Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-12-22
2002-08-06
Park, Hankyel T. (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S005000, C435S007200, C424S085100, C530S351000, C530S395000, C536S023400, C536S023500
Reexamination Certificate
active
06428970
ABSTRACT:
2. FIELD OF THE INVENTION
The present invention relates to therapeutic compositions and methods for treating and preventing infection by an immunodeficiency virus, particularly HIV infection, using chemokine proteins, nucleic acids and/or derivatives or analogs thereof.
3. BACKGROUND OF THE INVENTION
Human immunodeficiency virus (HIV) induces a persistent and progressive infection leading, in the vast majority of cases, to the development of the acquired immunodeficiency syndrome (AIDS) (Barre-Sinoussi et al., 1983, Science 220: 868-870; Gallo et al., 1984, Science 224:500-503). There are at least two distinct types of HIV: HIV-1 (Barre-Sinoussi et al., 1983, Science 220:868-870; Gallo et al., 1984, Science 224:500-503) and HIV-2 (Clavel et al., 1986, Science 233:343-346; Guyader et al., 1987, Nature 326:662-669). In humans, HIV replication occurs predominantly in CD4+ T lymphocyte populations, and HIV infection leads to depletion of this cell type and eventually to immune incompetence, opportunistic infections, neurological dysfunctions, neoplastic growth, and ultimately death.
HIV is a member of the lentivirus family of retroviruses (Teich et al., 1984, RNA Tumor Viruses, Weiss et al., eds., CSH-press, pp. 949-956). Retroviruses are small enveloped viruses that contain a single-stranded RNA genome, and replicate via a DNA intermediate produced by a virally-encoded reverse transcriptase, an RNA-dependent DNA polymerase (Varmus, H., 1988, Science 240:1427-1439). Other retroviruses include, for example, oncogenic viruses such as human T-cell leukemia viruses (HTLV-1,-II,-III), and feline leukemia virus.
The HIV viral particle consists of a viral core, composed in part of capsid proteins designated p24 and p18, together with the viral RNA genome and those enzymes required for early replicative events. Myristylated gag protein forms an outer viral shell around the viral core, which is, in turn, surrounded by a lipid membrane envelope derived from the infected cell membrane. The HIV envelope surface glycoproteins are synthesized as a single 160 kilodalton precursor protein, which is cleaved by a cellular protease during viral budding into two glycoproteins, gp41 and gp120. gp41 is a transmembrane glycoprotein and gp120 is an extracellular glycoprotein which remains non-covalently associated with gp41, possibly in a trimeric or multimeric form (Hammerskjold, M. and Rekosh, D., 1989, Biochem. Biophys. Acta 989:269-280).
HIV, like other enveloped viruses, introduces viral genetic material into the host cell through a viral envelope mediated fusion of viral and target membranes. HIV is targeted to CD4
+
cells because a CD4 cell surface protein (CD4) acts as the cellular receptor for the HIV-1 virus (Dalgleish et al., 1984, Nature 312:763-767; Klatzmann et al., 1984, Nature 312:767-768; Maddon et al., 1986, Cell 47:333-348). Viral entry into cells is dependent upon gp120 binding the cellular CD4 receptor molecules (Pal et al., 1993, Virology 194:833-837; McDougal et al., 1986, Science 231:382-385; Maddon et al., 1986, Cell 47:333-348), explaining HIV's tropism for CD4
+
cells, while gp41 anchors the envelope glycoprotein complex in the viral membrane. The binding of gp120 to CD4 induces conformational changes in the viral glycoproteins, but this binding alone is insufficient to lead to infection (reviewed by Sattentau and Moore, 1993, Philos. Trans. R. Soc. London (Biol.) 342:59-66).
