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H S Ginsberg

Publications and source records attributed to H S Ginsberg.

At least 19 recordsLinked to original sources
PubMed2001

Extended lung expression and increased tissue localization of viral IL-10 with adenoviral gene therapy.

IL-10 is a pleiotropic cytokine that acts as an important regulator of macrophage, T cell, and natural killer cell functions. Human IL-10 (hIL-10) has both stimulatory and inhibitory effects on a wide variety of cell types. Viral IL-10 (vIL-10) possesses only a subset of hIL-10's activities, predominantly its suppression of cytokine synthesis by T helper type 1 clones. In the present report, we evaluated tissue accumulation and biological activity of hIL-10 and vIL-10 in vivo in individual organs by using a first-generation adenoviral (Ad) vector administered intratracheally and intravenously. We report the observation that Ad vectors delivering vIL-10, but not hIL-10, are associated with prolonged expression in the lung (>42 days) when delivered intratracheally. In contrast, there was no prolongation in vIL-10 expression when Ad vectors were intravenously administered, although vIL-10 levels in the tissue, but not serum, were markedly increased relative to hIL-10. Moreover, we report an augmented capacity of expressed vIL-10 versus hIL-10 to suppress the acute inflammatory responses in the lung to intratracheal administration of Ad. These findings confirm fundamental differences in Ad-induced expression of vIL-10 and hIL-10 when administered to the lungs. The results further suggest that Ad vectors expressing vIL-10 may have a role as anti-inflammatory agents in the treatment of acute and chronic lung inflammation.

Adenoviridae↗
PubMed2001

Integrated pest management and allocation of control efforts for vector-borne diseases.

Applications of various control methods were evaluated to determine how to integrate methods so as to minimize the number of human cases of vector-borne diseases. These diseases can be controlled by lowering the number of vector-human contacts (e.g., by pesticide applications or use of repellents), or by lowering the proportion of vectors infected with pathogens (e.g., by lowering or vaccinating reservoir host populations). Control methods should be combined in such a way as to most efficiently lower the probability of human encounter with an infected vector. Simulations using a simple probabilistic model of pathogen transmission suggest that the most efficient way to integrate different control methods is to combine methods that have the same effect (e.g., combine treatments that lower the vector population; or combine treatments that lower pathogen prevalence in vectors). Combining techniques that have different effects (e.g., a technique that lowers vector populations with a technique that lowers pathogen prevalence in vectors) will be less efficient than combining two techniques that both lower vector populations or combining two techniques that both lower pathogen prevalence, costs being the same. Costs of alternative control methods generally differ, so the efficiency of various combinations at lowering human contact with infected vectors should be estimated at available funding levels. Data should be collected from initial trials to improve the effects of subsequent interventions on the number of human cases.

Animals↗
PubMed1999

Role of the type 5 adenovirus gene encoding the early region 1B 55-kDa protein in pulmonary pathogenesis.

Comparison of the inflammatory response of Sigmodon hispidus cotton rats to pulmonary infection with wild-type 5 adenovirus (Ad5) or with a viral mutant, in which the early region 1B gene encoding a 55-kDa protein, Ad5dl110 (dl110), was deleted, indicated that the inflammation in animals infected with dl110 was markedly reduced compared with the inflammation in animals infected with wild-type Ad5, although both viruses replicated to the same extent. Comparable experiments done with C57BL/6 mice yielded identical results, even though only the early phase of gene expression essential for viral replication occurs in mice. Cytokine analysis of infected mouse lungs indicated that tumor necrosis factor-alpha and IL-6 were produced in relatively large quantities in wild-type Ad5-infected mice and at significantly lower levels in dl110-infected mice during the early stages of infection.

Adenoviridae Infections↗
PubMed1999

The life and times of adenoviruses.

