Insights into neutralization of animal viruses gained from study of influenza virus

It has long been known that the binding of antibodies to viruses can result in a loss of infectivity, or neutralization, but little is understood of the mechanism or mechanisms of this process. This is probably because neutralization is a multifactorial phenomenon depending upon the nature of the virus itself, the particular antigenic site involved, the isotype of immunoglobulin and the ratio of virus to immunoglobulin (see below). Thus not only is it likely that neutralization of one virus will differ from another but that changing the circumstances of neutralization can change the mechanism itself. To give coherence to the topic we are concentrating this review on one virus, influenza type A which is itself well studied and reasonably well understood [1–3]. Reviews of the older literature can be found in references 4 to 7

CORMASS: A Compact and Efficient NIR Spectrograph for Studying Low-Mass Objects

CorMASS (Cornell Massachusetts Slit Spectrograph) is a compact, low-resolution (R=300), double-pass prism cross-dispersed near-infrared (NIR) spectrograph in operation on the Palomar Observatory 60-inch telescope. Its 2-dimensional spectral format provides simultaneous coverage from lambda ~ 0.75 microns to lambda ~ 2.5 microns (z'JHK bands). A remotely operated cold flip mirror permits its NICMOS3 detector to function as a K_s slit viewer to assist object placement into the 2 arcsec x 15 arcsec slit. CorMASS was primarily designed for the rapid spectral classification of low-mass stellar and sub-stellar objects identified by the Two-Micron All Sky Survey (2MASS). CorMASS' efficiency and resolution also make it a versatile instrument for the spectral observation and classification of many other types of bright objects (K<14) including quasars, novae, and emission line objects.Comment: To be published in Feb 2001 PASP, 19 pages, 12 Figures, High Resolution file can be retrieved from ftp://iras2.tn.cornell.edu/pub/wilson/papers/cormass.ps.g

Mechanistic Characterization and Molecular Modeling of Hepatitis B Virus Polymerase Resistance to Entecavir

BACKGROUND: Entecavir (ETV) is a deoxyguanosine analog competitive inhibitor of hepatitis B virus (HBV) polymerase that exhibits delayed chain termination of HBV DNA. A high barrier to entecavir-resistance (ETVr) is observed clinically, likely due to its potency and a requirement for multiple resistance changes to overcome suppression. Changes in the HBV polymerase reverse-transcriptase (RT) domain involve lamivudine-resistance (LVDr) substitutions in the conserved YMDD motif (M204V/I +/- L180M), plus an additional ETV-specific change at residues T184, S202 or M250. These substitutions surround the putative dNTP binding site or primer grip regions of the HBV RT. METHODS/PRINCIPAL FINDINGS: To determine the mechanistic basis for ETVr, wildtype, lamivudine-resistant (M204V, L180M) and ETVr HBVs were studied using in vitro RT enzyme and cell culture assays, as well as molecular modeling. Resistance substitutions significantly reduced ETV incorporation and chain termination in HBV DNA and increased the ETV-TP inhibition constant (K(i)) for HBV RT. Resistant HBVs exhibited impaired replication in culture and reduced enzyme activity (k(cat)) in vitro. Molecular modeling of the HBV RT suggested that ETVr residue T184 was adjacent to and stabilized S202 within the LVDr YMDD loop. ETVr arose through steric changes at T184 or S202 or by disruption of hydrogen-bonding between the two, both of which repositioned the loop and reduced the ETV-triphosphate (ETV-TP) binding pocket. In contrast to T184 and S202 changes, ETVr at primer grip residue M250 was observed during RNA-directed DNA synthesis only. Experimentally, M250 changes also impacted the dNTP-binding site. Modeling suggested a novel mechanism for M250 resistance, whereby repositioning of the primer-template component of the dNTP-binding site shifted the ETV-TP binding pocket. No structural data are available to confirm the HBV RT modeling, however, results were consistent with phenotypic analysis of comprehensive substitutions of each ETVr position. CONCLUSIONS: Altogether, ETVr occurred through exclusion of ETV-TP from the dNTP-binding site, through different, novel mechanisms that involved lamivudine-resistance, ETV-specific substitutions, and the primer-template

Discovery of a Bright Field Methane (T-type) Brown Dwarf by 2MASS

We report the discovery of a bright (J = 13.83$\pm$0.03) methane brown dwarf, or T dwarf, by the Two Micron All Sky Survey. This object, 2MASSI J0559191-140448, is the first brown dwarf identified by the newly commissioned CorMASS instrument mounted on the Palomar 60-inch Telescope. Near-infrared spectra from 0.9 - 2.35 \micron show characteristic CH$_4$ bands at 1.1, 1.3, 1.6, and 2.2 \micron, which are significantly shallower than those seen in other T dwarfs discovered to date. Coupled with the detection of an FeH band at 0.9896 \micron and two sets of K I doublets at J-band, we propose that 2MASS J0559-14 is a warm T dwarf, close to the transition between L and T spectral classes. The brightness of this object makes it a good candidate for detailed investigation over a broad wavelength regime and at higher resolution.Comment: 21 pages, 3 figures, 2 tables, accepted to AJ for publication August 200

