Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-02-26
2004-10-05
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S045000, C514S046000, C514S047000, C514S048000, C514S049000, C514S050000, C514S051000
Reexamination Certificate
active
06800616
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to methods of treating HIV and AIDS.
2. Description of Related Art
Current therapies for Human Immunodeficiency Virus (HIV) infections are typically built around highly active antiretroviral therapy (HAART). HAART therapies are often combinations or “cocktails” of two or more antiretroviral agents. R. M. Gulick, “Current antiretroviral therapy: an overview”,
Qual. Life Res.
6(6):471-474 (1997); K. Henry et al., “Antiretroviral therapy for HIV infection. Heartening Successes mixed with continuing challenges”,
Postgrad. Med.
102(4):100-107 (1997); C. B. Hicks, “Update on antiretroviral therapy”,
Radiol. Clin. North Am.
35(5):995-1005 (1997); R. H. Goldschmidt, “Antiretroviral drug treatment for HIV/AIDS”,
Am. Fam. Physician,
54(2):574-580 (1996). Drugs used in HAART regimens include the nuceloside analogs AZT, stavudine (d4T), and 3TC; nevirapine (a non-nucleoside reverse transcriptase inhibitor, which may be abbreviated NVP), and protease inhibitors such as RTV, SQV, IDV, and nelfinavir. HAART using these treatments may reduce plasma loads of active HIV virus in HIV-1-positive patients to undetectable amounts, apparently without the threat of developing resistant strains of HIV. M. Balter, “HIV Survives Drug Onslaught by Hiding Out in T Cells,”
Science
278:1227 (Nov. 14, 1997). This document, and all documents cited to herein, are incorporated by reference as if fully reproduced below.
The hope was that if active HIV replication was suppressed through HAART for a sufficiently long period, say three years or so, the virus would be completely removed. However, it appears that reducing the plasma concentration of active HIV is not sufficient to eradicate HIV infection completely.
In three studies, memory CD4+ cells were isolated from patients undergoing HAART, most of whom had undetectable plasma HIV-1. Memory CD4+ T cells are CD4+CD8− T lymphocytes that are “resting” or quiescent. These memory cells are generally non-proliferating, and are capable of being activated in case of a subsequent exposure to an antigen. In this way, they form part of the acquired immune response. Further information describing memory T cells can be found in a standard immunology textbook, such as E. Benjamin, et al., “Immunology: A Short Course,” (1996) (Wiley-Liss). Previous investigators had detected integrated viral DNA in memory T cells, but believed it to be defective. The investigators in the three studies found that once the memory T cells were activated, replication-competent HIV-1 was produced in most cases.
In the first study, replication competent virus was routinely recovered from memory CD4+ T lymphocytes of 22 patients who had been treated successfully with HAART for up to 30 months. The frequency of latently infected cells was low, but these frequencies did not decrease with increasing time on therapy, indicating long-term survival of latently infected cells. D. Finzi, et al., “Identification of a Reservoir for HIV-1 in Patients on Highly Active Antiretroviral Therapy”,
Science
278:1295 (Nov. 14, 1997).
In the second study, investigators found that highly purified memory CD4+ T cells from patients receiving HAART for an average of ten months were capable of producing infectious virus upon cellular activation in vitro. They also found unintegrated HIV-1 DNA in the memory T cells, which they suggest shows persistent active virus replication in vivo. T-W Chun et al., “Presence of an Inducible HIV-1 Latent Reservoir During Highly Active Antiretroviral Therapy”,
Proc. Natl. Acad. Sci.
94:13193-97 (1997).
In the third study, researchers took blood cells from HIV-positive patients undergoing HAART for up to two years and cultured them together with blood cells from HIV-negative donors, along with reagents that trigger memory T cells to become immunologically activated. The researchers observed virus from latently infected memory cells quickly infecting and replicating in the HIV-negative cells, even though the original level of infection of the HIV-positive cells was very low. J. Wong et al., “Recovery of Replication-Competent HIV Despite Prolonged Suppression of Plasma Viremia”,
Science
278:1291 (1997).
These results imply that the reservoirs of integrated and unintegrated HIV existing in memory T cells can potentially reestablish active HIV infection and AIDS. These results agree with earlier findings that removing patients from HAART may reestablish active HIV infection and AIDS.
However, conventional HAART does not reach these memory T cells. The drugs that make up HAART's are focused on actively replicating HIV in proliferating T cells and other proliferating immune system cells, such as macrophages. The drugs function by inhibiting virus replication and infection, and by inhibiting or killing infected proliferating cells. Accordingly, it does not seem likely that continued administration of HAART will reach the memory T cell HIV reservoir to eradicate the integrated and unintegrated virus contained within it.
There is therefore a need for methods, kits, and compositions that can address the existence of the HIV reservoir in memory T cells.
SUMMARY OF THE INVENTION
In one aspect, the invention relates to a method of treating an HIV-infected host comprising administering to the host a therapeutic agent that is cytotoxic or cytostatic with respect to CD4+ T cells, but has reduced cytotoxic or cytostatic activity with respect to T lymphocyte stem cells, in a CD4+ T cell cytotoxic or cytostatic effective amount.
In another aspect, the invention relates to a method of treating an HIV-infected host comprising administering highly active antiretroviral therapy; and coadministering to the host a therapeutic agent that is cytotoxic or cytostatic with respect to CD4+ T cells, but has reduced cytotoxic or cytostatic activity with respect to T lymphocyte stem cells, in a CD4+ T cell cytotoxic or cytostatic effective amount.
In yet another aspect, the invention relates to a kit comprising a therapeutic agent that is cytotoxic or cytostatic with respect to CD4+ T cells, but has reduced cytotoxic or cytostatic activity with respect to T lymphocyte stem cells, wherein the therapeutic agent is present in a CD4+ T cell cytotoxic or cytostatic effective amount.
In a further aspect, the invention relates to a composition comprising a therapeutic agent that is cytotoxic or cytostatic with respect to CD4+ T cells, but has reduced cytotoxic or cytostatic activity with respect to T lymphocyte stem cells, wherein the therapeutic agent is present in a CD4+ T cell cytotoxic or cytostatic effective amount.
In still another aspect, the invention relates to a method of ex vivo or in vitro treatment of blood derived cells, bone marrow transplants, or other organ transplants comprising treating the blood derived cells, bone marrow transplants, or other organ transplants with a therapeutic agent that is cytotoxic or cytostatic with respect to CD4+ T cells, but has reduced cytotoxic or cytostatic activity with respect to T lymphocyte stem cells, in a CD4+ T cell cytotoxic or cytostatic effective amount.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the invention relates to a method of treating an HIV-infected host comprising: administering to the host a therapeutic agent that is cytotoxic or cytostatic with respect to CD4+ T cells, but has reduced cytotoxic or cytostatic activity with respect to T lymphocyte stem cells, in a CD4+ T cell cytotoxic or cytostatic effective amount.
In another aspect, the invention relates to the above method, where the therapeutic agent comprises a nucleoside analog, or a CD4+ T cell specific antibody alone or coupled or conjugated to a moiety that is cytotoxic or cytostatic with respect to CD4+ T cells.
In one aspect, the invention relates to the above method, wherein the nucleoside analog comprises purine and pyrimidine and their analogs thereof. In a further aspect, the invention relates
SuperGen, Inc.
Wilson James O.
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