With Wallace Rowe et al.'s and Hilleman and Werner's isolations of viruses, subsequently termed "adenoviruses," a new area of research opened for me and gradually for many others. I was quickly able to associate the viruses with diseases in humans, and then our attention turned to the structure of the virion and how it replicated. Many virologists entered these areas of adenovirus research, for they were the central themes for most virologists at that time. We obtained more and more knowledge of the structure of the virion, its genome, and how it replicated and killed cells in culture so that they could no longer divide, although the virus infection did not lyse the infected cells, but we did not have the slightest idea how Ad5 produced disease in vivo. Then Wallace Clyde's timely note appeared, and we entered an exciting and profitable new field: an investigation of the mechanism by which Ad5 produces pneumonia. It must again be emphasized that the pneumonia that WtAd5 produces in cotton rats is pathologically very similar to that induced in humans. One of our earliest sets of experiments in the cotton rats was designed to determine whether region E3 was really nonessential even though the genes contained therein were not required for viral replication. We soon demonstrated that deletion of the E3 region produced a mutant that induced a highly pathogenic viral pneumonia. The potential role in pathogenesis of each of the genes within the E3 region was then investigated. Of maximum importance was the finding that deletion of the 19-kDa gene near the 5' end of the region produced a severe inflammatory response. This result led to the discovery that the E3 19-kDa protein regulated expression of the MHC factor on the surface of infected cells, and deletion of this gene produced a marked increase in MHC on the surfaces of infected cells and, therefore, a marked increase in the response of cytotoxic T cells. In addition, deletion of the gene encoding the 14.7-kDa protein, which was situated at the 3' end of the E3 region, resulted in an increase in polymorphonuclear leukocytes in the inflammatory response. A number of these findings led to hypotheses that could not be tested in the cotton rat since the necessary reagents were not available. Fortunately, our findings that only early viral genes are required to produce full pathogenesis led us to test mice because we had shown in a culture of mouse cells that all of the early viral genes are expressed. The C57BL/6N mouse proved to be an excellent host in which Ad5 produced full pulmonary inflammation. Thus, it was possible to test our hypotheses and to demonstrate their validity, showing that the virus induces cytokine elaboration, as well as to demonstrate the role of cytotoxic T cells in permitting Ad5 to produce persistent infections in lymphoid cells of organs such as the adenoid, from which the first adenovirus was isolated, and which had immediately led to my interest in investigating it and helping to develop the story of adenoviruses.

Adenovirus Infections, Human↗
PubMed1999

Infection of Ixodes ricinus (Acari: Ixodidae) by Borrelia burgdorferi sensu lato in North Africa.

Free-living adult Ixodes ricinus L, were collected in Amdoun, situated in the Kroumiry mountains in northwestern Tunisia (North Africa). Using direct fluorescence antibody assay, the infection rate of field-collected I. ricinus by Borrelia burgdorferi sensu lato was 30.5% (n = 72). No difference in infection rate was observed between male and female ticks. Spirochetes that had been isolated from I. ricinus from Ain Drahim (Kroumiry Mountains) in 1988 were identified as Borrelia lusitaniae (formerly genospecies PotiB2). This is the first identification of a genospecies of Borrelia burgdorferi sensu lato from the continent of Africa.

Africa, Northern↗
PubMed1999

Influence of deer abundance on the abundance of questing adult Ixodes scapularis (Acari: Ixodidae).

Nymphal and adult Ixodes scapularis Say were sampled by flagging at 2 sites on a barrier island, Fire Island, NY, and at 2 sites on the nearby mainland. Nymphal densities did not differ consistently between island and mainland sites, but adult densities were consistently lower on the island. We tested whether lower adult densities on the island resulted from greater nymphal mortality on the island than the mainland, or whether adult ticks on the island were poorly sampled by flagging because they had attached abundantly to deer, which were common on Fire Island. Differential nymphal mortality on islands versus mainland did not explain this difference in adult densities because survival of flat and engorged nymphs in enclosures was the same at island and mainland sites. Ticks were infected by parasitic wasps on the island and not the mainland, but the infection rate (4.3%) was too low to explain the difference in adult tick densities. In contrast, exclusion of deer by game fencing on Fire Island resulted in markedly increased numbers of adult ticks in flagging samples inside compared with samples taken outside the exclosures. Therefore, the scarcity of adult ticks in flagging samples on Fire Island resulted, at least in part, from the ticks being unavailable to flagging samples because they were on deer hosts. Differences in the densities of flagged ticks inside and outside the exclosures were used to estimate the percentage of questing adults on Fire Island that found deer hosts, excluding those that attached to other host species. Approximately 56% of these questing adult ticks found deer hosts in 1995 and 50% found deer hosts in 1996. Therefore, in areas where vertebrate hosts are highly abundant, large proportions of the questing tick population can find hosts. Moreover, comparisons of tick densities at different sites by flagging can be potentially biased by differences in host densities among sites.

