A Novel Therapeutic Strategy for HIV Infection
BACKGROUND: Tat is an HIV regulatory protein that is essential for viral replication and HIV disease progression. It critically regulates HIV transcription and allows the generation of full-length transcripts necessary for the formation of virus particles. Tat is also found in the circulation and can enter uninfected cells in an active form. Thus, Tat plays a role in the immune dysregulation and death of infected and uninfected T cells, helping to explain why the number of T cells that die each day during HIV infection exceeds the number of infected cells in the body. The stimulation of anti-Tat antibodies should specifically be useful to neutralize extracellular Tat and prevent its effects on uninfected or infected neighbor cells.
DESCRIPTION: Researchers at the University of California have discovered that Tat can exist in a modified, acetylated form. They further found that acetylated Tat plays a critical role in activating HIV transcription. In addition, unlike the unacetylated version, acetylated Tat is highly immunogenic. Upon microinjection, specific anti-acetylated Tat antibodies, generated in mice or rabbits, completely blocked Tat-mediated HIV transcription, supporting the model that acetylated Tat represents an active and important form of Tat. Similar antibodies could be generated by humans upon vaccination with specific acetylated Tat polypeptides. These antibodies would specifically neutralize active Tat in the circulation which should reduce viral spread and restore the immune function of infected and uninfected T cells in HIV infected individuals.
* HIV Tat protein, which is poorly immunogenic, becomes highly immunogenic when acetylated, thereby providing an effective strategy against HIV infection.
* Tat protein is produced early in HIV infection, such that a reduction in the level and/or activity of Tat protein would block HIV production at an early stage of the HIV life cycle.
* Because inhibition of Tat activity interferes with HIV production at a different stage than currently available methods, this invention could provide a new and potentially additional therapeutic for combating HIV/AIDS.
* Since Tat protein does not exhibit a high degree of amino acid variability, immunogenic compositions are advantageous in that the target virus is less likely to develop viable escape variants.
* Anti-acetylated Tat antibodies are very specific in targeting only the viral protein, without cross-reactivity with cellular proteins.
* The anti-acetylated Tat antibodies may be useful in the treatment of HIV/AIDS.
* Anti-acetylated Tat polypeptides may be useful as a vaccine for the prevention and treatment of HIV/AIDS.
US 7,482,016 [MORE INFO
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