HIV and CD4 transgenic animals and uses therefor

Details HIV and CD4 transgenic animals and uses therefor HIV and CD4 transgenic animals and uses therefor

2000-10-10

2003-12-09

Shukla, Ram R. (Department: 1632)

Multicellular living organisms and unmodified parts thereof and

Method of using a transgenic nonhuman animal in an in vivo...

C800S011000, C800S014000, C800S009000

Reexamination Certificate

active

06660904

ABSTRACT:

BACKGROUND OF THE INVENTION
Human immunodeficiency virus (HIV) is an etiological agent of Acquired Immune Deficiency Syndrome (AIDS). AIDS was first reported in the United States of America in 1981. As of January 1997, approximately 1.5 million cases of AIDS in adults and children had been reported to the World Health Organization (WHO); however, because reporting is difficult, WHO estimates that there were more than 8.4 million cases, about 580,000 of which reside in the United States. However, the number of HIV infected individuals is much higher: as of January 1997, WHO estimated that there were approximately 29.4 million HIV infected individuals world-wide, with about 1 million in the United States. It has been estimated that by the year 2000, between 40 and 100 million individuals will be infected with HIV.
HIV, which has also been referred to as lymphadenopathy-associated virus (LAV), HTLV-III, or AIDS related virus (ARV), is a lentivirus from the family of retroviruses and is composed of RNA consisting of about 9,700 base pairs, three gag proteins (having molecular weights of 55,000, 24,000 and 17,000 daltons), a reverse transcriptase (molecular weights of 66,000 and 51,000 daltons have been detected), three glycoproteins (two molecules having molecular weights of 120,000 and 41,000 daltons, and their precursor, a molecule with a molecular weight of 160,000 daltons, hereinafter abbreviated as gp120, gp41 and gp160, respectively) which comprise the envelope, and other components. Exposed, envelope proteins are particularly important for viral infection and therefor also, the prevention thereof. As a result of proteolysis, gp160 is cleaved into gp120 and gp41. Gp41is a transmembrane protein which is incorporated into the lipid bilayer of the viral envelope, while gp120 is exposed on the outside of the envelope and some of it is released from the virus. Both gp41 and gp120 possess many sugar-binding sites, and about half of the gp120 molecule is comprised of sugars. The gp120 molecule binds to the CD4 antigens on the surface of cells, in particular helper T cells. Once HIV is bound to CD4 via gp120, another env gene product, gp41, mediates fusion between the membranes of the cell and the virus allowing the core of the virus to enter the cell. Gp120, which is expressed on the plasma membrane of infected cells before virus is released, can bind to CD4 on another cell, initiating a membrane fusion event resulting in syncytia fornmation, and HIV genomes can be passed between the fused cells directly.
The env gene (gp120) is the primary determinant of cell tropism for both HIV and Simian Immunodeficiency Virus (SIV). Variable region 3 (V3) of gp120 is a key component within env that determines cell tropism. The efficiency of replication and the ability to induce the syncytia formation are also affected by changes in the V3 loop.
The first HIV virus isolated is referred to as HIV-1 and is generally described in several articles, e.g., Barre-Sinoussi et al., Science 220:868, 1983; Gallo et al., Science 224:500, 1984; Popovic et al., Science 224:497, 1984; and Levy et al., Science 225:840, 1984, each of which is hereby incorporated by reference. Various isolates of HIV-1 have been obtained from North America, Western Europe and Central Africa. These isolates differ somewhat in their nucleotide sequence, but the proteins they encode are generally antigenically cross-reactive.
A second virus related to HIV-1 has been isolated and termed HIV-2 (Guyader et al., Nature 326:662, 1987; Brun-Vezinet et al., The Lancet 1: 128, 1987; and Clavel et al., Science 233:343, 1986). The genetic organization of HIV-2 is similar to that of HIV-1. Of the two distinct subtypes, HIV-1 is predominant and found throughout the world, whereas HIV-2 has been isolated primarily in West African countries such as Guinea Bissay, Ivory Coast, and Senegal, whith some cases also identified in the Americas and western Europe. Epidemiological studies suggest that the incubation period for HIV-2 for the development of disease is longer than for HIV-1.