Animals↗
PubMed1999

Preliminary survey for entomopathogenic fungi associated with Ixodes scapularis (Acari: Ixodidae) in southern New York and New England, USA.

Free-living larval, nymphal, and adult Ixodes scapularis Say were collected from scattered locales in southern New England and New York to determine infection rates with entomopathogenic fungi. Infection rates of larvae, nymphs, males, and females were 0% (571), 0% (272), 0% (57), and 4.3% (47), respectively. Two entomopathogenic fungi were isolated from field-collected I. scapularis females from Fire Island, NY. Isolates were identified as Verticillium lecanii (Zimmermann) Viegas and Verticillium sp. (a member of the Verticillium lecanii species complex).

Animals↗
PubMed1999

Pathogenicity of Bacillus thuringiensis variety kurstaki to Ixodes scapularis (Acari: Ixodidae).

Pathogenicity of the entomopathogenic bacterium Bacillus thuringiensis variety kurstaki de Barjac & Lemille was tested against the black-legged tick, Ixodes scapularis Say. Engorged larvae dipped in a solution of 10(8) spores per milliliter showed 96% mortality 3 wk after infection. The LC50 value for engorged larve (concentration required to kill 50% of ticks) was 10(7) spores per milliliter. B. thuringiensis shows considerable potential as a microbial control agent for the management of I. scapularis.

Animals↗
PubMed1998

HIV type-1 infection of the cotton rat (Sigmodon fulviventer and S. hispidus).

Cotton rats (Sigmodon hispidus and S. fulviventer) are susceptible to many viruses that infect humans (e.g., poliovirus, respiratory syncytial virus, influenza virus, adenovirus, and parainfluenza virus) and have been influential in developing therapeutic clinical intervention strategies for many viral infections of man. This study set out to determine whether cotton rats are susceptible to infection with HIV type 1 (HIV-1). Results indicate that HIV-1 does infect the cotton rat and S. fulviventer is more susceptible than S. hispidus. The virus was passaged from animal to animal for a total of three serial passages; but HIV replicated poorly in vivo, was only detectable as proviral DNA, and never exceeded one provirus per 1.8 x 10(5) cotton rat peripheral blood mononuclear cells. Infection induced a distinct and characteristic anti-HIV antibody response that, in some animals, included neutralizing antibodies, recognized all of the major HIV-1 antigens and the antibodies lasted out to 52 wk post-infection. Neonate S. fulviventer were not more susceptible to infection than adults. In vitro culture studies produced indirect evidence of viral replication by detection of viral gag gene RNA in reverse transcriptase-PCR assays on viral culture supernatants. Collectively, these results indicate that HIV-1 can replicate in a nontransgenic rodent and that this system may have potential as an animal model for HIV-1 infection if viral replication rates can be improved in vivo.

Animals↗
PubMed1998

Reservoir competence of the meadow vole (Rodentia: Cricetidae) for the Lyme disease spirochete Borrelia burgdorferi.

The reservoir competence of the meadow vole, Microtus pennsylvanicus Ord, for the Lyme disease spirochete Borrelia burgdorferi Johnson, Schmid, Hyde, Steigerwalt & Brenner was established on Patience Island, RI. Meadow voles were collected from 5 locations throughout Rhode Island. At 4 of the field sites, M. pennsylvanicus represented only 4.0% (n = 141) of the animals captured. However, on Patience Island, M. pennsylvanicus was the sole small mammal collected (n = 48). Of the larval Ixodes scapularis Say obtained from the meadow voles on Patience Island, 62% (n = 78) was infected with B. burgdorferi. Meadow voles from all 5 locations were successfully infected with B. burgdorferi in the laboratory and were capable of passing the infection to xenodiagnostic I. scapularis larvae for 9 wk. We concluded that M. pennsylvanicus was physiologically capable of maintaining B. burgdorferi infection. However, in locations where Peromyscus leucopus (Rafinesque) is abundant, the role of M. pennsylvanicus as a primary reservoir for B. burgdorferi was reduced.

Animals↗
PubMed1997

Spontaneous occurrence of early region 1A reiteration mutants of type 5 adenovirus in persistently infected human T-lymphocytes.

