and origin of the target cell. Hamster brain cells at all examined ages were transformed by Ad12. Although the virus was not isolated, virus specific tumor antigen was demonstrated in the transformed cells. The histological features of tumors that developed by transplantation of transformed cells closely resembled Ad12-induced brain tumors. The transformed cell focus tended to appear near the embryonic brain cell (EB cell) or glioblastic cell (GB cell). The transformed cells were morphologically similar to the EB or GB cell. Some subcultured transformed cells showed a rosette-like pattern, and the surrounding space arrangement was similar to that of the ventricular wall. The incidence of brain cell transformations decreased with increased hamster age. This decreased incidence with age corresponded to the decreased numbers of EB or GB cells present in progressively older hamsters. From these results, it is concluded that the target cells of AD12 in hamster brain cell cultures are probably the EB or GB cells.

Adenoviridae↗
PubMed2003

Use of multiply deleted adenovirus vectors to probe adenovirus vector performance and toxicities.

Adenovirus (Ad)-based vectors have received considerable attention in recent years as the 'work-horse' of gene delivery, as evidenced by over 160 clinical trials utilizing this vector class. The Ad vectors utilized in these trials have been delivered into hundreds of humans via any number of intratumoral, intrabronchial, subcutaneous or intravenous routes. Most of these trials have utilized first-generation, E1-deleted [E1-] versions of these vectors. Multiple animal studies have demonstrated that [E1-]Ad vectors induce a variety of toxic responses, directed both to the Ad vector itself and the vector-transduced cells. Because of these limitations, the development of multiply attenuated (deleted) Ad vectors has been pursued by a number of research groups. These vectors retain many of the advantages of [E1-]Ad, while simultaneously improving the overall vector performance, primarily manifested as reduced sub-acute and chronic toxicities, combined with extended duration of persistence of the vectors within transduced cells. This review focuses upon the investigations that have been performed utilizing multiply deleted Ad vectors, and how these studies shed light upon the immune mechanisms directed against Ad vectors.

Adenoviridae↗
PubMedDate not supplied

Adenovirus expressing mutant p27kip1 enhanced apoptosis against cholangiocarcinoma than adenovirus-p27kip1 wild type.

BACKGROUND/AIMS: The prognosis of cholangiocarcinoma is extremely poor despite the aggressive multidisciplinary cancer therapies that have been used clinically. Thus, it is imperative to develop new and effective treatments, such as gene therapy in order to treat this disease. p53 is the most common target for cancer gene therapy treatment. However, cholangiocarcinoma has a low frequency of p53 mutation, which makes this protein a poor candidate for gene therapy in this disease and another suitable gene therapy target must be found. p27kip1 is a universal cyclin-dependent kinase (CDK) inhibitor that blocks cell cycle progression and inhibits proliferation. Our previous reports have demonstrated the role of p27kip1 in the induction of apoptosis using a recombinant adenoviral vector expressing p27kip1 (Adp27) in several different human cancer cells. p27kip1 is regulated by two mechanisms composed of a ubiquitin-proteasome system and proteolytic processing system that requires the phosphorylation of p27kip1 on Thr-187 by the cyclinE/Cdk2 complex followed by proteolytic degradation. METHODOLOGY: In this study, we focused our aim on the degradation of p27kip1 protein mediated by a recombinant adenoviral expressing a mutant p27kip1 (Adp27-mt), which has a mutation of Thr-187/Pro-188 (ACGCCC) to Met-187/Ile-188 (ATGATC). RESULTS: We observed that the mutated p27kip1 markedly inhibited ubiquitination and the subsequent degradation of p27kip1 when compared to wild type p27kip1. Consequently, we found that mutated p27kip1 induced a stronger induction of apoptosis and cell growth inhibition than wild type p27kip1 in cholangiocarcinoma cell lines TFK-1 and HuCCT-1. Furthermore, we demonstrated that Adp27-mt mainly caused G2/M arrest in the cell cycle progression and a decreased cyclinB1 and Cdc2 protein where as Adp27-wt mediated a G1/S arrest at 48 hours after infection. CONCLUSIONS: In this study, we showed that adenoviral vector expression of mutant p27kip1 protein inhibited degradation by the ubiquitin-proteasome system and strongly induced apoptosis and cell growth inhibition compared to wild type p27kip1. Thus recombinant adenovirus expressing mutant p27kip1 may be potentially useful for gene therapy against cholangiocarcinoma.

Adenoviridae↗
PubMed1988

Initiation of adenovirus DNA replication. I. Mechanism of action of a host protein required for replication of adenovirus DNA templates devoid of the terminal protein.

The in vitro replication of adenovirus (Ad) DNA covalently attached to the 55-kDa terminal protein requires at least five proteins including the 80-kDa preterminal protein, the Ad DNA polymerase, the Ad DNA binding protein, nuclear factor I, and topoisomerase I. The replication of Ad DNA templates devoid of the terminal protein requires an additional protein, designated factor pL, which has been purified from uninfected HeLa cell nuclei (Guggenheimer, R. A., Nagata, K., Kenny, M., and Hurwitz, J. (1984) J. Biol. Chem. 259, 7815-7825). Factor pL has been found to contain an intrinsic 5'----3' exonuclease activity. When Ad DNA templates lacking the terminal protein were pretreated with factor pL, the requirement for factor pL in the replication reaction was abolished. Synthetic partially duplex oligonucleotide templates containing Ad origin sequences were constructed in order to determine the structure of the DNA molecules that are active in the absence of factor pL. These experiments indicated that factor pL degrades the 5'-end of the nontemplate (displaced) strand of the Ad origin thereby creating a single-stranded region at the 3'-end of the template strand. Such DNAs are competent for initiation of Ad DNA replication in the absence of factor pL but remain dependent on nuclear factor 1.

