Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving virus or bacteriophage
Reexamination Certificate
2001-05-09
2004-02-24
Park, Hankyel T. (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving virus or bacteriophage
C435S003000, C435S004000, C435S007100, C435S007200, C435S007210, C435S008000
Reexamination Certificate
active
06696244
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates generally to the infection of target cells by HIV-1, HIV-2 and SIV and more particularly to agents identified herein that mediate the entry of retroviruses into such target cells, and to the diagnostic and therapeutic uses to which such agents may be put. Furthermore, the present invention relates to methods of identifying agents that can modulate the expression and/or function of Bonzo/STRL33. Such agents can be used to either treat inflamation, or alternatively, to enhance the immune response.
BACKGROUND OF THE INVENTION
The human immunodeficiency viruses infect CD4
+
macrophages and T helper cells. Although HIV-1 entry requires cell surface expression of CD4, to which the viral envelope glycoproteins bind, several studies have suggested that it is not sufficient for fusion of the viral envelope to the cellular plasma membrane. Early studies have shown that while human cells expressing a transfected CD4 gene were permissive for virus entry, murine cells expressing human CD4 were not. These findings led to the suggestion that there is a species-specific cell surface cofactor required in addition to CD4 for HIV-1 entry. Subsequent studies have shown that strains of HIV-1 that had been adapted for growth in transformed T-cell lines (T-tropic strains) could not infect primary monocytes or macrophages; in contrast, primary viral strains were found to infect monocytes and macrophages, but not transformed T cell lines. This difference in tropism was found to be a consequence of specific sequence differences in the gp120 subunit of the envelope glycoprotein, suggesting that multiple cell type-specific cofactors may be required for entry in addition to CD4.
The nature of the cofactors required for HIV entry proved elusive until it was recently discovered that the principal receptor for entry of macrophage-tropic (M-tropic) HIV-1 strains was CCR5, whereas the principal receptor for entry of T-cell line-tropic (T-tropic) strains was CXCR4. On the other hand, both M-tropic and T-tropic strains of simian immunodeficiency virus (SIV) can be mediated by CCR5, but not CXCR4 [Chew et al.,
J. Virol,
71:2705-2714 (1997); Marcon et al.,
J. Virol,
71:2522-2527 (1997); and Edinger et al.,
Proc. Natl. Acad. Sci. USA,
94:4005-4010 (1997)]. More importantly, SIV strains were also found to infect CD4
+
cells that lack CCR5 [Chen et al., 1997, supra; and Edinger et al., 1997, supra].
In humans, CCR5-tropic viruses are primarily involved in transmission, while viruses with broader tropism, particularly for CXCR4, emerge during progression to immunodeficiency [Fauci,
Nature,
384:529-534 (1996)]. It is not yet known whether appearance of CXCR4-tropic viruses is a consequence or the cause of immune system decline. Insight into this key problem of virus evolution is likely to require experimental manipulation in animal models. Infection of non-human primates with SIV is currently the only good animal model for studying pathogenesis of the immunodeficiency viruses [Desrosiers,
Annu Rev Immunol,
8:557-578 (1990)]. Moreover, different species of non-human primates vary widely in their responses to SIV infection. For example, Rhesus macaques succumb to immunodeficiency that closely resembles AIDS in humans, but sooty mangabeys and African green monkeys can sustain infection with little evidence of immune system damage [Kestler,
Science,
248:1109-1112 (1990)]. These interspecies differences provide important clues for understanding and combating disease progression in HIV-infected humans.
Therefore, there is a need to identify and structurally characterize translocation promoting agents other than CCR5 and CXCR4 that function in conjunction with CD4 during SIV and/or HIV infection of human cells as well in the subsequent disease progression. Further, there is a need to determine the specific strains of the retroviruses that can use such translocation promoting agents as alternatives to CXCR4 and CCR5. In addition, there is a need to provide methods of identifying drugs that can interfere with retroviral infection by hindering the interaction of CD4, the various translocation promoting agents and the retroviral envelope glycoproteins.
The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.
SUMMARY OF THE INVENTION
The present invention provides an expression cloning strategy to identify SIV receptors which may play a role in human acquired immunodeficiency disease. Two particular nucleic acids encoding two members of the 7-transmembrane G-protein coupled receptor family were identified and isolated by the methods described herein. These SIV receptors were also found to be used by particular strains of HIV-2 and M-tropic HIV-1.
One aspect of the present invention provides an isolated nucleic acid encoding a translocation promoting agent that is substantially homologous to SEQ ID NO:1. In a preferred embodiment of this type the nucleic acid is obtained from a primate. In one such embodiment the nucleic acid encodes a translocation promoting agent that is substantially homologous to SEQ ID NO:3. In another such embodiment the isolated nucleic acid encodes a translocation promoting agent that is substantially homologous to SEQ ID NO:5. In the most preferred embodiment the isolated nucleic acid encodes a translocation promoting agent isolated from a human source.
The present invention also includes nucleic acid primers and/or probes for all of the nucleic acids of the present invention. In addition, the nucleic acids of the present invention may be RNA, or single or doubled stranded DNA, including recombinant DNA.
The present invention also includes an isolated nucleic acid which encodes a translocation promoting agent having the amino acid sequence of SEQ ID NO:2 having one or more conservative substitutions. In a related embodiment the isolated nucleic acid encodes a translocating promoting agent having the amino acid sequence of SEQ ID NO:2. In a preferred embodiment of this type the isolated nucleic acid has a nucleic acid sequence of SEQ ID NO:1.
The present invention also includes an isolated nucleic acid encoding a translocation promoting agent having the amino acid sequence of SEQ ID NO:4 having one or more conservative substitutions. In a related embodiment the isolated nucleic acid encodes a translocation promoting agent having the amino acid sequence of SEQ ID NO:4. In a preferred embodiment of this type the isolated nucleic acid has the nucleic acid sequence of SEQ ID NO:3.
The present invention also includes an isolated nucleic acid encoding a translocation promoting agent having the amino acid sequence of SEQ ID NO:6 having one or more conservative substitutions. In a related embodiment the isolated nucleic acid encodes a translocating promoting agent having the amino acid sequence of SEQ ID NO:6. In a preferred embodiment of this type the isolated nucleic acid has the nucleic acid sequence of SEQ ID NO:5.
The present invention also includes an isolated nucleic acid encoding a translocation promoting agent having the amino acid sequence of SEQ ID NO:10 having one or more conservative substitutions. In a related embodiment the isolated nucleic acid encodes a translocating promoting agent having the amino acid sequence of SEQ ID NO:10. In a preferred embodiment of this type the isolated nucleic acid has the nucleic acid sequence of SEQ ID NO:9.
The present invention also includes an isolated nucleic acid encoding a translocation promoting agent having the amino acid sequence of SEQ ID NO:12 having one or more conservative substitutions. In a related embodiment the isolated nucleic acid encodes a translocating promoting agent having the amino acid sequence of SEQ ID NO:12. In a preferred embodiment of this type the isolated nucleic acid has the nucleic acid sequence of SEQ ID NO:11.
The present invention also includes nucleic acids which contain 18 or more nucleotides that hy
Deng Hongkui
Kewalramani Vineet N.
Littman Dan R.
Unutmaz Derya
Klauber & Jackson
New York University
Park Hankyel T.
LandOfFree
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