Chemistry: molecular biology and microbiology – Process of mutation – cell fusion – or genetic modification
Reexamination Certificate
1998-10-30
2003-07-22
Scheiner, Laurie (Department: 1648)
Chemistry: molecular biology and microbiology
Process of mutation, cell fusion, or genetic modification
C435S005000, C435S006120, C435S455000, C435S456000, C435S457000
Reexamination Certificate
active
06596539
ABSTRACT:
COPYRIGHT NOTICE
A portion of the disclosure of this patent document contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever.
FIELD OF THE INVENTION
The invention relates to methods and compositions for forced evolution of a virus genome, such as a genome of an HIV-1 virus strain, to produce a variant virus having an altered phenotype that provides a desired property that may be advantageous for development of small animal models of viral diseases, and for the development of novel therapeutic approaches to viral diseases, among others (e.g., evolving a virus to replicate in an advantageous tissue culture system). The invention relates to novel viral genomes and virions which are capable of replication in non-human animals and cells, and further relates to transgenic non-human animals and cell lines capable of supporting replication of such evolved virus variants. The invention also relates to methods for identifying novel antiviral agents.
BACKGROUND OF THE INVENTION
HIV-1 and AIDS
Human immunodeficiency virus type I (HIV-1) is a human retrovirus that is believed to be an etiologic agent of acquired immune deficiency syndrome (AIDS), an infectious disease characterized by a profound loss of immune system function. An aspect of HIV-1 disease is the typically delayed onset of disease symptoms, such as opportunistic infections, Kaposi's sarcoma, dementia, and wasting syndrome. Often it may take 10 to 15 years after initial infection before symptoms are evident; however, in some instances disease onset is quite rapid. Moreover, the specific pathology of HIV-1 disease can be quite variable between individuals and between strains of the HIV-1 virus (for a review, see Field's Virology, Third Edition, Fields et al. Eds., Lippincott-Raven Publishers, Vol. 2, Chapters 60 and 61). At present, HIV-1 appears to be almost always pathogenic in humans, and although certain chemotherapeutic agents (e.g., protease inhibitors, nucleoside analogs) have shown clinical promise in arresting or slowing HIV-1 disease, there is no established cure or preventative for HIV-1 disease at present.
Unfortunately, the HIV-1 virus is also characterized by an extraordinarily high frequency of mutational change, including deletions, base pair substitutions, insertions, and recombinations between HIV-1 genomes. It has been estimated that on the average at least one quarter of the progeny virus from a single cycle of retrovirus replication will have some kind of mutation relative to the parent genome, and recombination will further recombine these variant genomes (Temin H M (1989) Genome 31: 17). This characteristic of HIV-1 (and other lentiviruses, such as retroviruses) makes it difficult to obtain therapeutic solutions which the virus cannot escape due to its inherently high rate of mutation and propensity to generate variants which are resistant to the particular therapeutic solution selected. For this reason, the currently used therapeutic method to treat HIV-1 disease is to combine a cocktail of multiple chemotherapeutic agents (e.g., protease inhibitors and nucleoside analogs) to make it less likely that a resistant variant can arise during therapy. Nonetheless, it is almost certain that resistant HIV-1 variants will arise, particularly in view of imperfect patient compliance with chemotherapeutic regimens, pharmacogenetic differences between individuals in bioavailability of the chemotherapy agents, and use of partially degraded or inaccurately dispensed chemotherapy agents in less-advanced nations.
