Title:  Induction of REV and TAT specific cytotoxic T-cells for prevention and treatment of human immunodeficiency virus (HIV) infection

United States Patent:  6,319,666

Assignee:  Erasmus Universiteit Rotterdam (Rotterdam, NL)

Filed:  June 17, 1999

PCT NO:  PCT/IB97/01402

102(e) Date:  June 17, 1999

PCT PUB. Date:  April 30, 1998

The presence of cytotoxic T-cells to the Rev and/or Tat protein in samples from a subject infected with immunodeficiency virus, particularly HIV in humans, is an indication of a stable disease condition and a favorable prognosis of lack of progression to disease. Immunogenic compositions containing at least one cytotoxic T-cell epitope of the Rev and/or Tat protein of an immunodeficiency virus, particularly HIV, or a vector encoding the T-cell epitope, may be used to prevent infection by disease caused by the immunodeficiency virus, by stimulating, in the host, a specific cytotoxic T-cell response specific for the respective Rev and/or Tat proteins.

SUMMARY OF INVENTION

The present invention is concerned with the diagnosis of the disease condition of a host infected by immunodeficiency virus, particularly humans infected by human immunodeficiency virus and, in particular, to the identification of immunological correlation of AIDS-free survival following HIV infection. Such identification leads to the provision of immunogenic compositions and immunization procedures which can prevent progression to AIDS in seropositive HIV patients.

The inventors have found that the presence of Rev and Tat specific CTL precursors during the asymptomatic stage of infection is correlated with AIDS-free survival, while no such correlation was found for CTL precursors of other HIV proteins, including Gag, RT and Nef, indicating that CTL responses against Rev and/or Tat are important for protection from disease progression.

In one aspect of the present invention, there is provided an immunogenic composition effective for preventing disease caused by infection by an immunodeficiency virus, particularly a human immunodeficiency virus, which comprises at least one T-cell epitope selected from the Rev and Tat proteins of the immunodeficiency virus or a vector encoding the at least one cytotoxic T-cell epitope.

The at least one cytotoxic T-cell epitope may be from the Rev protein, the Tat protein or from both the Rev and Tat proteins. The cytotoxic T-cell epitope may be provided by the Rev and/or Tat protein or a homolog thereof in which amino acids have been deleted, inserted or substituted without essentially detracting from the immunological properties thereof, generally in combination with a pharmaceutically-acceptable carrier therefor.

The at least one cytotoxic T-cell epitope also may be provided by a recombinant vector, such as a recombinant virus vector, such as a recombinant vaccinia or Semliki virus, or a non-replicating vector encoding the at least one cytotoxic T-cell epitope, which encode the Rev and/or Tat protein of HIV or other immunodeficiency virus or a homolog thereof in which amino acids have been deleted, inserted or substituted without essentially detracting from the immunological properties thereof.

The at least one cytotoxic T-cell epitope further may be provided by a synthetic peptide having an amino acid sequence corresponding to the T-cell epitope or a homolog thereof in which amino acids have been deleted, inserted or substituted without essentially detracting from the immunological properties thereof, generally in combination with a pharmaceutical carrier therefor.

The present invention further comprises a method of immunizing a host against disease caused by infection by an immunodeficiency virus, particularly HIV, which comprises stimulating, in the host, a cytotoxic T-cell response which is specific for the Rev and/or Tat proteins of the immunodeficiency virus. The stimulation of the cytotoxic T-cell response may be effected by administering to the host at least one T-cell epitope selected from the Rev and Tat protein of HIV or other immunodeficiency virus or- a vector encoding the at least one T-cell epitope. Such T-cell epitope or vector encoding the same may be provided in any of the manners described above.

In an additional aspect of the present invention, there is provided a method of immunizing a host against disease caused by infection by immunodeficiency virus, specifically human immunodeficiency virus, which comprises selectively stimulating a protective Rev and/or Tat protein-specific cytotoxic T-cell response in the host. The selective stimulation of the protective cytotoxic T-cell response may be achieved by administering to the host at least one T-cell epitope selected from Rev and Tat protein of HIV. The administration of the T-cell epitope may be effected by any of the procedures described above.

The discoveries made by the inventors further lead, in accordance with an additional aspect of the invention, to a method of determining a favourable prognosis in an HIV-positive subject, which comprises detecting in the subject the presence of a cytotoxic T-cell response to the Rev and/or Tat protein of HIV as an indication of the favourable prognosis.

In addition, the present invention provides a method of diagnosing a stable disease condition associated with HIV in a human, which comprises:

obtaining peripheral blood mononuclear cells from the human, and

testing the sample for the presence of a specific cytotoxic T-cell response to Rev and/or Tat proteins as an indication of the stable disease condition.

The present invention extends to at least one cytotoxic T-cell epitope selected from the Rev and Tat proteins of HIV or a vector encoding the at least one cytotoxic T-cell epitope when used as a medicament. The invention further includes the use of at least one cytotoxic T-cell epitope selected from the Rev and Tat proteins of HIV or a vector encoding the at least one cytotoxic T-cell epitope in the manufacture of a medicament, particularly a medicament for immunizing a host against disease caused by HIV by stimulating a specific cytotoxic T-cell response which is specific to the Rev and/or Tat proteins of HIV or by selectively stimulating a protective Rev and/or Tat protein-specific cytotoxic T-cell response in the host. The cytotoxic T-cell epitope may be provided in any of the manners described above.

Claim 1 of 14 Claims

What is claimed is:

1. A method of treatment of a host, which comprises:

stimulating in the host a specific cytotoxic T-cell response which is specific for the Rev and/or Tat proteins of the immunodeficiency virus.

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