HIV-specific T-cell induction

Details HIV-specific T-cell induction HIV-specific T-cell induction

1999-11-16

2003-12-02

Stucker, Jeffrey (Department: 1648)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Amino acid sequence disclosed in whole or in part; or...

C424S185100, C424S186100, C424S187100, C530S324000, C530S325000, C530S826000

Reexamination Certificate

active

06656471

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of diagnosis and treatment to prevent the onset of AIDS. More particularly, it concerns the use HIV peptides and HLA-restricted T-cell responses in both prediction of long-term non-progression of AIDS and prevention of AIDS.
2. Description of Related Art
During progressive human immunodeficiency virus type 1 (HIV-1) infection, the virus-specific immune responses of an infected subject gradually deteriorate, leading to the development of acquired immunodeficiency syndrome (AIDS). Most infected patients do not exhibit overt clinical manifestations of the disease for six to ten years following initial infection. Reports indicate, however, that approximately 5% of HIV-1 infected persons remain free of disease for ten or more years. (Haynes, 1996; Munoz, 1995; Rinaldo, 1995; Rowland-Jones, 1995; Rowland-Jones, 1993; Clerici, 1991; Lifson, 1991). Such a person, termed a long-term non-progressor (LTNP), exhibits lower viral loads and stable CD4
+
cell counts.
The induction of a cytotoxic T-lymphocyte (CTL) response constitutes a significant defense mechanism against viral infections; occasionally, a virus-specific CTL response can render full protection without a concomitant antibody response (Sastry 1992; Bevan, 1989; Lukacher, 1984). Recent studies suggest the importance of cell-mediated immunity (CMI) for maintenance of disease-free status in an LTNP and in individuals belonging to high-risk groups (Rosenberg, 1997; Haynes, 1996; Munoz, 1995; Rinaldo, 1995; Roos, 1995; Rowland-Jones, 1995; Koup, 1994; Pantaleo, 1994; Rowland-Jones, 1993; Picard, 1992; Clerici, 1991; Lifson, 1991). Importantly, a small number of apparently uninfected children born to HIV-infected mothers and HIV-exposed but uninfected Gambian women have demonstrated HIV-specific cytotoxic T lymphocyte (CTL) responses (Rowland-Jones, 1995; Rowland-Jones, 1993). Also, Rinaldo et al reported that both high levels of anti-HIV-1 memory CTL activity and low viral loads are associated with the lack of disease in HIV-1-infected LTNPs.
The immune system may effectively eliminate virus-infected cells during the clinical course of HIV-1 infection using virus-specific major histocompatibility complex (MHC) class-I restricted CTL activity (Koup, 1994). The above evidence suggests that HIV-1-specific CTL activity is important for controlling viral spread during the clinical course of HIV-1 infection (Klein, 1995; Koup, 1994), for maintaining low levels of viral load during the asymptomatic phase (Musey, 1997; Rinaldo, 1995; Koup, 1994; Walker, 1987), and possibly for complete elimination of virus-infected cells, as implied from the observation of HIV-exposed, but virus-negative, children and women (Rowland-Jones, 1995; Rowland-Jones, 1993). Furthermore, observations from cross-sectional studies have shown the absence, or severely decreased levels, of HIV-1-specific CTL responses during advanced stages of HIV-1 infection (Carmichael, 1993). Therefore, researchers have focused on identifying virus-specific CTL epitopes.
The induction of specific CTL responses in the context of human MHC class I antigens has been demonstrated by many investigators with respect to HLA-A and HLA-B. HLA-A and -B act as strong transplantation antigens and as restriction molecules for recognition of foreign antigens by CTLs (Dill, 1988; McMichael, 1977). In contrast, little is known about the functional properties of the third class I antigen, HLA-C. HLA-C antigens are encoded by a DNA sequence that is closely related to the sequences encoding HLA-A and -B and lies between them. HLA-C antigens are expressed on lymphoid cells, although to a lesser extent (approximately 10%) than either HLA-A or -B (Schendel, 1992; Gasson, 1987; Sodoyer, 1984).
