@article{okamoto_amarasekare_petty_2014, title={Modeling oncolytic virotherapy: Is complete tumor-tropism too much of a good thing?}, volume={358}, ISSN={["1095-8541"]}, DOI={10.1016/j.jtbi.2014.04.030}, abstractNote={The specific targeting of tumor cells by replication-competent oncolytic viruses is considered indispensable for realizing the potential of oncolytic virotherapy. Yet off-target infections by oncolytic viruses may increase virus production, further reducing tumor load. This ability may be critical when tumor-cell scarcity or the onset of an adaptive immune response constrain viral anti-tumoral efficacy. Here we develop a mathematical framework for assessing whether oncolytic viruses with reduced tumor-specificity can more effectively eliminate tumors while keeping losses to normal cell populations low. We find viruses that infect some normal cells can potentially balance the competing goals of tumor elimination and minimizing the effects on normal cell populations. Particularly when infected tissues can be regenerated, moderating rather than completely eliminating the ability of oncolytic viruses to infect and lyse normal cells could improve cancer treatment, with potentially fewer side-effects than conventional treatments such as chemotherapy.}, journal={JOURNAL OF THEORETICAL BIOLOGY}, author={Okamoto, Kenichi W. and Amarasekare, Priyanga and Petty, Ian T. D.}, year={2014}, month={Oct}, pages={166–178} }
 @article{pollara_spesock_pickup_laster_petty_2012, title={Production of prostaglandin E-2 in response to infection with modified vaccinia Ankara virus}, volume={428}, ISSN={["0042-6822"]}, DOI={10.1016/j.virol.2012.03.019}, abstractNote={Prostaglandin E₂ (PGE₂) is an arachidonic acid (AA)-derived signaling molecule that can influence host immune responses to infection or vaccination. In this study, we investigated PGE₂ production in vitro by cells infected with the poxvirus vaccine strain, modified vaccinia Ankara virus (MVA). Human THP-1 cells, murine bone marrow-derived dendritic cells, and murine C3HA fibroblasts all accumulated PGE₂ to high levels in culture supernatants upon infection with MVA. We also demonstrated that MVA induced the release of AA from infected cells, and this was, most unusually, independent of host cytosolic phospholipase A₂ activity. The accumulation of AA and PGE₂ was dependent on viral gene expression, but independent of canonical NF-κB signaling via p65/RelA. The production of PGE₂ required host cyclooxygenase-2 (COX-2) activity, and COX-2 protein accumulated during MVA infection. The results of this study provide insight into a novel aspect of MVA biology that may affect the efficacy of MVA-based vaccines.}, number={2}, journal={VIROLOGY}, author={Pollara, Justin J. and Spesock, April H. and Pickup, David J. and Laster, Scott M. and Petty, Ian T. D.}, year={2012}, month={Jul}, pages={146–155} }
 @article{pollara_laster_petty_2010, title={Inhibition of poxvirus growth by Terameprocol, a methylated derivative of nordihydroguaiaretic acid}, volume={88}, ISSN={["0166-3542"]}, DOI={10.1016/j.antiviral.2010.09.017}, abstractNote={Terameprocol (TMP) is a methylated derivative of nordihydroguaiaretic acid, a phenolic antioxidant originally derived from creosote bush extracts. TMP has previously been shown to have antiviral and anti-inflammatory activities, and has been proven safe in phase I clinical trials conducted to evaluate TMP as both a topical and parenteral therapeutic. In the current study, we examined the ability of TMP to inhibit poxvirus growth in vitro, and found that TMP potently inhibited the growth of both cowpox virus and vaccinia virus in a variety of cell lines. TMP treatment was highly effective at reducing infectious virus yield in multi-step virus growth assays, but it did not substantially inhibit the synthesis of infectious progeny viruses in individual infected cells. These contrasting results showed that TMP inhibits poxvirus growth in vitro by preventing the efficient spread of virus particles from cell to cell. The canonical mechanism of poxvirus cell-to-cell spread requires morphogenesis of cell-associated, enveloped virions. The virions then trigger the formation of actin tails to project them from the cell surface. The number of actin tails present at the surface of poxvirus-infected cells was reduced dramatically by treatment with TMP. Whether TMP inhibits poxvirus morphogenesis, or subsequent events required for actin tail formation, remains to be determined. The results of this study, together with the clinical safety record of TMP, support further evaluation of TMP as a poxvirus therapeutic.