HIV isolates from around the world were found to differ in nucleotide sequence. These sequences have been collected in a specialized database (Myers et al. (1994) Los Alamos National Laboratory, Los Alamos, N.Mex.). Two major groups of HIV has been identified. Viruses of group M (for “main”) are responsible for the majority of infections worldwide; group O (for “outgroup”) is a relatively rare group currently found in Cameroon, Gabon , and France. Group M can be divided into at least eight distinct subtypes or clades (A through H) (Myers, supra; Louwagie et al. (1995) J. Virol. 69:263). Isolates from HIV-1 from different clades may differ by 30-40% in the amino acid sequence of the gp120 SU protein; isolates within a clade vary from 5% to 20%. Clade B predominates in North America and Europe and clade E predominates in northern Thailand. Similarly, there are five HIV-2 sequence subtypes.
A group of viruses isolated from monkeys, termed simian immunodeficiency virus (SIV or STLV-III), is related to HIV-1 and HIV-2, particularly the latter. See Daniel et al., Science 228:1201-1204 (1985); Kanki et al., Science 230:951-954 (1985); Chakrabarti et al., Nature 328:543-547 (1987); and Ohta et al., Int'l. J. Cancer 41:115-222 (1988). Members of this viral group exhibit minor variations in their genomic sequences, and have some differences in their restriction enzyme maps.
Although human CD4 is essential for HIV infection, it is not sufficient. Expression of human CD4 on rodent cells renders them capable of binding virus but still nonpermissive for fusion or infection (Maddon et al. (1986) Cell 47:333). The host component or coreceptors, sometimes referred to as the “fusion receptors”, were identified only recently. These coreceptors are receptors for chemokines (i.e. small proteins which serve as chemoattractants in inflammation) and they permit HIV infection of-virtually any mammalian or avian cell that expresses human CD4 (Bates (1996) Cell 86:1-3). The most important coreceptors are CXCR4 (also called “fusin” or “LESTR) (Endres et al. (1996) Cell 87:745; Feng et al. (1996) Science 272:872) and CCR5 (Akhatib et al. (1996) Science 272:1955; Choe et al. (1996) Cell 85:1135; Deng et al. (1996) Nature 381:661; Doranz et al. (1996) Cell 85:1149; and Dragic et al. (1996) Nature 381:667). CXCR4 is the receptor for the chemokine SDF-1, whereas CCR5 serves as a receptor for the chemokines MIP-1 and and RANTES. These coreceptors play a crucial function for viral entry into cells, and they are also the principal determinants of tropism among CD4+ cells.
Two distinct types of HIV-1 have been identified based on the cells in which they replicate in vitro. Viruses that replicate in T cell lines, but not macrophages or monocytes, are referred to as T tropic, whereas viruses with the cormplementary specificity are referred to as M tropic. The tropism is at least a function of the coreceptor: M tropic viruses can use only CCR5 for entry, and T tropic viruses use CXCR4. A few dual tropic isolates capable of using both are also known. T tropic viruses often cause infected cells to fuse with uninfected cells if the latter express both human CD4 and CXCR4. Such viruses are referred to as “syncytium-inducing” (SI). All isolates can infect activated T cells freshly isolated from peripheral blood, which are present in PBMC cultures, since such cells express both CXCR4 and CCR5. Furthermore, cell tropisms are not fixed and can change when the virus is passaged in cell culture (Metlzer et al. (1990) Immunology Today 11.217; Levy (1993) Microbiol. Rev. 57:183).
Two animal species (i.e., man and chimpanzee) are known to be susceptible to HIV infection, but only in man does the disease develop. HIV-1 transgenic mice carrying intact copies of the HIV-1 provirus have been obtained (Leonard et al. (1988) Science 242:1665). These mice develop a spontaneous and fatal disease that mimics some of the features described in human AIDS. Other HIV-1 transgenic mice carrying the HIV-1 proviral DNA in whic

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