Biomedical subjects

Jay Wells

Publications and source records attributed to Jay Wells.

5 recordsLinked to original sources

PubMed2006

Antiviral activity of CHO-SS cell-derived human omega interferon and other human interferons against HCV RNA replicons and related viruses.

The fully glycosylated human omega interferon produced from CHO-SS cells (glycosylated IFN-omega) has been shown to be well-tolerated in man and to induce a sustained virologic response in patients infected with hepatitis C virus (HCV). We examined the antiviral activity of glycosylated IFN-omega and various human IFNs (IFN-alpha, -beta, -gamma and non-glycosylated bacterial (Escherichia coli) recombinant IFN-omega (non-glycosylated IFN-omega)) against HCV RNA replicons and several viruses related to HCV. Since none of the IFNs displayed cytotoxicity we compared their activities based on the effective concentration of the IFN that inhibited virus growth by 50% (EC50). Glycosylated IFN-omega was found to be the most potent antiviral agent of all the IFNs tested against bovine viral diarrhea virus (BVDV), yellow fever virus and West Nile virus. With HCV RNA replicons, non-glycosylated IFN-omega was comparable in activity to IFN-alpha while glycosylated IFN-omega was markedly more potent, indicating that glycosylation has an important effect on its activity. Drug combination analysis of glycosylated IFN-omega+ribavirin (RBV) in BVDV showed a synergy of antiviral effects similar to IFN-alpha+RBV, as well as a unique antagonism of RBV cytotoxic effects by glycosylated IFN-omega. Transcription factor (TF) profiling indicated that IFN-alpha or glycosylated IFN-omega treatment upregulated the same 17 TFs. IFN-alpha and glycosylated IFN-omega also upregulated 9 and 40 additional unique TFs, respectively. The differences in the expression of these TFs were modest, but statistically significantly different for eight of the TFs that were upregulated exclusively by glycosylated IFN-omega. The activation of these additional TFs by glycosylated IFN-omega might contribute to its high potency.

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PubMed2005

Smallpox vaccine does not protect macaques with AIDS from a lethal monkeypox virus challenge.

It is unknown whether smallpox vaccination would protect human immunodeficiency virus type 1 (HIV-1)-infected individuals, because helper CD4(+) cells, the targets of HIV-1 infection, are necessary for the induction of both adaptive CD8(+) cell and B cell responses. We have addressed this question in macaques and have demonstrated that, although smallpox vaccination is safe in immunodeficient macaques when it is preceded by immunization with highly attenuated vaccinia strains, the macaques were not protected against lethal monkeypox virus challenge if their CD4(+) cell count was <300 cells/mm(3). The lack of protection appeared to be associated with a defect in vaccinia-specific immunoglobulin (Ig) switching from IgM to IgG. Thus, vaccination strategies that bypass CD4(+) cell help are needed to elicit IgG antibodies with high affinity and adequate tissue distribution and to restore protection against smallpox in severely immunocompromised individuals.

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PubMed2004

Prevention of lethal respiratory vaccinia infections in mice with interferon-alpha and interferon-gamma.

The antiviral efficacy of interferons (IFNs) was evaluated using a vaccinia intranasal infection model in mice in this study. We provide evidence that intranasal administration of IFN-alpha and IFN-gamma (days -1 to +3) resulted in 100 and 90% survival against a lethal respiratory vaccinia infection (8 LD50) in mice, respectively; whereas no animals in the placebo group survived through the study period (21 days). The IFN treatment consisted of a single daily dose of 5x10(3) U per mouse for 5 consecutive days. The efficacy of IFN-gamma was evident even when the IFN-gamma treatments started 1-2 days after infection and when a lower dose (2x10(3) U per mouse) was used. The treatment of IFN-alpha and IFN-gamma reduced the virus titers in the lungs of infected mice by 1000-10,000-fold, when the administration started 1 day after infection. Our data suggest that IFN-alpha and IFN-gamma are effective in protecting vaccinia-infected mice from viral replication in lungs and mortality, and may be beneficial in other human orthopoxvirus infections.

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PubMed2004

Antiviral activity of hop constituents against a series of DNA and RNA viruses.

We investigated whether crude hop extracts and purified hop components representing every major chemical class of hop compound have antiviral activity. These hop constituents were tested for antiviral activity against bovine viral diarrhea virus (BVDV) as a surrogate model of hepatitis C virus (HCV), human immunodeficiency virus (HIV), influenza A virus (FLU-A), influenza B virus (FLU-B), rhinovirus (Rhino), respiratory syncytial virus (RSV), yellow fever virus (YFV), cytomegalovirus (CMV), hepatitis B virus (HBV), and herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). The extracts all failed to prevent the replication of HIV, FLU-A, FLU-B, RSV and YFV. A xanthohumol-enriched hop extract displayed a weak to moderate antiviral activity against BVDV (therapeutic index (TI)=6.0), HSV-2 (TI=>5.3), Rhino (TI=4.0) and HSV-1 (TI=>1.9) with IC(50) values in the low microg/ml range. Pure iso-alpha-acids demonstrated low to moderate antiviral activity against both BVDV (TI=9.1) and CMV (TI=4.2) with IC(50) values in the low microg/ml range. No antiviral activity was detected using beta-acids or a hop oil extract. Ultra-pure preparations (>99% pure) were used to show that xanthohumol accounted for the antiviral activity observed in the xanthohumol-enriched hop extract against BVDV, HSV-1 and HSV-2. Xanthohumol was found to be a more potent antiviral agent against these viruses than the isomer iso-xanthohumol. With Rhino, the opposite trend was observed with iso-xanthohumol showing superior antiviral activity to that observed with xanthohumol. Xanthohumol also showed antiviral activity against CMV, suggesting that it might have a generalized anti-herpesvirus antiviral activity. Again, superior antiviral activity was observed with the xanthohumol isomer against CMV. In summary, iso-alpha-acids and xanthohumol were shown to have a low-to-moderate antiviral activity against several viruses. These hop constituents might serve as interesting lead compounds from which more active anti-HCV, anti-Rhino and anti-herpesvirus antiviral agents could be synthesized.

Animals↗

PubMed2004

Systemic cytokine response in murine anthrax.

Systemic pro-inflammatory cytokine release has been previously implicated as a major death-causing factor in anthrax, however, direct data have been absent. We determined the levels of IL-1 beta, IL-6 and TNF-alpha in serum of mice challenged with virulent (Ames) or attenuated (Sterne) strains of Bacillus anthracis. More than 10-fold increase in the IL-1beta levels was detected in Ames-challenged Balb/c mice, in contrast to more susceptible C57BL/6 mice, which showed no IL-1beta response. Balb/c mice have also responded with higher levels of IL-6. The A/J mice demonstrated IL-1beta and IL-6 systemic response to either Ames or Sterne strain of B. anthracis, whereas no increase in TNF-alpha was detected in any murine strain. We used RT-PCR for gene expression analyses in the liver which often is a major source of cytokines and one of the main targets in infectious diseases. A/J mice challenged with B. anthracis (Sterne) showed increased gene expression for Fas, FasL, Bax, IL-1 beta, TNF-alpha, TGF-beta, MIP-1alpha, KC and RANTES. These data favour the hypothesis that apoptotic cell death during anthrax infection causes chemokine-induced transmigration of inflammatory cells to vitally important organs such as liver. Administration of caspase inhibitors z-VAD-fmk and ac-YVAD-cmk improved survival in Sterne-challenged mice indicating a pathogenic role of apoptosis in anthrax.

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