}, number={3}, journal={ANTIVIRAL RESEARCH}, author={Pollara, Justin J. and Laster, Scott M. and Petty, Ian T. D.}, year={2010}, month={Dec}, pages={287–295} }
 @article{lynch_ray_oie_pollara_petty_sadler_williams_pickup_2009, title={Modified vaccinia virus Ankara can activate NF-kappa B transcription factors through a double-stranded RNA-activated protein kinase (PKR)-dependent pathway during the early phase of virus replication}, volume={391}, ISSN={["0042-6822"]}, DOI={10.1016/j.virol.2009.06.012}, abstractNote={Modified vaccinia virus Ankara (MVA), which is a promising replication-defective vaccine vector, is unusual among the orthopoxviruses in activating NF-κB transcription factors in cells of several types. In human embryonic kidney (HEK 293T) cells, the MVA-induced depletion of IκBα required to activate NF-κB is inhibited by UV-inactivation of the virus, and begins before viral DNA replication. In HEK 293T, CHO, or RK13 cells, expression of the cowpox virus CP77 early gene, or the vaccinia virus K1L early gene suppresses MVA-induced IκBα depletion. In mouse embryonic fibroblasts (MEFs), MVA induction of IκBα depletion is dependent on the expression of mouse or human double-stranded RNA-activated protein kinase (PKR). These results demonstrate that events during the early phase of MVA replication can induce PKR-mediated processes contributing both to the activation of NF-κB signaling, and to processes that may restrict viral replication. This property may contribute to the efficacy of this vaccine virus.}, number={2}, journal={VIROLOGY}, author={Lynch, Heather E. and Ray, Caroline A. and Oie, Katrina L. and Pollara, Justin J. and Petty, Ian T. D. and Sadler, Anthony J. and Williams, Bryan R. G. and Pickup, David J.}, year={2009}, month={Sep}, pages={177–186} }
 @article{eads_hansen_oyegunwa_cecil_culver_scholle_petty_laster_2009, title={Terameprocol, a methylated derivative of nordihydroguaiaretic acid, inhibits production of prostaglandins and several key inflammatory cytokines and chemokines}, volume={6}, ISSN={["1476-9255"]}, DOI={10.1186/1476-9255-6-2}, abstractNote={Extracts of the creosote bush, Larrea tridentata, have been used for centuries by natives of western American and Mexican deserts to treat a variety of infectious diseases and inflammatory disorders. The beneficial activity of this plant has been linked to the compound nordihydroguaiaretic acid (NDGA) and its various substituted derivatives. Recently, tetra-O-methyl NDGA or terameprocol (TMP) has been shown to inhibit the growth of certain tumor-derived cell lines and is now in clinical trials for the treatment of human cancer. In this report, we ask whether TMP also displays anti-inflammatory activity. TMP was tested for its ability to inhibit the LPS-induced production of inflammatory lipids and cytokines in vitro. We also examined the effects of TMP on production of TNF-alpha in C57BL6/J mice following a sublethal challenge with LPS. Finally, we examined the molecular mechanisms underlying the effects we observed.RAW 264.7 cells and resident peritoneal macrophages from C57BL6/J mice, stimulated with 1 mug/ml LPS, were used in experiments designed to measure the effects of TMP on the production of prostaglandins, cytokines and chemokines. Prostaglandin production was determined by ELISA. Cytokine and chemokine production were determined by antibody array and ELISA.Western blots, q-RT-PCR, and enzyme assays were used to assess the effects of TMP on expression and activity of COX-2.q-RT-PCR was used to assess the effects of TMP on levels of