Variant varicella-zoster viruses and methods of use

Details Variant varicella-zoster viruses and methods of use Variant varicella-zoster viruses and methods of use

2000-09-14

2003-03-04

Salimi, Ali R. (Department: 1648)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Virus or component thereof

C424S230100, C424S204100, C435S091100, C435S091330, C435S089000, C536S023720

Reexamination Certificate

active

06528066

ABSTRACT:

BACKGROUND
Varicella-zoster virus (VZV) is an ancient virus. Estimations of its origins have established that the modem herpesviruses arose some 60-80 million years ago. VZV is a member of the alphaherpesvirus subfamily of herpesviridae. It is the etiologic agent of chickenpox in childhood, after which the virus enters a latent state in the dorsal root ganglia; decades later, the same virus reactivates and causes the disease shingles (herpes zoster). The entire sequence of the 125 kbp VZV genome has been published (see Davison et al.,
J. Gen. Virol
., 67:1759-1816 (1986)). With the subsequent publication of sequence data from other herpesviruses, the alphaherpesvimuses have now been subdivided into two genera called Simplexvirus and Varicellovirus. VZV is considered to have one of the most stable genomes of all herpesviruses. The Oka strain of varicella vaccine derived from a Japanese child with chickenpox has a few minor genomic differences from North American strains, but to date no antigenic variation has been discovered amongst the major surface immunogens of the virion (Arvin et al.,
Annu. Rev. Microbiol
., 50:59-100 (1996)).
Based on their extensive analyses of herpesviral molecular evolutionary history, it has been estimated that herpesvirus DNA sequences mutate 10-100 times faster than the equivalent classes of sequences on the host genome. For glycoprotein gB, a highly conserved open reading frame (ORF) among all herpesviruses, it has been calculated that nonsynonymous substitutions have occurred at a rate of 2.7×10
−8
substitutions per site per year and synonymous substitutions at 10
−7
substitutions per site per year. Convincing arguments have been made in favor of the concept of cospeciation; in other words, herpesvirus lineages arise by way of co-evolution with their specific host. In the case of VZV, the progenitor virus most likely arose 60-70 million years before the present.
Of all the human herpesviruses, VZV may undergo the fewest replication cycles during the lifetime of the infected host. Based on a probable schema of pathogenesis, the virus actively replicates for a period of 10-14 days after infection of the human host. During a bout of chickenpox, therefore, VZV has at most 20 replication cycles. Based on the current understanding of VZV latency and reactivation, no further replication occurs unless the individual develops herpes zoster in late adulthood. Because of the above scenario, the genetic stability of the VZV genome has been presumed.
VZV contains the smallest genome of the human herpesviruses, containing about 70 ORFs within the complete VZV-Dumas sequence. Of these ORFs, at least seven code for glycoproteins, of which glycoprotein B (gB), glycoprotein E (gE), glycoprotein H (gH), and glycoprotein I (gI) are present on the exterior of the virion. VZV gE, in complex with glycoprotein I (gI), acts as a human Fc receptor on the surface of infected cells (Litwin et al.,
J. Virol
., 66:3643-51 (1992), Litwin et al.,
Virology
, 178:263-72 (1990)). The cytoplasmic tails of both gE and gI contain endocytosis motifs, allowing internalization and recycling of the complex to and from the cell (Olson et al.,
J. Virol
., 71:110-119 (1997), Olson et al.,
J. Virol
., 71:4042-4054 (1992)). The gE and gI cytoplasmic tails also are modified by both serine/threonine and tyrosine phosphorylation motifs. The fact that gE cannot be deleted suggests that it is essential (Cohen et al.,
Proc. Natl. Acad. Sci. USA
, 90:7376-7380 (1993), Mallory et al.,
J. Virol
., 71:8279-88 (1997)).
In VZV infection in humans, VZV gE is the most abundantly produced viral glycoprotein during infection. VZV gE is a major antigenic determinant to which numerous humoral and cytolytic responses are observed (Arvin et al.,
J. Immunol
., 137:1346-1351 (1986); Bergen et al.,
Viral Immunol
., 4:151-166 (1991); and Ito et al.,
J. Virol
., 54:98-103 (1985)). Recently, an immunodominant B-cell epitope was demarcated in the gE ectodomain; the epitope is defined by murine monoclonal antibody (MAb) 3B3 (Duus et al.,