Mutants of type 5 adenovirus (Ad5) with reiterated DNA sequences in the E1a region appeared in a human T-lymphocyte cell line, Molt-4, persistently infected with H5sub304, a deletion/substitution mutant that has a wild-type phenotype in viral replication. Endonuclease analyses and DNA sequencing revealed DNA reiteration in each mutant. In the four representative mutants investigated, the DNA reiterations all started within a six-base-pair consensus sequence, G(or C)CTGTG, located in the second exon of the E1a region (at nt 1333, 1367, or 1419). There was not any DNA homology between the breakpoints in the second exon and the inserting sequences (starting at nt 532, 710, or 792). Northern analyses suggested that the reiterated splicing sites of the representative mutants were all used in RNA splicing, and the closest donor and recipient joints were used most frequently. These observations imply that during persistent infection Ad5 underwent spontaneous mutations by sequence-specific breakage and nonhomologous end-end joining recombination events. These E1a reiteration mutants could be propagated in HeLa, A549, and KB cells; they were genetically stable; and they killed CREF cells at a strikingly high frequency. Preliminary observations tend to correlate this CREF cell killing with the accumulation of the early viral proteins and/or viral DNA in the infected cells. This degree of cell damage was not observed in Ad5wt or H5sub304 infection of CREF cells. The observed E1a reiterations provide a model to gain insight into understanding the evolutionary events of some, if not all, adenovirus types during many years of symbiotic, persistent relationship in human tonsils and adenoids and possibly other lymphoid organs.

Adenovirus E1A Proteins↗
PubMed1997

Spatial distribution of larval Ixodes scapularis (Acari:Ixodidae) on Peromyscus leucopus and Microtus pennsylvanicus at two island sites.

Larval blacklegged ticks, Ixodes scapularis, were collected from white-footed mice. Peromyscus leucopus, on Prudence Island (where Microtus pennsylvanicus were not captured) and from meadow voles. M. pennsylvanicus, on Patience Island (where P. leucopus was absent) in Narragansett Bay, Rhode Island from June to October 1992. Ixodes scapularis larvae were also collected by flagging in the vicinity of host captures. On both islands, the relative density of larvae changed from July to September in samples from hosts, but not in flagging samples. Consequently, different sampling techniques can give different assessments of tick populations. Larvae were highly aggregated on both of the host species throughout the sampling period. As the mean relative density of larvae increased in the environment (based on flagging samples), larvae on the hosts became more dense and more crowded. Increased densities of larvae in the environment were not correlated with increased patchiness in the distribution of larvae among host animals on either island. Changes in the spatial distribution of larval I. scapularis on each host species had similar trends as larval densities and distributions within the environment. These results suggest that M. pennsylvanicus can serve as an alternative host for immature I. scapularis in a P. leucopus-free environment and have similar distributional characteristics.

Analysis of Variance↗
PubMed1997

Pathogenicity of the entomopathogenic fungus Metarhizium anisopliae (Deuteromycetes) to Ixodes scapularis (Acari: Ixodidae).

The entomopathogenic fungus Metarhizium anisopliae is highly pathogenic to the black-legged tick, Ixodes scapularis. Spore concentrations of 10(8)/ml for engorged larvae and 10(7)/ml for engorged females resulted in 100% tick mortality, 2 wk postinfection. The LC50 value for engorged larvae (concentration to kill 50% of ticks) was 10(7) spores/ml. Metarhizium anisopliae shows considerable potential as a microbial control agent for the management of Ixodes scapularis.

Animals↗
PubMed1996

The ups and downs of adenovirus vectors.

Owing to the detailed knowledge of the structure of the adenovirus virions, including their DNA genomes, especially types 2 and 5, they are convenient viruses for construction of vectors for gene therapy and vaccine immunization. It is critical to note, however, that adenoviruses produce pathogenic inflammatory responses to infection. The inflammation occurs even if the adenovirus does not replicate when the inoculum is sufficiently large, because only early gene expression is responsible for the pathogenic reaction. The inflammation consists of an early phase, in which tumor necrosis factor alpha (TNF-alpha) plays a major role, and a late phase consisting of an extensive T-cell response. It is important in the construction of adenovirus vectors not to delete a major portion of the early region 3 (E3) because: the E3 19 kD glycoprotein markedly reduces the capacity of the Class I major histocompatibility complex (Class I MHC) from transporting viral antigens to the surfaces of infected cells; and the E3 14.7 kD protein significantly inhibits the production of TNF-alpha and, therefore, reduces the polymorphonuclear response. Unfortunately the first generation of adenovirus gene therapy vectors contained large E3 deletions and, therefore, presented a significant safety problem. Subsequent adenovirus vectors consist of other deletions to overcome this difficulty.