Studies of HIV-1 isolates have revealed a heterogeneity in their ability to infect different human cell types (reviewed by Miedema et al., 1994, Immunol. Rev. 140:35-72). The majority of extensively passaged laboratory strains of HIV-1 readily infect cultured T cell lines and primary T lymphocytes, but not primary monocytes or macrophages. These strains are termed T-tropic. T-tropic HIV-1 strains are more likely to be found in HIV-1 infected individuals during the late stages of aids (Weiss et al., 1996, Science 272:1885-1886). The majority of primary HIV-1 isolates (i.e., viruses not extensively passaged in culture) replicate efficiently in primary lymphocytes, monocytes and macrophages, but grow poorly in established T cell lines. These isolates have been termed M-tropic. The viral determinant of T- and M-tropism maps to alterations in the third variable region of gp120 (the V3 loop)(Choe et al., 1996, Cell 85:1135-1148; Cheng-Mayer et al., 1991, J. Virol. 65:6931-6941; Hwang et al., 1991, Science 253:71-74; Kim et al., 1995, J. Virol., 69:1755-1761; and O'Brien et al., 1990. Nature 348:69-73). The characterization of HIV isolates with distinct tropisms taken together with the observation that binding to the CD4 cell surface protein alone is insufficient to lead to infection, suggest a requirement for cell-type specific cofactors, in addition to CD4, for HIV-1 entry into the host cell.
Recently, certain chemokines produced by CD8
+
T cells have been implicated in suppression of HIV infection. The chemokines RANTES (regulated on activation normal T cell expressed and secreted), macrophage-inflammatory protein-1&agr; and -1&bgr; (MIP-1&agr; and MIP-1&bgr;, respectively), which are secreted by CD8
+
T cells, were shown to suppress HIV-1 p24 antigen production in cells infected with HIV-1 or HIV-2 isolates in vitro (Cocchi et al., 1995, Science 270:1811-1815). Additionally, high levels of these chemokines have been found to be secreted by CD4
+
T lymphocytes in individuals that have been exposed to HIV-1 on multiple occasions but, remain uninfected (Paxton et al., 1996, Nature Med. 2:412-417). While RANTES, MIP-1&agr; and MIP-1&bgr; alone or in combination, potently suppress a variety of primary HIV-1 isolates and macrophage tropic isolates, such as HIV-1
BaL
, some established laboratory strains, such as HIV-1
IIIB
, are refractory to inhibition of infection or replication by these chemokines (Cocchi et al., 1995, Science 270:1811-1815).
Chemokines, or chemoattractant cytokines, are a subgroup of immune factors that mediate chemotactic and other pro-inflammatory phenomena (See, Schall, 1991, Cytokine 3:165-183). Chemokines are small molecules of approximately 70-80 residues in length and can generally be divided into two subgroups, &agr; which have two N-terminal cysteines separated by a single amino acid (CxC) and &bgr; which have two adjacent cysteines at the N terminus (CC). RANTES, MIP-1&agr; and MIP-1&bgr; are members of the &bgr; subgroup (reviewed by Horuk, R., 1994, Trends Pharmacol. Sci, 15:159-165; Murphy, P. M., 1994, Annu. Rev. Immunol., 12:593-633). The amino terminus of the &bgr; chemokines RANTES, MCP-1, and MCP-3 have been implicated in the mediation of cell migration and inflammation induced by these chemokines. This involvement is suggested by the observation that the deletion of the amino terminal 8 residues of MCP-1, amino terminal 9 residues of MCP-3, and amino terminal 8 residues of RANTES and the addition of a methionine to the amino terminus of RANTES, antagonize the chemotaxis, calcium mobilization and/or enzyme release stimulated by their native counterparts (Gong et al., 1996 J. Biol. Chem. 271:10521-10527; Proudfoot et al., 1996 J. Biol. Chem. 271:2599-2603). Additionally, &agr; chemokine-like chemotactic activity has been introduced into MCP-1 via a double mutation of Tyr 28 and Arg 30 to leucine and valine, respectively, indicating that internal regions of this protein also play a role in regulating chemotactic activity (Beall et al., 1992, J. Biol. Chem. 267:3455-3459).
The monomeric forms of all chemokines characterized thus far share significant structural homology, although the quaternary structures of &agr; and &bgr; groups are distinct. While the monomeric structures of the &bgr; and &agr; chemokines are very similar, the dimeric structures of the two groups are completely different. An additional chemokine, lymphotactin, which has only one N terminal cysteine has also been identified and may represent an additional subgroup (&ggr;) of chemokines (Yoshida et al., 1995, FEBS Lett. 360:155-159; and Kelner et al., 1994, Science 2
De Vico Anthony
Gallo Robert C.
Garzino-Demo Alfredo
Fuierer Marianne
Park Hankyel T.
University of Maryland Biotechnology Institute
Yang Yonqzhi
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