Induction of REV and TAT specific cytotoxic T-cells for...

Details Induction of REV and TAT specific cytotoxic T-cells for... Induction of REV and TAT specific cytotoxic T-cells for...

1999-06-17

2001-11-20

Park, Hankyel T. (Department: 1648)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving virus or bacteriophage

C424S208100, C536S023720, C530S388750

Reexamination Certificate

active

06319666

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to the field of immunology and is particularly concerned with methods and compositions for the induction of cytotoxic T-cells to prevent and treat human immunodeficiency virus (HIV) infection and AIDS.
BACKGROUND TO THE INVENTION
It is believed that most people with HIV infection will ultimately develop clinical AIDS. Furthermore, death from the complications of AIDS often occurs within months or years after clinical AIDS is diagnosed. Most HIV-infected individuals remain healthy for many years despite the infection. Likewise, some individuals with past clinical diagnosis continue to live productive lives for many years after first developing clinical AIDS.
Among HIV-1 infected individuals, the duration of the asymptomatic period after seroconversion may differ considerably (refs. 1 to 3—throughout this specification, various references are referred to in parenthesis to more fully describe the state of the art to which this invention pertains. Full bibliographic information for each citation is found at the end of the specification, immediately preceding the claims. The disclosures of these references are hereby incorporated by reference into the present disclosure). Mechanisms suggested to play a role in long-term survival include viral characteristics, as well as host genetic and immunological factors. However, immunological correlates of AIDS-free survival have not been conclusively identified (refs. 1 and 3).
The human immunodeficiency virus type 1 (HIV-1) and related lentiviruses have more complex genomes than typical retroviruses. In addition to the gag, pol and env genes common to all retroviruses, HIV-1 also encodes genes for tat, rev, nef, vif, vpu, and vpr. The HIV-1 protein Rev (regulator of expression of the virion) plays an essential role in the temporal regulation of virus gene expression during a replication cycle. The genes expressed by HIV-1 can be separated into two groups based on whether their expression is Rev-dependent or not. The Rev-independent or early genes encode Tat, Rev, and Nef. The Rev-dependent or late genes are important for virion production and encode the structural proteins Gag, Pol and Env and the accessory products Vif, Vpu and Vpr. Rev is absolutely required for HIV-1 replication. Proviruses that lack Rev function remain transcriptionally active, but fail to generate new viral particles. The biology of the Rev protein is summarized in reference 30.
Cis- and trans-acting elements which regulate HIV gene expression have been identified. An 86 amino acid viral protein, Tat is required for HIV-1 gene expression and for subsequent viral replication. Tat is unique among viral transactivators. Unlike E1A and Tax, which activate a number of viral and cellular genes, Tat activation is relatively specific for HIV-1. A cis-acting element in the HIV-1 LTR, located downstream of the RNA initiation site, is critical for high-level gene expression. This element, which extends from +1 to +60 in the HIV-1 LTR, was designated the trans-acting response element, or TAR. TAR forms a double-stranded RNA structure which is required for high-level gene expression in response to Tat. The function of Tat is described in reference 31.
The present invention is concerned with the role of HIV-1 specific cytotoxic T lymphocytes (CTL) in AIDS-free long-term survival of HIV-1 infected individuals. In previous studies, CTL specific for the structural proteins Gag and RT have been detected in at least 80% of seropositive individuals (refs. 4 to 9), whereas CTL against Nef and Vif have been reported in approximately 50% of seropositive individuals (refs. 10 to 12). These studies have also indicated that the regulatory proteins Rev and Tat are less frequently recognized (refs. 10 to 12). Cross-sectional studies have shown that HIV-1 specific CTL precursors (CTLp) are generally present in the asymptomatic stage, but their frequencies tend to be low in advanced disease (refs. 13, 14). Longitudinal analyses have shown that HIV-1 specific CTL responses are associated with initial control of viremia (ref. 15) and that Gag specific CTLp decline with disease progression, probably as a result of HIV-1 induced CD4
+
cell decline (refs. 16, 17) and cytokine dysfunction (ref. 17). Viral loads have been shown to be predictive of disease progression and can be measured by commercially available tests (refs. 18, 19).
Furthermore, there are no commercially available immunological tests to determine favorable prognosis of a patient infected with HIV.
There is a need for laboratory tests that identify those HIV-infected individuals who are more likely to have a favorable prognosis, slower disease progression, and stable disease compared with those individuals who are likely to have poor prognosis, or more rapid disease progression.
Infection with HIV leads to a serious immunodeficiency disease, AIDS. There is no cure for AIDS nor is there any vaccine against infection and the disease. It would be desirable to provide methods and compositions (including immunogenic compositions, such as vaccines) for the prevention and treatment of AIDS. It would also be desirable to provide test procedures and materials to identify those patients who are likely to have a favourable prognosis and a slower disease progression.
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

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