The globally circulating strains of HIV-1 exhibit extreme genetic diversity (Robertson et al. (1995) Nature 374: 124). To evaluate the extent of global HIV-1 variation, sequences of virus strains originating from numerous countries have been compared. These studies have shown that HIV-1 can be classified into two major groups, designated M and O, which are defined as distinct clusters on phylogenetic trees. Groups M comprises the great majority of HIV-1 isolates and can be further subdivided into at least nine sequence subtypes or clades, designated A to I, with additional variants being added to the classification scheme continually (Gao et al. (1996) J. Virol. 70: 1651). Given this degree of diversity, it is widely believed that a vaccine based on a single strain or subtype of HIV-1 will be unsuccessful against the larger spectrum of globally circulating HIV-1 variants, as well as against new variants which continually arise. Furthermore, the HIV-1 virus appears to undergo sequence variation and functional mutation in patients; isolates from different phases of HIV-1 infection exhibit stage-specific replication characteristics (Asjo et al. (1986) Lancet 2: 660; Cheng-Meyer et al. (1988) Science 240: 80; Fenyo et al. (1988) J. Virol. 62: 4414; Tersmette (1989) J. Virol. 63: 2118).
In view of the propensity of HIV-1 to undergo rapid mutation and generate variants that are resistant to chemotherapeutic agents and candidate “universal” vaccines, it is desirable to have non-human animal models of HV-1 replication and disease in order to speed the identification an d development of new generations of antiviral agents that can be used to treat resistant HIV-1 variants, or to prevent the generation of such variants in vivo. Unfortunately, such non-human models of HIV-1 disease are presently lacking.
Non-human Models of HIV-1 Disease
The absence of a suitable animal model has remained one of the major barriers to the development of an effective therapy for HIV-1 infection. Ideally, a readily available small animal model that could sustain HIV-1 infection and develop clinical symptoms that reflect the disease in humans would prove useful for modeling pathogenesis and developing new antiviral agents. An animal model that could duplicate human immune responses would greatly facilitate the development of vaccines. Unfortunately, no current model fulfills these varied needs (for review see, Klotman et al. (1995) AIDS 9: 313; Chang et al. (1996) Transfus. Sci. 17: 89; and Bonyhadi M L and Kaneshima H (June, 1997) Molec. Med. Today pp. 246-253; Mosier D E (September, 1996) Hosp. Prac. Pp. 41-60).
In general, non-human animals are not susceptible to infection with HIV-1 (Morrow et al. (1987) J. Gen. Virol. 68: 2253). However, several animal models exist in which to study retroviruses related to HIV-1 and their related pathology; these include SIV in macaque monkeys, FIV in cats, and murine acquired immunodeficiency syndrome virus (MAIDS) in mice, among others. HIV-1 replicates weakly in chimpanzees, but causes no detectable disease symptoms, and chimpanzees are quite expensive and not suited for large-scale studies. Lewis A D and Johnson P R (1995) TIBTECH 13: 142 discuss various non-human animal model systems and their limitations.
Several HIV-2 isolates, including three molecular clones of HIV-2 (HIV-2ROD, HIV-2SBL-ISY, and HIV-2UC1), have also been reported to infect macaques (
M. mulatta
and
M. nemestrina
) or baboons (Franchini, et al. (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 2433-2437; Barnett, et al. (1993) Journal of Virology 67, 1006-14; Boeri, et al. (1992) Journal of Virology 66, 4546-50; Castro, et al. (1991) Virology 184, 219-26; Franchini, et al. (1990) Journal of Virology 64, 4462-7; Putkonen, et al. (1990) Aids 4, 783-9; Putkonen, et al. (1991) Nature 352, 436-8).
As alternatives to the above, models of HIV-1 pathogenesis have been experimentally derived in mice that are transgenic for portions of the HIV genome or an entire HIV-1 genome, as well as in SCID mice which have been reconstituted with HIV-infected immune cells (Ramezani et al. (1996) Transfus. Sci. 17: 99; Chang et al. (1996) op.cit). HIV transgenic mice have been developed to model the in vivo regulation and pathological consequences of expression of various HIV open reading frames
Patten Phillip
Soong Nay Wei
Stemmer Willem P. C.
Kruse Norman J.
Maxygen Inc.
Parkin J. S.
Powers Margaret A.
Scheiner Laurie
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