Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving virus or bacteriophage
Reexamination Certificate
2000-08-10
2003-12-23
Stucker, Jeffrey (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving virus or bacteriophage
C435S007100, C435S325000, C435S372000, C435S374000, C424S188100
Reexamination Certificate
active
06667151
ABSTRACT:
FIELD OF INVENTION
This invention relates generally to vaccines and immunotherapeutics used to treat and prevent diseases caused by lentiviruses and methods for producing and using same. Specifically, this invention relates to vaccines and immunotherapeutics used to treat and prevent diseases caused by the Human Immunodeficiency Virus (HIV) and methods for producing and using same. More specifically, the present invention relates to vaccines and immunotherapeutics derived from HIV's trans-activation of transcription (Tat) proteins. In addition, related methods for assessing the immunosuppressive activity of Tat are disclosed.
BACKGROUND OF THE INVENTION
Human Immunodeficiency Virus (HIV) disease has killed over 12 million people world wide since it was first recognized in 1981. Today, it is estimated that over 31 million people are infected with HIV and nearly 16,000 new infections occur daily. The Untied Nations HIV/AIDS surveillance committee estimates that over 40 million people will be infected by the year 2000, the majority of these new infections will occur in developing countries. HIV disease, which includes acquired immune deficiency syndrome (AIDS), is caused by a virus belonging to the group Retroviridae (retroviruses). Specifically, HIV is a lentivirus which is a genus of the Retroviridae.
Many developing countries are confronted with health care issues such as malaria and tuberculosis (TB) which combine to kill more people annually than HIV. The World Health Organization can provide effective therapies against TB for 36 US dollars per person, and malaria can be treated for as little as $1.00 a month. However, even these seemingly insignificant amounts can cause severe economic hardship for individuals and families in developing countries. When the costs of these treatments are compared to the $12,000/individual/year cost associated with new combination drug therapies referred to as HAART (highly active anti-retroviral therapy), it becomes evident that HAART is an economic impossibility in developing countries where effective anti-retroviral therapy is needed most.
Combination drug therapy for HIV began to replace monotherapy (single drug treatments) in early 1996, and by 1999, the Food and Drug Administration (FDA) had approved 11 drugs which could be used in various HAART protocols. These eleven drugs are broken down into three classes which include nucleoside reverse-transcriptase inhibitors (NRTI) divided into two sub-groups A and B, non-nucleoside reverse-transcriptase inhibitors (NNRTI) and protease inhibitors (PI). Current recommendations for combination drug therapy include two NRTIs (one A and one B) combined with either a PI or an NNRTI. This combination drug therapy has proven to be highly effective in significantly reducing viral load (the amount of HIV present in the blood or tissues of an infected person) and preventing the onset of severe immune deficiency in many compliant patients (patients who take their medications exactly as directed). However, there are significant drawbacks associated with combination drug therapy.
For many patients the toxic side effects diminish their quality of life to such an extent that they simply stop taking their medications. For others, the therapeutic schedules are so complicated and inconvenient that they find compliance nearly impossible to fit into a normal lifestyle. Still, many infected persons do not benefit from combination drug therapy due to virus strain variation and other unknown factors. Other patients experience excellent results initially, but due to mutations in the virus, they suffer viral load relapses in spite of full compliance with the therapeutic regime. Many of these patients can be treated with other drug combinations that knock the viral load back down, but the risk of mutation, repeated drug failure, and the onset of new drug side effects are persistent fears. In total, the side effects, psychological burden, cost and uncertainty of efficacy continue to take a steep toll on patients currently undergoing combination drug therapy, rendering the best available option for treating this deadly virus worse than the disease for many people.
Another significant limitation of combination drug therapy is that these treatment regimes do not completely eliminate the virus from the body. Due to the complex nature of our immune system and human retrovirus genetics, HIV is able to sequester itself inside dormant immune cells where it remains unaffected by the drugs. Consequently, if the patient stops taking the medications, a rapid resurgence in HIV viral load occurs, requiring the patent to take anti-retroviral drugs for life. Moreover, studies have demonstrated that seropositive (HIV infected) compliant patients who have undetectable virus in their body are still capable of transmitting the virus sexually or through contact with their blood. Ultimately, the best defense against any disease is prevention, and presently the best prophylaxis against the threats of infectious agents is vaccination.
Medical researchers have been seeking an effective HIV vaccine since the virus was first discovered in 1983. Previous vaccine efforts have included inactivated whole virus, structurally modified, inactivated whole virus, viral sub-unit vaccines including gag (group associated, or core antigens), pol (viral polymerases), and env (viral envelope antigens). In the latter group, both native and recombinant proteins have been investigated. Various vaccination techniques, including frequency of administration, routes of administration and adjuvant mixtures (inert ingredients mixed with the viral antigens to help stimulate the host response), have been tried. Many of these vaccine approaches have elicited detectable immune response in animals including humans, and a few have afforded the animal with limited protection against infection after being challenged with live virus. However, a safe and effective HIV prophylactic suitable for widespread human use remains elusive. Therefore, there is a pressing need for a cost effective, non-toxic, highly active treatment for HIV infected individuals, and even more importantly, for an effective prophylactic vaccine.
Recently, significant advances have been made in understanding the HIV disease process. For many years, researchers have been unable to explain the seemingly immediate and profound destruction of the immune system following the initial HIV infection. Equally puzzling was a phenomenon seen in a few patients referred to as long term non-progessors (LTNP). In LTNP patients, viral loads are high and the virus can be isolated easily from the HIV target immune cells such as CD4+ T lymphocytes (referred to herein as T4 cells). However, unlike the majority of infected individuals who develop AIDS, the LTNP do not demonstrate significant reduction in their T4 cells and do not progress to AIDS.
One possible, non-binding, theory that may explain these two phenomena involves a non-structural protein (a protein encoded by the virus genome that is not actually part of the virus itself) called trans-activator of transcription, or Tat for short. Tat is a variable RNA binding peptide of 86 to 110 amino acids in length that is encoded on two separate exons of the HIV genome. Tat is highly conserved among all human lentiviruses and is essential for viral replication. When lentivirus Tat binds to the TAR (trans-activation responsive) RNA region, transcription (conversion of viral RNA to DNA then to messenger RNA) levels increase significantly. The Tat protein associated with lentivirus virulence will be referred to hereinafter at C-Tat, or “conventional Tat.” Recently, it has been demonstrated that C-Tat increases viral RNA transcription and it has been proposed that C-Tat may initiate apoptosis (programmed cell death) in T4 cells and macrophages (a key part of the body's immune surveillance system for HIV infection) and possibly stimulates the over production of alpha interferon (&agr;INF is a well established immunosuppressive cytokine). These, and other properties of lent
Cullman Louis C.
InIst, Inc.
Stucker Jeffrey
LandOfFree
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