Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues
Reexamination Certificate
1997-09-16
2003-04-15
Scheiner, Laurie (Department: 1648)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
C530S351000, C435S069500
Reexamination Certificate
active
06548631
ABSTRACT:
1. INTRODUCTION
The present invention relates to therapeutic compositions of macrophage derived chemokine (MDC) and methods for treating and preventing infection by a lentivirus, in particular an immunodeficiency virus, particularly HIV infection, using MDC proteins, nucleic acids and/or derivatives or analogues thereof. The present invention further relates to methods of prognosis for a lentivirus infection, particularly an HIV infection using the MDC as a prognostic indicator.
2. 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 prominently 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.
Lentiviruses are a subfamily of the retroviruses which include the classic ungulate lentiviruses (visna virus of sheep, caprine arthritis encephalitis virus and equine infectious anemia virus) and the immunodeficiency viruses of humans (HIV), monkeys (SIV), cats (FIV) and cattle (BIV).
Lentivirus particles are approximately 80-110 nm in size and consist of an RNA genome and viral enzymes enclosed in a core of viral proteins encased by a cell-derived membrane spiked with viral envelope glycoproteins. Lentiviruses can be distinguished from other subgroups of retroviruses by a cylindrical or rod-shaped nucleoid in mature particles and the absence of preformed particles in the cytoplasm. Lentiviruses are not oncogenic, but produce long-term, persistent infections which eventually lead to chronic debilitating disease. All lentiviruses studied to date replicate and persist in cells of the monocyte/macrophage lineage. See
Encyclopedia of Virology
, Vol. 3, page 1316 (Academic Press Limited, London, England, 1994).
The HIV viral particle consists of a viral core, composed in part of capsid proteins designated p24 and p17, together with the viral RNA genome and those enzymes required for 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 infection (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 that cell-type specific cofactors might be required in addition to CD4 for HIV-1 entry into the host cell.
The chemokine receptor CCR5 is normally present in cells of the host and serves as the natural receptor for the &bgr; cysteine-cysteine chemokines RANTES, MIP-1&agr;, and MIP-1&bgr;. It serves in addition, however, as a co-receptor for HIV-1 (Feng et al.,
Science
272:872-877; Cocchi et al.,
Science
270:1811-1815.)
CCR5 is a seven transmembrane domain, G-protein-coupled protein that is expressed on the surfaces of CD4+ and CD8+ T lymphocytes (types of human peripheral blood mononuclear cells (PBMC) (Raport et al. 1996
, J. Biol. Chem
. 271:17161-17166), and on KG-1A promyeloblastic cells (Samson et al., 1996
, Biochemistry
35:3362-3367). The binding of &bgr; cysteine-cysteine chemokines to CCR5 to these cells triggers a variety of normal cellular events in leukocytes (white blood cells) including increases in intracellular calcium, tyrosine kinase activity and chemotaxis towards areas of inflammation.
In addition to serving these normal signal-transduction and immune response functions, CCR5 serves as a co-receptor that facilitates the attachment and fusion of certain primary M-tropic, non-syncytium inducing strains of HIV-1, to their target cells, i.e., monocyte-macrophages and primary CD4+ T lymphocytes.
Because the chemokines RANTES, MIP-1&agr; and MIP-1&bgr; compete with HIV-1 for binding to CCR5, they act as natural suppressors of HIV-1 infection (Cocchi et al., 1995
, Science
270:1811-1815; Baier et al. 1995
, Nature
378:563) and may be part of the body's general defenses against many types of viruses. Cocchi et al. (1995
, Science
270:1811-1815) have shown that RANTES, MIP-1&agr; and MIP-1&bgr; inhibit infection of monocyte-macrophages and CD4+ T cells by M-tropic HIV-1. They inhibit HIV infection or replication at a stage prior to HIV transcription.
Recently, certain factors produced by activated CD8
+
T cells have been implicated in suppression of HIV infection (Walker et al., 1986
, Science
DeVico Anthony L.
Gallo Robert C.
Garzino-Demo Alfredo
Markham Phillip D.
Pal Ranajit
bioMerieux Inc.
Parkin Jeffrey S.
Rothwell Figg Ernst & Manbeck p.c.
Scheiner Laurie
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