Infrared Observations of the Candidate LBV 1806-20 & Nearby Cluster Stars

We report near-infrared photometry, spectroscopy, and speckle imaging of the hot, luminous star we identify as candidate LBV 1806-20. We also present photometry and spectroscopy of 3 nearby stars, which are members of the same star cluster containing LBV 1806-20 and SGR 1806-20. The spectroscopy and photometry show that LBV 1806-20 is similar in many respects to the luminous ``Pistol Star'', albeit with some important differences. They also provide estimates of the effective temperature and reddening of LBV 1806-20, and confirm distance estimates, leading to a best estimate for the luminosity of this star of $> 5 \times 10^6 L_{\odot}$. The nearby cluster stars have spectral types and inferred absolute magnitudes which confirm the distance (and thus luminosity) estimate for LBV 1806-20. If we drop kinematic measurements of the distance ($15.1 ^{+1.8}_{-1.3}$ kpc), we have a lower limit on the distance of $>9.5$ kpc, and on the luminosity of $>2 \times 10^6 L_{\odot}$, based on the cluster stars. If we drop both the kinematic and cluster star indicators for distance, an ammonia absorption feature sets yet another lower limit to the distance of $>5.7$ kpc, with a corresponding luminosity estimate of $>7 \times 10^5 L_{\odot}$ for the candidate LBV 1806-20. Furthermore, based on very high angular-resolution speckle images, we determine that LBV 1806-20 is not a cluster of stars, but is rather a single star or binary system. Simple arguments based on the Eddington luminosity lead to an estimate of the total mass of LBV 1806-20 (single or binary) exceeding $190 M_{\odot}$. We discuss the possible uncertainties in these results, and their implications for the star formation history of this cluster.Comment: 36 pages, including 8 figures (Figures 1 and 7 in JPG format due to space); Accepted for publication in Ap

Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B

BACKGROUND: Entecavir is a potent and selective antiviral agent that has demonstrated efficacy in phase 2 studies in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. METHODS: In this phase 3, double-blind trial, we randomly assigned 648 patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue to receive 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks. The primary efficacy end point was histologic improvement (a decrease by at least two points in the Knodell necroinflammatory score, without worsening of fibrosis). RESULTS: Histologic improvement after 48 weeks of treatment occurred in 208 of 296 patients in the entecavir group who had adequate baseline liver-biopsy specimens that could be evaluated (70 percent), as compared with 174 of 287 such patients in the lamivudine group (61 percent, P=0.01). More patients in the entecavir group than in the lamivudine group had undetectable serum hepatitis B virus (HBV) DNA levels according to a polymerase-chain- reaction assay (90 percent vs. 72 percent, P<0.001) and normalization of alanine aminotransferase levels (78 percent vs. 71 percent, P = 0.045). The mean reduction in serum HBV DNA levels from baseline to week 48 was greater with entecavir than with lamivudine (5.0 vs. 4.5 log [on a base-10 scale] copies per milliliter, P<0.001). There was no evidence of resistance to entecavir. Safety and adverse-event profiles were similar in the two groups. CONCLUSIONS: Among patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue, the rates of histologic improvement, virologic response, and normalization of alanine aminotransferase levels were significantly higher at 48 weeks with entecavir than with lamivudine. The safety profile of the two agents was similar, and there was no evidence of viral resistance to entecavir. Copyright © 2006 Massachusetts Medical Society.published_or_final_versio

Influenza A Virus Expresses High Levels of an Unusual Class of Small Viral Leader RNAs in Infected Cells

Evidence has recently accumulated suggesting that small noncoding RNAs, and particularly microRNAs, have the potential to strongly affect the replication and pathogenic potential of a range of human virus species. Here, we report the use of deep sequencing to comprehensively analyze small viral RNAs (18 to 27 nucleotides [nt]) produced during infection by influenza A virus. Although influenza A virus differs from most other RNA viruses in that it replicates its genome in the nucleus and is therefore exposed to the nuclear microRNA processing factors Drosha and DGCR8, we did not observe any microRNAs encoded by influenza virus genes. However, influenza virus infection did induce the expression of very high levels—over 100,000 copies per cell by 8 h postinfection—of a population of 18- to 27-nt small viral leader RNAs (leRNAs) that originated from the precise 5′ ends of all eight influenza virus genomic RNA (vRNA) segments. Like the vRNAs themselves, our data indicate that the leRNAs also bear a 5′-terminal triphosphate and are therefore not capable of functioning as microRNAs. Instead, the high-level production of leRNAs may imply a role in another aspect of the viral life cycle, such as regulation of the switch from viral mRNA transcription to genomic RNA synthesis

Antiviral efficacy of lobucavir (BMS-180194), a cyclobutyl-guanosine nucleoside analogue, in the woodchuck (Marmota monax) model of chronic hepatitis B virus (HBV) infection

Abstract Lobucavir (BMS-180194), a cyclobutyl-guanosine nucleoside analogue, effectively reduced WHV-viremia in chronically infected carrier woodchucks (Marmota monax) by daily per os treatment. WHV-viremia in the animals was measured by the serum content of hybridizable WHV-genomic DNA. Lobucavir, given at daily doses of 10 and 20 mg/kg body weight, reduced WHV-viremia by a 10-to 200-fold range during therapy. Lobucavir, given at 5 mg/kg, suppressed WHV-viremia by a 10-to 30-fold range, whereas a 0.5 mg/kg dose had no significant effect. WHV-viremia was also measured by hepadnaviral endogenous polymerase activity (EPA) in sera of animals treated for 6 weeks at 5 and 0.5 mg/kg. Changes in EPA in sera of lobucavir treated animals were comparable to changes in WHV DNA levels. Viremia in treated carriers recrudesced to pretreatment levels by 2 weeks of therapy cessation. These results indicated that the minimally effective antiviral daily per os dose of lobucavir in WHV-carrier woodchucks was : 5 mg/kg