Recent reports suggest that expression of HLA-C confers protection against lysis by natural killer (NK) cells and also by non-MHC-restricted effector T cells (Falk, 1995; Falk, 1993). In particular, expression of Cw7 was demonstrated to govern directly resistance to lysis against both these types of effector populations (Falk, 1995).
Typically, induction of virus-specific CTLs can be effected by infection with a virus or recombinant virus that expresses a viral gene product. The viral gene product is processed and presented as a peptide on the surface of infected cells in association with an MHC class I molecule for recognition by the CTL (Unanue, 1989; Branciale, 1987).
Additionally, research efforts have concentrated on identifying and characterizing HIV peptides that elicit a viral-specific CTL response. Townsend et al. illustrated the concept of using T-cell epitopes in proteins as vaccine candidates when their group demonstrated the use of short synthetic peptides from influenza nucleoprotein as epitopes for CTL responses. The inventors and others have reported using synthetic peptides to generate virus-specific CTLs in vivo (Kast, 1991; Aichele, 1990; Deres, 1989; Sastry, 1992; Sastry, 1994; Casement, 1995) against influenza, lymphocytic choriomenengitis, Sendai virus and HIV. HIV-infected patients or humans and mice immunized with HIV proteins exhibit a specific CTL response against various HIV gene products (Chenciner, 1989; Tsubota, 1989; Nixon, 1988; Walker, 1988; Plata, 1987; Walker, 1987).
The identification and characterization of additional HIV-specific HLA haplotypes and HIV peptides capable of inducing a specific CTL response would be useful for the diagnosis and treatment of AIDS, particularly if the haplotypes were related to the disease-free status of LTNPs and to peptides from highly conserved HIV sequences.
SUMMARY OF THE INVENTION
The invention generally relates to diagnostic, preventative, and treatment therapies of AIDS. The present invention provides a method of predicting long-term non-progression in an HIV-infected patient. The invention also provides a method of preventing AIDS in both infected and uninfected subjects. It is based on the observation that an HLA-C-specific CTL response can be demonstrated against some HIV envelope peptides.
The present invention first provides a method for predicting long-term non-progression in an HIV-infected patient by determining whether the patient demonstrates an HLA-Cw7 CTL response against a target cell. In one embodiment, the patient is infected with, or at risk of infection by, HIV-1. Methods of assaying for the existence of an HLA-Cw7-restricted CTL response comprise obtaining cells from a patient and exposing them to target cells that express the HLA-Cw7 haplotype. The invention is understood to include cells obtained from peripheral blood mononuclear cells (PMBC), mucosal lymphocytes, lymph node cells, and spleen cells. In another embodiment, the PMBCs are stimulated with phytohemagglutinin, anti-CD3 antibody, or HIV antigens prior to exposing them to target cells.
An HIV-infected subject may be tested for an HLA-Cw7-restricted CTL response or possession of the HLA-Cw7 haplotype. The CTL response also can include CD4- and CD8-expressing (CD4
+
and CD8
+
) cells. The method for detecting an HLA-Cw7 restricted CTL response uses target cells that include cells from an autologous B cell line, dendritic cells, or MHC-matched cells.
The CTL response can be assayed by lysis of the target cell, which could be labeled using [
51
Cr]sodium chromate, or by production of &ggr;-interferon, or by tetramer assay.
In another embodiment, the method of the present invention provides a target cell that presents at least an HIV polypeptide, which includes the HIV envelope (env) polypeptide or the gag polypeptide, in addition to HIV polypeptide fragments thereof. In a preferred embodiment, the polypeptide is gp160, or fragments thereof. In further embodiments, the invention predicts long-term non-progression of AIDS by using a target cell that presents a synthetic peptide whose amino acid sequence is derived from an HIV gene product such as a synthetic peptide, which can be from 11 to 25 residues in length. In additional embodime

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