J. Virol
., 70:8961-8971 (1996); Hatfield et al.,
BioTechniques
22:332-337 (1997); and Grose, U.S. Pat. No. 5,710,348).
It has long been believed that varicella zoster virus exists in nature as a single serotype (Rentier,
Neurol
., 45(Suppl. 8), S8 (1995), and that all varicella zoster viruses had essentially the same immunological properties. The first strain of varicella zoster virus that was sequenced was VZV-Dumas. Following the publication of this sequence, it was further believed that all varicella zoster viruses had essentially the same genetic properties as VZV-Dumas.
Significant progress has been made in the diagnosis of and vaccination against the sole VZV serotype that is believed to exist and cause disease in the United States. However, the production of the reagents used in diagnosis and vaccination of VZV is time consuming and expensive due to the slow growth rate of the strain grown to produce antigens for diagnostic and vaccine use.
SUMMARY OF THE INVENTION
The present invention represents a significant advance in the art of detecting and preventing varicella zoster virus infection and disease. During the characterization of a varicella zoster virus isolated from a patient, the surprising and unexpected observation was made that the virus had a different serotype. This strain was designated VZV-MSP. The molecular basis of the different serotype was found to be a single nucleotide polymorphism in the genome between VZV-Dumas and VZV-MSP. It was also determined that this single nucleotide polymorphism resulted in the loss of an epitope that is the epitope to which most protective antibody is produced upon vaccination with most currently used vaccines.
Typically, varicella zoster virus isolates can be divided into two groups with respect to growth rate in tissue culture cells. Some isolates, for instance VZV-Oka and VZV-Ellen, grow at a rate that results in complete lysis of a monolayer in about 5 to 7 days. Clinical isolates typically grow at a rate that results in complete lysis of a monolayer in about 4 to 5 days. Further investigation revealed that the new strain, VZV-MSP, unexpectedly and surprisingly had by in vitro tissue culture a growth rate that was significantly higher than previously characterized isolates, and was able to lyse a monolayer in about 2 days.
The present invention provides a method for detecting antibodies that specifically bind to a varicella zoster polypeptide. A biological sample that includes an antibody is contacted with a preparation that includes a varicella zoster polypeptide, for instance an isolated varicella zoster polypeptide or fragment thereof, to form a mixture. The varicella zoster polypeptide includes a polymorphism and can encoded by a polymorphism of ORF37. The polymorphism in the polypeptide encoded by the polymorphic ORF37 can be due to a single amino acid polymorphism, which can be present in the polypeptide as a leucine at amino acid 269. Alternatively, the varicella zoster polypeptide includes a polymorphism and can encoded by a polymorphism of ORF68. The polymorphism in the polypeptide encoded by the polymorphic ORF68 can be due to a single amino acid polymorphism, which can be present in the polypeptide as an asparagine at amino acid 150. The mixture is incubated under conditions to allow the antibody to specifically bind the polypeptide to form a polypeptide:antibody complex. The presence or absence of the polypeptide:antibody complex is then detected. Detecting the polypeptide:antibody complex indicates the presence of antibodies that specifically bind to a varicella zoster polypeptide.
The preparation can include whole varicella zoster virus, for instance VZV-MSP or a modified varicella zoster virus, where the modified virus has the ATCC designation VR-795 wherein the nucleotide sequence of the virus has been modified to comprise the polymorphism of ORF37 or ORF68. The biological sample can be blood, vesicle fluid, bone marrow, brain tissue, or combinations thereof. Also provided are k

Affiliated with

Also associated with

Rating

Variant varicella-zoster viruses and methods of use does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Variant varicella-zoster viruses and methods of use, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Variant varicella-zoster viruses and methods of use will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3060686