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Related post: type. Serotype is specified by the viral structural proteins. The dengue viral genome, an 11
kilobase strand of positive-sense RNA, contains of three structural protein genes followed by a series
of 7 non- structural protein genes. Earlier, we constructed a full-length cDNA copy of the entire
dengue 4 (D4) genome, RNA transcripts from which were infectious when transfected into
mammalian cells. We subsequently replaced the structural protein genes of the full-length clone
with the structural protein genes of Dl or D2 virus, and used these templates to create chimeric
Dl/4 and D2/4 viruses. The D4/D1 chimeric virus grows well in ceils and makes the structural
proteins of Dl virus. Two D4/D2 chimeric viruses have been made, one using a D2 virus isolated
from a human patient, the other a mutant of that virus selected for mouse neurovirulence through
serial mouse brain passage. The chimeric D4/neurovirulent D2 virus retained the neurovirulence
property of its parent, but the level of neurovirulence was less than that of the parental type 2 virus.
This indicated that at least some of the genetic loci responsible for neurovirulence are located in the
structural protein genes. Sequencing of these genes in the neurovirulent D2 mutant and in its non-
neurovirulent parent revealed 7 Naprelan 750mg Naprelan 500mg mutations resulting in amino acid changes. In order to determine
which mutation(s) cause neurovirulence, I plan to make a series of chimeric viruses in Naprelan 375 which these
mutations are isolated against a background of the prototype sequence. Elimination of Buy Naprelan the
neurovirulence property may result in a chimeric D4/D2 Naprelan 375 Mg virus safe for humans. Since the D4/D2
chimeric viruses appear to replicate more slowly than the parental viruses, they may also have
properties of attenuation desirable in a vaccine. A set of suitably engineered chimeric viruses might
serve together as a safe and effective tetravalent live dengue virus vaccine.
10-69
PHS 6040 (Rev. 1/84)
USGOVEFWUEHTPdNniGCITICE: ini OWi-OI
DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBUC HEALTH SERVICE
NOTICE OF INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl AI 00598-02 LID
PERIOD COVERED
October 1. 1991 to September 30, 1992
TITLE OF PROJECT (BO characters or less. Title muslfit on or^e line between tha borders.)
Dengue Type 4 Virus Mutants Restricted in Polyprotein Processing
PRINCIPAL INVESTIGATOR (List other professional personnel belcm the Principal InvesHgator.) (Name, title, laboratory, and institute affiliation)
PI: Hiroshi Kawano, M.D. Visiting Associate LID, NIAID
Others: Ching-Juh Lai, Ph.D.
Head, MVB Section
LID, NIAID
COOPERATING UNITS (It any)
LAB/BRANCH
Laboratory of Infectious Naprelan 500 Mg Diseases
SECTION
Molecular Viral Biology Section
INSTITUTE AND LOCATION
NIAID, NIH, Bethesda, MD 20892
TOTAL MAN- YEARS:
1.0
PROFESSIONAL:
1.0
CHECK APPROPRIATE BOX(ES)
□ (a) Human subjects
n (a1) Minors
D (a2) Interviews
n (b) Human tissues
IS (c) Neither
SUMMARY OF WORK (Use Standard unreduced type. Do not exceed the space provided.)
The dengue virus genome codes for a polyprotein in the order of NH2-C-PreM-E-NSl-NS2A-
NS2B-NS3-NS4A-NS4B-NS5-COOH that is proteolytically cleaved to generate the 10 individual
proteins. Our previous studies indicated that cleavage between NS2B and NS3 is critical for the
functional activity of the viral proteinase. Our goal is to elucidate the mechanism of polyprotein
processing and apply the information to engineer stable dengue virus mutants that exhibit restriction
of viral replication because a subset of such mutants should be less virulent than wild-type virus but
still able to achieve a satisfactory level of immunogenicity during infection. This project was
initiated to investigate the sequence requirements for proteolytic processing of dengue virus NS2B-
NS3. Deletion analysis showed that two amino acids upstream of the NS2B-NS3 junction are
sufficient for cleavage to take place. Subsequently, mutants of NS2B-NS3 containing single amino
acid substitutions at the cleavage junction were constructed for analysis of their cleavage phenotype.
Several substitutions resulted in an intermediate or a low level of cleavage. The finding that
mutants of NS2B-NS3 containing substitutions at the Naprelan Coupon cleavage junction exhibited a reduction of
cleavage efficiency has provided a body of information for molecular analysis such as engineering
of dengue virus mutants that are restricted in growth in a cell culture and perhaps in infected
animals. Finally, Naprelan Naproxen full-length dengue type 4 cDNA constructs containing single amino acid
substitutions at the NS2B-NS3 cleavage junction were prepared and used as templates for in vitro
transcription. Recovered dengue Naprelan Cr virus mutants were verified for the presence of the Naprelan 500 mutant
sequence in genomic RNA. Work is in progress to analyze the growth phenotype of these mutants.
A series of deletion constructs of NS2A or NS2B tiiat has been shown to affect poly protein
processing will be employed to construct deletion mutants of dengue virus. Deletion mutants should
be less subject to reversion of phenotype than amino acid substitution mutants. Future plans will
include evaluation of virulence and immunogenicity of these mutants in infected animals.
10-70
PHS 6040 (Rev. 1/84)
uaGOWsmcHrPRHTMicma: iniowMa
DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBUC HEALTH SERVICE
NOTICE OF INTRAMURAL RESEARCH PROJECT
PROJECT NUMBER
ZOl AI 00599-01 LID
PERIOD COVERED
October 1, 1991 to September 30, 1992
TfTLE OF PROJECT (80 characters or less. TiOe must fit on one line between the borders.)
Cleavage of the Dengue Virus Capsid Protein by the Naprelan 750 Viral Protease, NS3
PRINCIPAL INVESTIGATOR (List other prolessional personnel betow the Principal Investigator.) Naprelan 750 Mg (Name, title, laboratory, and institute affiliation)
PI: Lewis J. Markoff, M.D. Medical Officer LID, NIAID
Others: Barry N. Falgout, Ph.D.
Senior Staff Fellow
LID, NIAID
COOPERATING UNITS (ilany)
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