Killer T cell receptor recognizing human immunodeficiency virus

Details Killer T cell receptor recognizing human immunodeficiency virus Killer T cell receptor recognizing human immunodeficiency virus

2000-03-27

2003-01-28

Park, Hankyel T. (Department: 1648)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing compound containing saccharide radical

C435S005000, C424S208100, C424S160100, C530S350000

Reexamination Certificate

active

06511830

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a polypeptide which is a constituent of a killer T cell receptor capable of specifically injuring human immunodeficiency virus-infected cells; a DNA encoding this polypeptide; a vector containing the DNA; a transformant obtained by transferring the vector into a host cell; a process for producing the polypeptide which is a constituent of a T cell receptor; transgenic animals having the polypeptide expressed therein; antibodies reacting specifically with the polypeptide; and anti-HIV agents containing the polypeptide which is a constituent of the killer T cell receptor.
BACKGROUND ART
Recently, there have been reports on the importance of a CD8 molecule-positive killer T cell involved in the initial phylaxis [Koup, R. A. et al., Nature, 370, 416 (1994)], delay in the development of AIDS [Levy, J. A. et al., Immunol. Today, 17, 217 (1996)] and resistance to the infection [Rowland-Jones, S. et al., Nature Med., 1, 59 (1995)] of human immunodeficiency virus (HIV), and further the HIV suppressive ability of a humoral factor secreted by the killer T cell [Cocchi, F. et al., Science, 270, 1811 (1995); Baier, M. et al., Nature, 378, 563 (1995)] have been reported.
Ho et al., reported that as a result of tracing with the viral loads of HIV-infected individuals and the immune responses induced by the virus with the elapse of time, the virus temporarily increased in vivo after infection but rapidly decreased as CD8
+
killer T cell precursor specific to the virus (cytotoxic T lymphocyte precursor; hereinafter referred to as CTL-p) appeared; and 6 to 8 weeks after that most of the viruses were cleared virus-specific IgG antibodies appeared. Thus the study suggested the importance of the cell-mediated immunity mainly with CD8
+
killer T cells in the initial phylaxis [Nature, 370, 416 (1994)].
Then, several articles reported that the presence of asymptomatic patients whose CD4 T cell counts have not decreased over ten and several years and who have not developed AIDS, and in these patients the cell-mediated immunity, in which CD8 positive T cells and Th1 type helper T cells are mainly involved, is dominant in vivo over the humoral immunity, and CD8 positive T cells secreting MIP-1 &agr;, &bgr; [Science, 270, 1811 (1994)] or IL-16 [Nature, 378, 563 (1995)], capable of suppressing the proliferation of HIV, were identified. Thereafter the importance of the CD8 positive T cells including killer T cells and the cell-mediated immunity in the initial phylaxis and in the protection of the development of AIDS is increasingly noticed [Immunol. Today, 17, 217 (1996)].
The invasion of HIV into cells is, for example on T cells, regulated by fusin on the cell surface [Feng, Y. et al., Science, 272, 872 (1996)], and on macrophages, regulated by chemokine receptors, i.e., CC-CKR-5 [Deng, H. et al., Nature, 381, 661 (1996); Drajic, T. et al., Nature, 381, 667 (1996)]. It was reported that chemokines, i.e., MIP-1 &agr;, &bgr;, or IL-16, binding specifically to a variety of chemokine receptors, inhibit the invasion of HIV into cells [Cocchi, F. et al., Science, 270, 1811 (1995); Bleul, C. C. et al., Nature, 382, 829 (1996)]. It was also reported that HIV-invasive sites are chemokine receptors, i.e., CC-CKR-4 or CC-CKR-5 [Science, 272, 872 (1996); Nature, 381, 661 (1996)] based on the fact that human races congenitally having a deletion in gene CC-CKR-5 escape from being infected with HIV [Nature, 382, 722 (1996); Cell, 86, 367 (1996)]. That is, it has been found that factors, e.g., MIP-1 &agr;, &bgr;, and RANTES released by CD8
+
CTL, block chemokine receptors so as to obstruct the invasion of HIV into cells, thereby suppressing the intracellular increase of HIV.
