Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving virus or bacteriophage
Reexamination Certificate
2000-03-27
2003-07-22
Scheiner, Laurie (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving virus or bacteriophage
C424S234100
Reexamination Certificate
active
06596477
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to lipopolysaccharide (LPS) or lipid A variants, derivatives, and analogs with non-pyrogenic and non-endotoxic properties as well as methods for treatment and prevention of immunodeficiency virus infection, in particular HIV infection, using these LPS or lipid A variants and analogs and derivatives. The present invention also relates to LPS and lipid A antagonists and their use as therapeutics in the treatment and prevention of HIV infection. The LPS and lipid A variants, derivatives, and analogs of the present invention preferably induce the secretion of &bgr; chemokines but exhibit decreased induction relative to LPS and lipid A of secretion of proinflammatory cytokines, such as IL-1&bgr;, IL-6 and TNF-&agr;. The present invention further relates to pharmaceutical compositions for the treatment and prevention of HIV infection.
BACKGROUND OF THE INVENTION
The Human Immunodeficiency Virus
The human immunodeficiency virus (HIV) has been implicated as the primary cause of the slowly degenerative immune system disease termed acquired immune deficiency syndrome (AIDS) (Barre-Sinoussi, F., et al., 1983,
Science
220:868-870; Gallo, R., et al., 1984,
Science
224:500-503). There are at least two distinct types of HIV: HIV-1 (Barre-Sinoussi, F., et al., 1983,
Science
220:868-870; Gallo, R., et al., 1984,
Science
224:500-503) and HIV-2 (Clavel, F., et al., 1986,
Science
233:343-346; Guyader, M., et al., 1987,
Nature
326:662-669). Further, a large amount of genetic heterogeneity exists within populations of each of these types. 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, N., et al., 1984,
RNA Tumor Viruses;
Weiss, R., 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).
The HIV viral particle comprises a viral core, composed in part of capsid proteins, together with the viral RNA genome and those enzymes required for early replicative events. Myristylated gag protein forms an outer 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 (Hammarskjold, M., & Rekosh, D., 1989,
Biochem. Biophys. Acta
989:269-280).
HIV is targeted to CD4
+
cells because a CD4 cell surface protein (CD4) acts as the cellular receptor for the HIV-1 virus (Dalgleish, A., 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 (McDougal, J. S., et al., 1986,
Science
231:382-385; Maddon, P. J., 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. While these virus:cell interactions are necessary for infection, there is evidence that additional virus:cell interactions are also required.
HIV Treatment
HIV infection is pandemic and HIV-associated diseases represent a major world health problem. Although considerable effort is being put into the design of effective therapeutics, currently no curative anti-retroviral drugs against AIDS exist. In attempts to develop such drugs, several stages of the HIV life cycle have been considered as targets for therapeutic intervention (Mitsuya, H., et al., 1991,
FASEB J.
5:2369-2381). Many viral targets for intervention with HIV life cycle have been suggested, as the prevailing view is that interference with a host cell protein would have deleterious side effects. For example, virally encoded reverse transcriptase has been one focus of drug development. A number of reverse-transcriptase-targeted drugs, including 2′,3′-dideoxynucleoside analogs such as AZT, ddI, ddC, and d4T have been developed which have been shown to been active against HIV (Mitsuya, H., et al., 1991,
Science
249:1533-1544).
The new treatment regimens for HIV-1, referred to as Highly Active Anti-Retroviral Therapy (HAART), which involves administration of two or three anti-HIV drugs, which target reverse transcriptase (RT) (such as azidothymidine (AZT), lamivudine (3TC), dideoxyinosine (ddI), dideoxycytidine (ddC)) in combination with an HIV-1 protease inhibitor have a far greater effect (2 to 3 logs reduction) on viral load compared to AZT alone (about 1 log reduction)(Perelson, A. S., et al., 1996,
Science
15:1582-1586; Ho, D. D., 1997,
Clin. Invest.
99:2565-2567; Ho, D. D., 1998,
Science
280:1866-1867; Ho, D. D., 1996,
Science.
272:1124-1125). Individuals who respond to HAART display a dramatic drop in their plasma viral loads, to the point where they drop below the level of detection (Perelson, A. S., et al., 1996,
Science
15:1582-1586; Ho, D. D., 1997,
Clin. Invest.
99:2565-2567; Ho, D. D., 1998,
Science
280:1866-1867; Ho, D. D., 1996,
Science.
272:1124-1125.
Originally, there was a belief that continued HAART treatment for a period of about two years after the point at which the plasma viremia becomes undetectable, might result in a complete cure (Perelson, A. S., et al., 1996,
Science
Ho, D. D., 1996,
Science.
272:1124-1125). This belief was based on a mathematical model that extrapolated the rate of viral decline using viral half-life input values that were determined empirically (Perelson, A. S., et al., 1996,
Science
15:1582-1586; Ho, D. D., 1998,
Science
280:1866-1867; Ho, D. D., 1996,
Science.
272:1124-1125). However, this model assumed that there was no latent HIV-1 reservoir and that all infected cells carried actively replicating virus (Perelson, A. S., et al., 1996,
Science
15:1582-1586; Ho, D. D., 1997,
Clin. Invest.
99:2565-2567; Ho, D. D., 1998,
Science
280:1866-1867; Ho, D. D., 1996,
Science.
272:1124-1125).
A compilation of evidence now suggests that this is not the case and that there are significant numbers of circulating T cells that carry latent HIV-1 infections (Chun et al., 1998,
Proc. Natl. Acad. Sci.
95: 8869-8873; Chun et al., 1997.
Proc. Natl. Acad. Sci.
94: 13193-13197; Coen, D. M., 1998,
Trends in Microbiol.
6: 129-130; Finzi et al., 1997,
Science,
278: 1295-1300; Ho, D. D. 1998,
Science,
280: 1866-1867; Stevenson, M. 1997,
AIDS
11:S25-S33). In addition, cells that remain resident in the peripheral compartment have been detected that carry latent HIV-1 infections (Ho, D. D. 1998,
Science.
280:1866-1867). Currently, these latently infected cells appear to be refractory to HAART and are a major hurdle preventing eradication of progressive HIV-1 infections (Chun et al., 1998,
Proc. Natl. Acad. Sci.
95: 8869-8873; Chun et al., 1997.
Proc. Natl. Acad. Sci.
94: 13193-13197; Coen, D. M., 1998,
Trends in Microbiol.
6: 129-130; Finzi et al., 1997,
Science,
278: 1295-1300; Ho, D. D. 1998,
Science,
280: 1866-1867; Stevenson, M. 1997,
AIDS
11:S25-S33)(Chun et al., 1998,
Proc. Natl. Acad. Sci.
95: 8869-8873; Chun et al., 1997.
Proc. Natl. Acad. Sci.
94: 13193-13197; Coen, D. M., 1998,
Trends in Microbiol.
6: 129-130; Finzi et al., 1997,
Science,
278: 1295-1300; Ho, D. D. 1998,
Science,
280: 1866-1867; Stevenson, M. 1997,
AIDS
11: S25-S33).
In addition to the problem of latently infected cells, it is likely t
Crowley Richard
Hone David M.
Lewis George
Fuierer Marianne
Hultquist Steven J.
Parkin Jeffrey S.
Scheiner Laurie
University of Maryland Biotechnology Institute
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