cytokine and chemokine mRNA.C57BL6/J mice injected i.p. with LPS were used in experiments designed to measure the effects of TMP in vivo. Serum levels of TNF-alpha were determined by ELISA.TMP strongly inhibited the production of prostaglandins from RAW 264.7 cells and normal peritoneal macrophages. This effect correlated with a TMP-dependent reduction in levels of COX-2 mRNA and protein, and inhibition of the enzymatic activity of COX-2.TMP inhibited, to varying degrees, the production of several cytokines, and chemokines from RAW 264.7 macrophages and normal peritoneal macrophages. Affected molecules included TNF-alpha and MCP-1. Levels of cytokine mRNA were affected similarly, suggesting that TMP is acting to prevent gene expression.TMP partially blocked the production of TNF-alpha and MCP-1 in vivo in the serum of C57BL6/J mice that were challenged i.p. with LPS.TMP inhibited the LPS-induced production of lipid mediators and several key inflammatory cytokines and chemokines, both in vitro and in vivo, raising the possibility that TMP might be useful as a treatment for a variety of inflammatory disorders.}, journal={JOURNAL OF INFLAMMATION-LONDON}, author={Eads, D. and Hansen, R. L. and Oyegunwa, A. O. and Cecil, C. E. and Culver, C. A. and Scholle, F. and Petty, I. T. D. and Laster, S. M.}, year={2009}, month={Jan} }
 @article{hung_petty_2001, title={Functional equivalence of late gene promoters in bean golden mosaic virus with those in tomato golden mosaic virus}, volume={82}, ISSN={["0022-1317"]}, DOI={10.1099/0022-1317-82-3-667}, abstractNote={In the bipartite geminivirus tomato golden mosaic virus (TGMV), the activity of late gene promoters is up-regulated by the multifunctional viral protein AL2. Cis-acting sequences required for AL2-mediated promoter responses have not been well characterized. However, nucleotide sequence analysis has implicated a motif termed the conserved late element (CLE). The CLE is present in TGMV and many other begomoviruses, although it is not ubiquitous. Here we analysed the regulation of late gene expression in bean golden mosaic virus (BGMV), one of the begomoviruses which lacks the CLE. Transient reporter gene assays showed that BGMV late gene promoters were trans-activated in Nicotiana benthamiana protoplasts, both by the homologous BGMV AL2 protein and by the heterologous TGMV AL2 protein. The BGMV AL2 protein also trans-activated TGMV late gene promoters. Consistent with these results, we found that hybrid viruses with the late gene promoters exchanged between BGMV and TGMV were viable in planta.}, journal={JOURNAL OF GENERAL VIROLOGY}, author={Hung, HC and Petty, ITD}, year={2001}, month={Mar}, pages={667–672} }
 @article{qin_petty_2001, title={Genetic analysis of bipartite geminivirus tissue tropism}, volume={291}, ISSN={["0042-6822"]}, DOI={10.1006/viro.2001.1205}, abstractNote={The bipartite geminiviruses bean golden mosaic virus (BGMV), cabbage leaf curl virus (CabLCV), and tomato golden mosaic virus (TGMV) exhibit differential tissue tropism in Nicotiana benthamiana. In systemically infected leaves, BGMV remains largely confined to vascular-associated cells (phloem-limited), whereas CabLCV and TGMV can escape into the surrounding mesophyll. Previous work established that TGMV BRi, the noncoding region upstream from the BR1 open reading frame (ORF), is required for mesophyll invasion, but the virus must also contain the TGMV AL23 or BL1/BR1 ORFs. Here we show that, in a BGMV-based hybrid virus, CabLCV AL23 also directed efficient mesophyll invasion in conjunction with TGMV BRi, which suggests that host-adaptation of AL23 is important for the phenotype. Cis-acting elements required for mesophyll invasion were delineated by analyzing BGMV-based hybrid viruses in which various parts of BRi were exchanged with those of TGMV. Interestingly, mesophyll invasion efficiency of hybrid viruses was not correlated with the extent of viral DNA accumulation. In conjunction with TGMV AL23, a 52-bp region of TGMV BRi with sequence homology to DNA A was sufficient for mesophyll invasion. This 52-bp sequence also directed mesophyll invasion in combination with the TGMV BL1/BR1 ORFs. Overall, these results are consistent with a model for mesophyll invasion in which AL2 protein, in association with host factors, acts through the 52-bp region in TGMV BRi to affect expression of the BR1 gene.}, number={2}, journal={VIROLOGY}, author={Qin, Y and Petty, ITD}, year={2001}, month={Dec}, pages={311–323} }