Adenoviridae↗
PubMed1995

Pathogenicity of Steinernema carpocapsae and S. glaseri (Nematoda: Steinernematidae) to Ixodes scapularis (Acari: Ixodidae).

The entomopathogenic nematodes Steinernema carpocapsae (Weiser) and S. glaseri (Steiner) are pathogenic to engorged adult, blacklegged ticks, Ixodes scapularis (Say), but not to unfed females, engorged nymphs, or engorged larvae. Nematodes apparently enter the tick through the genital pore, thus precluding infection of immature ticks. The timing of tick mortality, and overall mortality after 17 d, did not differ between infections by S. carpocapsae and S. glaseri. These nematodes typically do not complete their life cycles or produce infective juveniles in I. scapularis. However, both species successfully produced infective juveniles when the tick body was slit before nematode infection. Mortality of engorged I. scapularis females infected by S. carpocapsae was greater than uninfected controls, but did not vary significantly with nematode concentration (50-3,000 infective juveniles per 5-cm-diameter petri dish). The LC50 was 347.8 infective juveniles per petri dish (5 ticks per dish). Hatched egg masses of infected ticks weighed less than those of uninfected controls. Mortality of infected ticks was greatest between 20 and 30 degrees C, and was lower at 15 degrees C.

Animals↗
PubMed1994

Human immunodeficiency virus type 1 strains in the lungs of infected individuals evolve independently from those in peripheral blood and are highly conserved in the C-terminal region of the envelope V3 loop.

To determine whether human immunodeficiency virus type 1 (HIV-1) strains in the lungs of infected individuals are derived from proviral forms contemporaneously present in the peripheral blood or whether they evolve independently as an autonomous pool of viral quasispecies, HIV-1 envelope V3 domain structures at these sites were analyzed and compared. The V3 loop proviral nucleotide and inferred amino acid sequences from lung bronchoalveolar lavage, where HIV-1 is primarily found in macrophages, were more homogeneous within individuals than those from unseparated peripheral blood mononuclear cells, where virus is predominantly in T cells. Comparison between individuals revealed that strains from bronchoalveolar lavage, but not from peripheral blood mononuclear cells, contained V3 domain nucleotide sequences with a great degree of homogeneity in the C-terminal region and a highly conserved, negatively charged amino acid motif. This V3 loop C-terminal structure could be important in the ability of HIV-1 to infect alveolar macrophages. Phylogenetic analyses of V3 domain nucleotide sequences in cells of monocyte/macrophage lineage at both sites revealed the strains in lung macrophages to have evolved further from a presumed ancestral species than those in blood monocytes and to differ considerably in the inferred V3 loop amino acid structures. These results show that, as disease progression occurs, viral strains in monocyte/macrophage lineage cells within the lung and blood microenvironments are not in a state of unrestricted bidirectional traffic but, instead, evolve independently.

Amino Acid Sequence↗
PubMed1994

Deletion of the E4 region of the genome produces adenovirus DNA concatemers.

Two mutants containing large deletions in the E4 region of the adenovirus genome H5dl366 (91.9-98.3 map units) and H2dl808 (93.0-97.1 map units) were used to investigate the role of E4 genes in adenovirus DNA synthesis. Infection of KB human epidermoid carcinoma cells with either mutant resulted in production of large concatemers of viral DNA. Only monomer viral genome forms were produced, however, when mutants infected W162 cells, a monkey kidney cell line transformed with and expressing the E4 genes. Diffusible E4 gene products, therefore, complement the E4 mutant phenotype. The viral DNA concatemers produced in dl366- and dl808-infected KB cells did not have any specific orientation of monomer joining: the junctions consisted of head-to-head, head-to-tail, and tail-to-tail joints. The junctions were covalently linked molecules, but molecules were not precisely joined, and restriction enzyme maps revealed a heterogeneous size distribution of junction fragments. A series of mutants that disrupted single E4 open reading frames (ORFs) was also studied: none showed phenotypes similar to that of dl366 or dl808. Mutants containing defects in both ORF3 and ORF6, however, manifested the concatemer phenotype, indicating redundancy in genes preventing concatemer formation. These data suggest that the E4 ORFs 3 and 6 express functions critical for regulation of viral DNA replication and that concatemer intermediates may exist during adenovirus DNA synthesis.

Adenoviruses, Human↗