Treatment and prevention of immunodeficiency virus infection by administration of non-pyrogenic derivatives of lipid A

Abstract

The present inventors have found that certain preparations containing LPS and / or lipid A variants, derivatives, and / or analogs demonstrate non-pyrogenic properties and exhibit anti-viral activities. In particular, non-pyrogenic preparations of LPS, lipid A, LPS antagonists and lipid A antagonists, and derivatives thereof induce beta chemokine secretion, such as MIP-1beta, but not proinflammatory cytokines, such as TNFalpha, IL-1beta and IL-6. Non-pyrogenic preparations of the invention have been demonstrated by the Applicant to suppress HIV replication in human peripheral blood monocytes, as described by way of example herein. The present invention provides preparations of LPS or lipid A variants, analogs and derivatives of decreased or absent pyrogenicity which can be used as therapeutics for the treatment or prevention of immunodeficiency virus infection and its consequences.

Description

[0001] This application is a divisional of co-pending application Ser. No. 09 / 383,709 filed on Aug. 26, 1999, which claims priority to U.S. patent application Ser. No. 08 / 938,106 filed Sep. 26, 1997, now U.S. Pat. No. 6,368,604.1. FIELD OF THE INVENTION[0002] 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 .beta. chemokines but exhibit decreased induction relative to LPS and lipid A of secretion of proinflammatory cytokines, such as IL-1.beta., IL-6...

AI Technical Summary

Benefits of technology

"The present invention provides non-pyrogenic preparations of LPS and lipid A, which have been found to have anti-viral activities, particularly against HIV. These non-pyrogenic preparations induce the production of certain proteins that inhibit HIV replication, such as MIP-beta, while simultaneously suppressing the production of proinflammatory cytokines like IL-1 beta, IL-6, and TNF-alpha. The invention also includes synthetic lipid A antagonists that have been modified to have reduced pyrogenicity and proinflammatory activity. The invention provides a therapeutic compound for the treatment and prevention of HIV infection, which is a chronic and debilitating disease that currently has no cure. The invention also provides methods for assessing the efficacy of the therapeutic compounds and pharmaceutical compositions for the treatment and prevention of HIV infection."

Problems solved by technology

Further, a large amount of genetic heterogeneity exists within populations of each of these types.

In humans, HIV replication occurs prominently in CD4.sup.+ 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 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.

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.

However, it is likely that long-term use of combinations of these chemicals will lead to toxicity, especially to the bone marrow.

To this end, vaccines directed against HIV proteins are problematic in that the virus mutates rapidly rendering many of these vaccines ineffective.

However, due to the toxicity of this molecule, LPS and lipid A are not viable candidates for the treatment of HIV.

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