 @article{petty_carter_morra_jeffrey_olivey_2000, title={Bipartite geminivirus host adaptation determined cooperatively by coding and noncoding sequences of the genome}, volume={277}, ISSN={["0042-6822"]}, DOI={10.1006/viro.2000.0620}, abstractNote={Bipartite geminiviruses are small, plant-infecting viruses with genomes composed of circular, single-stranded DNA molecules, designated A and B. Although they are closely related genetically, individual bipartite geminiviruses frequently exhibit host-specific adaptation. Two such viruses are bean golden mosaic virus (BGMV) and tomato golden mosaic virus (TGMV), which are well adapted to common bean (Phaseolus vulgaris) and Nicotiana benthamiana, respectively. In previous studies, partial host adaptation was conferred on BGMV-based or TGMV-based hybrid viruses by separately exchanging open reading frames (ORFs) on DNA A or DNA B. Here we analyzed hybrid viruses in which all of the ORFs on both DNAs were exchanged except for AL1, which encodes a protein with strictly virus-specific activity. These hybrid viruses exhibited partial transfer of host-adapted phenotypes. In contrast, exchange of noncoding regions (NCRs) upstream from the AR1 and BR1 ORFs did not confer any host-specific gain of function on hybrid viruses. However, when the exchangeable ORFs and NCRs from TGMV were combined in a single BGMV-based hybrid virus, complete transfer of TGMV-like adaptation to N. benthamiana was achieved. Interestingly, the reciprocal TGMV-based hybrid virus displayed only partial gain of function in bean. This may be, in part, the result of defective virus-specific interactions between TGMV and BGMV sequences present in the hybrid, although a potential role in adaptation to bean for additional regions of the BGMV genome cannot be ruled out.}, number={2}, journal={VIROLOGY}, author={Petty, ITD and Carter, SC and Morra, MR and Jeffrey, JL and Olivey, HE}, year={2000}, month={Nov}, pages={429–438} }
 @article{morra_petty_2000, title={Tissue specificity of geminivirus infection is genetically determined}, volume={12}, ISSN={["1040-4651"]}, DOI={10.1105/tpc.12.11.2259}, abstractNote={The types of cells and tissues infected by a virus define its tissue tropism. Determinants of tissue tropism in animal-infecting viruses have been extensively investigated, but little is known about plant viruses in this regard. Some geminiviruses in the genus Begomovirus exhibit phloem limitation and are restricted to cells of the vascular system, whereas others can invade mesophyll tissue. To identify viral genetic determinants of tissue tropism, we established a model system using two begomoviruses and their common host plant, Nicotiana benthamiana. Analysis by DNA in situ hybridization confirmed that tomato golden mosaic virus invades mesophyll tissues in systemically infected leaves, whereas bean golden mosaic virus remains phloem limited. Through genetic complementation and analysis of recombinant hybrid viruses, we demonstrated that three genetic elements of tomato golden mosaic virus determine its mesophyll tissue tropism. A noncoding region of the viral genome is essential for the phenotype, but it must be accompanied by one of two different coding regions. To our knowledge, this is the first example documented in a plant virus of noncoding DNA sequences that determine tissue tropism.}, number={11}, journal={PLANT CELL}, author={Morra, MR and Petty, ITD}, year={2000}, month={Nov}, pages={2259–2270} }