Moreover, it was shown that a part of the virus that invades via a chemokine receptor into a cell is HIV envelope protein gp160 V3 region [Nature, 384, 179 (1996); Nature, 384, 184 (1996)]. It is said that the HIV envelope protein gp160 V3 region determines the type of a cell, tropism infected with virus. Particularly, in a mouse, Env-K1 (or 18IIIB:RIQRGPGRAFVTIGKP18)[Takahashi, H. et al., Proc. Natl. Acad. Sci. USA, 85, 3105(1988)], the amino acid sequence 315 to 329 in the HIV envelope protein gp160 V3 region derived from HIV IIIB strain is presented on the cell surface together with Class I MHC molecule (D
d
), and recognized by a specific killer T cell receptor [Takahashi, H. et al., J. Exp. Med., 170, 2023 (1989)]. At the same time, Env-K1 is presented on the cell surface together with Class I MHC molecules, HLA-A2, HLA-A3 and the like, which are recognized relatively widely in human, and the in vivo presence of killer T cells recognizing Env-K1 is confirmed in HIV-infected individuals [Clerici, M. et al., J. Immunol., 146, 2214 (1991); Dadaglio, G. et al., 147, 2302 (1991)].
When vaccinia virus recombined with HIV envelope (gp160) gene was inoculated in vivo into a healthy individual, killer T cells recognizing specifically ENV-K1 presented as an antigen by a variety of HLAs were induced, and the killer T cells specifically injured self-cells infected with the gp160 recombinant vaccinia virus [Achour, A. et al, Fifth International Conference on AIDS, p.546 (Abstract) (1989)]. However, killer T cell clones have not been produced.
Further, the V3 region within envelope gp160 including Env-K1 is known to be the recognition site of a neutralization antibody specific to HIV [Palker, T. J. et al., Proc. Natl. Acad. Sci. USA, 85, 1932 (1988); Rusche, J. R. et al., Proc. Natl. Acad. Sci. USA, 85, 3198 (1988); Goudsmit, J. et al., Proc. Natl. Acad. Sci. USA, 85, 4478 (1988)] or the recognition site of a helper T cell [Takahashi, H. et al., J. Exp. Med., 111, 579 (1990); Clerich, M. et al., Nature, 339, 383 (1989); Takeshita, T. et al., J. Immunol., 154, 1973 (1995)].
An anti-V3 antibody has a neutralizing activity against HIV. However, the anti-V3 antibody must be administered in vivo in a large quantity to suppress the proliferation of HIV. On the other hand, since an antibody is a macromolecule, such mass administration is undesirable. Therefore, establishing the killer T cell clone, which specifically recognizes V3, especially Env-K1, and detailed investigations of the molecular structure of the T cell receptor are considered to be useful in developing next generation agents for inhibiting the invasion of the virus by blocking the invasion of HIV.
Accordingly, it has been expected for the analysis of the HIV-specific killer T cell clone and for the development of a transgenic animal as an individual to express the functional receptor gene of such killer T cell to bring information extremely useful in treatment and researches for AIDS. However, so far neither such development nor analysis has not been reported.
It is required that HIV specific killer T cells be used in searching the fate of human immunodeficiency virus, and in developing treatment and pharmaceuticals for AIDS. Further it is also required to investigate how the previous expression of the gene can have an effect on the prevention of the infection, and how shutting the virus in, in which the gene are expressed after infection, can have an effect on the treatment. That is, there is a desire to analyze the CD8 positive killer T cell clone specifically injuring human immunodeficiency virus-infected cells and to develop a transgenic animal expressing the killer T cell receptor.
DISCLOSURE OF THE INVENTION
The present invention relates to (1) to (17) as shown below.
(1) A polypeptide which is a constituent of a killer T cell receptor and is capable of injuring specifically human immunodeficiency virus-infected cells;
(2) The polypeptide according to the above (1) wherein the human immunodeficiency virus is HIV-1;
(3) The polypeptide according to the above (2) wherein the HIV-1 is HIV-1 IIIB;
(4) The polypeptide according to any one

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