Antisense IL-4 inhibits viral replication in the liver, lungs, spleen, and even the lymph nodes; can be used in combination with other antiretroviral agents or vaccines
Inventors
Narayan, Opendra • Buch, Shilpa
Assignees
University of Kansas Medical Center
Publication Number
US-7585675-B2
Publication Date
2009-09-08
Expiration Date
2025-11-15
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Abstract
A method of treating or preventing SHIV or HIV infection in a subject comprising administering a therapeutically effective amount of a antisense IL-4. The antisense IL-4 inhibits viral replication in the liver, lungs, spleen, and even the lymph nodes of the subject. Further, the antisense IL-4 can be used in combination with other antiretroviral agents or vaccines.
Core Innovation
The invention provides a method for treating or preventing HIV or SHIV infection by administering a therapeutically effective amount of antisense (AS) nucleic acids targeting interleukin-4 (IL-4). The antisense IL-4 inhibits viral replication specifically in cells such as T cells or macrophages, which are located in tissues like the liver, lungs, spleen, and lymph nodes of the subject, including both macaques and humans. The AS IL-4 comprises nucleic acid molecules with at least 50%, and preferably up to 100%, complementarity to the IL-4 target sequence.
The background of the invention identifies the problem of HIV infection leading to immune incompetence, opportunistic infections, and death, with HIV replicating in CD4+ T cells and macrophages. Previous research demonstrated that IL-4 enhances viral replication, while the use of IL-4 antagonists, such as antisense nucleic acids, was only theorized and not substantiated by in vitro or in vivo studies prior to this invention. The present invention solves this problem by using AS IL-4 to inhibit viral replication, as shown by successful results both in cell culture and in animal models.
Administration of AS IL-4 can occur via various routes, including subcutaneous, intramuscular, intranasal, intraarterial, intravenous, topical, transvaginal, transdermal, or transanal methods, with liposome encapsulation preferred for delivery to target tissues. The invention further encompasses the use of AS IL-4 in combination with other therapeutic agents, such as antiretroviral drugs, antibacterial, antifungal, anti-protozoal agents, and DNA vaccines. Pharmaceutical compositions containing AS IL-4 and suitable carriers or adjuvants are also covered, highlighting potential for broadened clinical application.
Claims Coverage
There are two independent claims in this patent, each introducing a separate inventive feature regarding inhibiting or treating SHIV or HIV replication with antisense IL-4 and a specific DNA construct.
Method of inhibiting SHIV or HIV viral replication using antisense IL-4 and a non-pathogenic DNA construct
This inventive feature comprises administering to an infected cell: - An antisense IL-4 nucleic acid; - A DNA construct having a sequence encoding at least one viral protein capable of stimulating an immune response against HIV, with one or more non-functional genes that render the DNA construct non-pathogenic; and observing decreased SHIV or HIV viral replication. The host cell can be a macrophage or cells from liver, spleen, or lymph nodes, and administration may include a pharmaceutically acceptable carrier.
Method of treating or inhibiting SHIV replication in a non-human subject with antisense IL-4 and a non-pathogenic DNA construct
This inventive feature involves administering, to a non-human subject having or at risk of contracting a SHIV infection: - A therapeutically effective amount of an antisense IL-4 nucleic acid; - A DNA construct encoding at least one viral protein to stimulate an anti-HIV immune response, with non-functional genes making the construct non-pathogenic. The subject can be a macaque or mouse, administration may be via various routes (e.g., subcutaneous, intravenous, etc.), and formulations may include encapsulation in liposomes or a pharmaceutically acceptable carrier.
The claims center on the use of antisense IL-4 molecules combined with a non-pathogenic viral DNA construct to inhibit or treat SHIV or HIV infection, specifying the use in both infected cells and non-human mammalian subjects, with multiple administration and carrier options.
Stated Advantages
Antisense IL-4 successfully inhibits replication of pathogenic SHIV in cultures of CD4+ T cells and macrophages, and in vivo in macaques.
Treated animals exhibit reduced viral RNA and antigen concentrations in organs such as the liver, lungs, spleen, and lymph nodes compared to untreated controls.
Use of antisense IL-4 results in increased numbers and activation of CD8+ T cells, with improved preservation of lymph node architecture and enhanced cell-mediated immune responses.
The therapy targets host factors involved in viral replication, potentially reducing efficacy issues related to high mutation rates and genetic variation in the HIV genome.
Administration of AS IL-4 offers the potential for adjunct therapy in combination with vaccines or various antiretroviral and anti-infective agents.
Documented Applications
Treatment or prevention of SHIV or HIV infection in subjects such as macaques or humans by administration of antisense IL-4.
Inhibition of viral replication in the liver, lungs, spleen, and lymph nodes of infected hosts.
Use in combination with other therapeutic agents, including antiretroviral drugs, DNA vaccines, antibacterial, antifungal, anti-protozoal, and antiviral agents for treating or preventing opportunistic infections.
Incorporation of antisense IL-4 into DNA immunogenic compositions or vaccines for enhanced immune response modulation.
Potential adjunct therapy to target specific organ symptoms caused by virus replication in tissue macrophages, including organs like the brain.
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