Adenoviridae↗
PubMed1988

Initiation of adenovirus DNA replication. II. Structural requirements using synthetic oligonucleotide adenovirus templates.

Adenovirus (Ad) virions contain a 55-kDa terminal protein covalently linked to both 5'-ends of the linear duplex DNA genome. The origin of DNA replication is contained within the terminal 50 base pair of the inverted terminal repeats. In the accompanying paper (Kenny, M. K., Balogh, L. A., and Hurwitz, J. (1988) J. Biol. Chem. 263, 9801-9808), it was demonstrated that synthetic oligonucleotide templates which contain the Ad origin, but lack the 55-kDa terminal protein, can serve as templates for the initiation of Ad DNA replication. Partially duplex oligonucleotides that lacked up to 14 nucleotides from the 5'-end of the nontemplate (displaced) strand supported initiation as much as 20-fold more efficiently than fully duplex oligonucleotides. The removal of 18 nucleotides or more from the 5'-end of the displaced strand resulted in a sharp decrease in the ability of the DNA templates to support initiation. The poor template efficiency of certain DNAs could be explained by their inability to bind nuclear factor I. The initiation efficiency observed with other DNAs correlated with their ability to bind the preterminal protein-Ad DNA polymerase complex. At low concentrations of the Ad DNA-binding protein, protein-primed initiation was also observed on single-stranded DNAs. The single-stranded template strand of the Ad origin was at least 5-20-fold better at supporting initiation than other single-stranded DNAs. These findings suggest a model in which the 3'-end of the template strand is rendered single-stranded as a prerequisite for initiation of Ad DNA replication.

Adenosine Triphosphate↗
PubMed1986

The adenovirus DNA binding protein and adenovirus DNA polymerase interact to catalyze elongation of primed DNA templates.

The adenovirus-encoded 140-kDa DNA polymerase (Ad Pol) and the 59-kDa DNA binding protein (Ad DBP) are both required for the replication of viral DNA in vivo and in vitro. Previous studies demonstrated that, when poly(dT).oligo(dA) was used as a template-primer, both proteins were required for poly(dA) synthesis. In this report, the interaction between the Ad Pol and Ad DBP was further investigated using poly(dT).oligo(dA) as well as a linear duplex molecule containing 3' poly(dT) tails. DNA synthesis with the tailed template required Ad Pol, Ad DBP, and an oligo(dA) primer hydrogen bonded to the poly(dT) tails. Incorporation was stimulated 8-10-fold by ATP; however, no evidence of ATP hydrolysis to ADP was observed. Synthesis was initiated at either end of the tailed molecule and proceeded through the duplex region to the end of the molecule. This ability to translocate through duplex DNA and to synthesize long poly(dA) chains suggests that the Ad Pol.Ad DBP complex can act efficiently in the elongation reactions involved in the replication of Ad DNA (both type I and type II). During the replication reaction, substantial hydrolysis of deoxynucleoside triphosphates to the corresponding deoxynucleoside monophosphates occurred. This reaction required DNA synthesis and most likely reflects an idling reaction similar to that observed with other DNA polymerases containing 3'----5' exonuclease activity in which the polymerase first incorporates and then hydrolyzes a dNMP.

Adenosine Triphosphate↗
PubMed1998

SV40 in adenovirus vaccines and adenovirus-SV40 recombinants.

During the development of adenovirus (Ad) vaccines in the 1950s, Ad strains 1-5 and 7 recombined with SV40 during adaptation to growth in rhesus monkey kidney cells. The recombination events between the Ad and SV40 genomes produced hybrid viruses that contained, within the Ad genome, either portions of the early region of the SV40 genome or single or multiple copies of the entire SV40 genome inserted in a configuration that permitted the generation of SV40 progeny. When portions of the SV40 early region were inserted into the Ad2 E3 region, a region non-essential for viral replication, the resulting Ad-SV40 hybrids were non-defective in that they were capable of independent replication. Such hybrids have no known selective advantage for replication in human tissues; however, through inadvertent human exposure it is theoretically possibly that they could be induced to spread in the environment. Because of deletions in the Ad genome, the Ad-SV40 hybrids that contain infectious SV40 DNA were defective and were not capable of replication without a helper virus. Due to the low frequency with which cells in an infected individual could be co-infected with both defective hybrid and helper virions, it is unlikely that such defective viruses could be established in the population. Based on the Ad-SV40 model, it is theoretically possible that SV40 could recombine with other DNA viruses that infect humans. The introduction of Ad-SV40 hybrids or SV40-other virus hybrids into the environment could contribute to establishing SV40 as a human polyomavirus and to the SV40 DNA sequences that are being detected in human tissues.

Adenoviridae↗