Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1996-10-24
1998-07-14
Walsh, Stephen
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
435 5, 435 72, 436501, 530350, 530300, G01N 33566, C07K 14705, C07K 1447
Patent
active
057802386
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a human receptor protein which binds to the human immunodeficiency virus (HIV) viral protein R (vpr), to pharmaceutical compositions that comprise the receptor protein, to compositions useful to produce the receptor protein and to methods of making and using the receptor protein. The present invention is related to U.S. application Ser. No. 08/167,519 filed Dec. 15, 1993, which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
Since the demonstration in 1987 that the small open reading frame within HIV-1 designated R encodes a 15 kd protein (Wong-Staal, F., et al., (1987) AIDS Res. Hum. Retroviruses 3:33-39), relatively little regarding the function of the viral protein R (vpr) has been reported. The vpr open reading frame is conserved within all genomes of HIV-1 and HIV-2 and within most, if not all, simian immunodeficiency virus (SIV) genomes. VPR is immunogenic in vivo in that a large subset of HIV individuals makes antibodies that can react with a bacterially produced vpr peptide (Wong-Staal, F., et al. , (1987) AIDS Res. Hum. Retroviruses 3:33-39).
The progression from HIV infection to AIDS is in large part determined by the effects of HIV on the cells that it infects, including CD4.sup.+ T lymphocytes and macrophages. On the other hand, cell activation, differentiation and proliferation are in turn thought to regulate HIV infection and replication in T cells and macrophages. Gallo, R. C. et al. (1984) Science 224:500; Levy, J. A. et al., (1984) Science 225:840; Zack, J. A. et al. (1988) Science 240:1026; Griffin, G. E. et al., (1988) Nature 339:70; Valentin, A. et al. (1991) J. AIDS 4:751; Rich, E. A. et al., (1992) J. Clin. Invest. 89:176; and Schuitemaker, H. et al. (1992) J. Virol. 66:1354. Cell division per se may not be required since HIV and other lentiviruses can proliferate in nonproliferating, terminally differentiated macrophages and growth-arrested T lymphocytes. Rose, R. M. et al. (1986) Am. Rev. Respir. Dis. 143:850; Salahuddin, S. Z. et al. (1986) Blood 68:281; and Li, G. et al. (1993) J. Virol. 67:3969. The ability of lentiviruses, including HIV, to replicate in nonproliferating cells, particularly in macrophages, is believed to be unique among retroviruses and it may be significant that several lentiviruses contain a vpr-like gene. Myers, G. et al. (1992) AIDS Res. Hum. Retrovir. 8:373. HIV infection of myeloid cell lines can result in a more differentiated phenotype and increase the expression of factors such as NF-KB which are necessary for HIV replication. Roulston, A. et al. (1992) J. Exp. Med. 175:751; and Chantal Petit, A. J. et al. (1987) J. Clin. Invest. 79:1883.
The most evidence for the function of the vpr protein comes from several studies reporting the activities of HIV strains that have mutations in the vpr gene. It has been reported that mutations in the vpr gene results in a decrease in the replication and cytopathogenicity of HIV-1, HIV-2, and SIV in primary CD4.sup.+ T lymphocytes and transformed T cell lines (Ogawa, K., et al., (1989) J. Virol. 63:4110-4114; Shibata, R., et al. (1990a). J. Med. Primatol. 19:217-225; Shibata, R., et al. (1990b) J. Virol. 64:742-747 and Westervelt, P. et al. (1992) J. Virol. 66:3925), although others have reported mutated vpr gene had no effect on replication (Dedera, D., et al. (1989) Virol. 63:3205-3208). Interestingly HIV-2 mutated for vpr has been reported unable to infect primary monocyte/macrophages (Hattori, N., et al. (1990) Proc. Nati. Acad. Sci. U.S.A. 87:8080-8084). Transactivation of the HIV long terminal repeat and heterologous promoters by HIV is increased about 3-fold in wild-type versus vpr-negative HIV-1, though the mechanism through which vpr may transactivate transcription is unknown and may be indirect (Cohen, E. A., et al., (1990b) J. Acquir. Immune Defic. Syndr. 3:11-18). The relationship between the effects of vpr on promoter activity and viral infectivity is not clear. Vpr protein is incorporated into the viral particle, and this finding
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Ratn
Levy David Nathan
Refaeli Yosef
Weiner David B.
Kaufman Claire M.
The Trustees of the University of Pennsylvania
Walsh Stephen
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