 @article{gillette_meade_jeffrey_petty_1998, title={Genetic determinants of host-specificity in bipartite geminivirus DNA A components}, volume={251}, ISSN={["0042-6822"]}, DOI={10.1006/viro.1998.9424}, abstractNote={Geminiviruses are small, ssDNA-containing plant viruses. Bean golden mosaic virus (BGMV) and tomato golden mosaic virus (TGMV) have bipartite genomes, the components of which are designated A and B. Although they are closely related, BGMV and TGMV nevertheless exhibit distinct host-specific phenotypes, with BGMV being well adapted to beans and TGMV being well adapted to Nicotiana benthamiana. A previous study showed that the two open reading frames (ORFs) of DNA B only partially determine the host-adapted phenotypes of BGMV and TGMV. We have now investigated the contributions of A component ORFs to host adaptation. Co-inoculated TGMV DNA A enhances the accumulation of BGMV in N. benthamiana. Using mutant and hybrid TGMV A components, the determinant of this phenotype was mapped to a region encompassing the overlapping AL2 and AL3 ORFs (AL23). BGMV- and TGMV-based hybrid A components containing the heterologous AL23 region each displayed host-specific gain-of-function phenotypes, which indicates that these sequences contribute to host adaptation in both viruses. In N. benthamiana, al2 and al3 mutants of either virus can be complemented in trans by the heterologous A component, so adaptation of the AL23 region to this host is likely mediated through a virus nonspecific, trans-acting factor. In beans, however, co-inoculated BGMV A does not affect the accumulation of TGMV, and TGMV did not complement BGMV al2 or al3 mutants. Thus host-adaptation of the AL23 region may have a different mechanistic basis in beans than it does in N. benthamiana. Although our experiments did not reveal significant host adaptation of the coat protein, which is encoded by the AR1 ORF, a virus-specific effect on viral ssDNA accumulation was observed.}, number={2}, journal={VIROLOGY}, author={Gillette, WK and Meade, TJ and Jeffrey, JL and Petty, ITD}, year={1998}, month={Nov}, pages={361–369} }
 @article{petty_miller_meadehash_schaffer_1995, title={COMPLEMENTABLE AND NONCOMPLEMENTABLE HOST ADAPTATION DEFECTS IN BIPARTITE GEMINIVIRUSES}, volume={212}, ISSN={["0042-6822"]}, DOI={10.1006/viro.1995.1481}, abstractNote={Members of the geminvirus group of plant viruses collectively infect a broad spectrum of species. Individual viruses which are genetically very similar may nevertheless have distinct host ranges. Two such geminiviruses are tomato golden mosaic virus (TGMV) and been golden mosaic virus (BGMV), for which common hosts have not previously been reported. Each virus has two genome components, designated A and B. The A component is capable of autonomous replication and encapsidation, whereas the B component provides viral functions required for the spread of infection in plants. To investigate the basis for the distinctive host ranges of BGMV and TGMV, we have introduced plasmids containing cloned viral genome components into Nicotiana benthamiana, a good host for TGMV, and bean, Phaseolus vulgaris, a good host for BGMV. We found that TGMV has a low specific infectivity for bean and is virulent, whereas BGMV has a high specific infectivity for N. benthamiana, but infections are asymptomatic and viral DNA accumulation is low. To investigate which viral functions were defective in the poor host in each case, we attempted to complement them by co-inoculation with the well-adapted virus. After inoculation of beans with both viruses, only BGMV was detected. Thus, TGMV exhibits a noncomplementable host adaptation defect in beans. This suggests that the defect has a cis-acting or virus-specific trans-acting genetic basis. In contrast, the BGMV phenotype of low DNA accumulation in N. benthamiana was partially complemented by TGMV A alone and complemented further by the complete TGMV genome. This suggests that a virus nonspecific, trans-acting factor encoded by the BGMV A component is poorly adapted to N. benthamiana. The results of this study indicate that bipartite geminivirus host range may be limited by defective virus-host interactions of more than one kind.}, number={1}, journal={VIROLOGY}, author={PETTY, ITD and MILLER, CG and MEADEHASH, TJ and SCHAFFER, RL}, year={1995}, month={Sep}, pages={263–267} }