Immunogenic composition and method of developing a vaccine based on factor H binding sites

Abstract

An immunogenic composition able to provide an immune response to Human Complement Factor H binding on one or more HIV glycoproteins is disclosed, which is characterized by at least one binding site epitope of the glycoproteins. Such immunogenic composition wherein the glycoprotein comprises gp120, gp41, or both glycoproteins gp120 and gp41 is hereby disclosed. Sialic acid is removed to enhance immune recognition of the composition and to impair Factor H binding. A medication having an inhibitive action on autoimmune response by specific inhibition of the cleavage of C3b by Factor H into inactive cell fragments.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] The present application claims priority from U.S. Provisional Application Ser. No. 60 / 513,827 filed 10 / 23 / 2003.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] This invention relates to the field of virology and immunology. Particularly, but not exclusively, it relates to a method of inducing an immune response, and a substance based on certain glycoprotein factor H binding sites for achieving the same. [0004] 2. Description of the Related Art [0005] Immunosuppressive diseases are medically challenging because, among other things, they attack the ability of the host to defend against viral invasion. The immune system can be considered as having a non-specific aspect and a specific aspect. The nonspecific aspect includes components, such as macrophages and neutrophils, which simply engulf foreign organisms and kill them without a need for antibodies. The specific aspect involves the production of soluble proteins or an...

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Benefits of technology

[0066] An efficient cellular response in the early stages of HIV infection correlates with a rapid decrease in viremia. (Stoiber H, et al., Ann. Rev. Immunology, Vol. 15, p 649-674 (1997)) This advantageous aspect, however, may be detrimental since HIV infected CD4+ cells may be killed through a conventional, virus-specific CD8 cell-mediate mechanism in which one part of the immune system eliminates the other. Moreover, the cytotoxic T lymphocyte (CTL) response may efficiently eliminate most virus-infected cells and those presenting peptides of viral proteins. (Stoiber, Heribert, et al, Ann. Rev. Immunology, Vol. 15, pages 649-674 (1997)) This will select cells bearing HIV in a latent form that escapes recognition.

[0067] HIV triggers a domino effect by its inactivation of complement cascade. The pivotal immune effect of HIV is its capability to assimilate Factor H into its surface glycoproteins. (Pinter, Claudia, AIDS Research in Human Retroviruses, Vol 11, November 8 (1995)) (Pinter Claudia, et al., AIDS Research and Human Retroviruses, Vol 11, #5, pp 577-588 (1995)) (Stoiber, Heribert, et al., Immunobiology, Vol 193, pp 98-113 (1995)) HIV escapes complement cascade, enhances its own replication, and sequesters itself within the lymph nodes of the human body. This distorts or destroys basic lymph node architecture and function. Additionally, the inactive C3b fragments enhance viral replication.

[0068] Because Factor H is a host or cellular protein, it is not subject to the viral mutation common in HIV. (Ripoche, 1988) (Aslam, 2002) (Kirkitadze, Marina, et al., Immun. Rev., Vol 180, pp 146-151 (2001)) (Feifel, Elisabeth, et al., Immunogenetics, Vol 36, pp 104-109 (1992)) (Discipio, R. G., J. Immunology, Vol 149, Iss 8, pp 2592-2599 (1992)). (Ault, Bettina, et al., Biological Chemistry, Vol 272, #40, pp 25,168-25,175 (1997)) The amino acid sequences that comprise the primary structure of Factor H are constant and immutable. Accordingly, the binding sites for Factor H and related proteins on gp120 and gp41 are also conserved. (Pinter, 1995) If there were mutations at the binding site, then the humoral arm of the immune system would then be able to proceed normally to inactivate the virus. Thus, HIV cannot tolerate mutations at the Factor H binding sites, providing another advantage for use in a subunit vaccine.

[0069] The present invention is a composition and subunit vaccine composed of the Factor H binding epitope of glycoprotein gp120, gp41, or preferably, a combination of gp120 and gp41. The immunogenic composition may include the binding sites for Factor H, FHL-1, and similarly behaving FHR 1-5. Factor H in circulation assumes two separate conformational states or two separate tertiary structures, φ1 and φ2. The composition may include binding sites for both of these conformational states on both of the gp120 and gp41 glycoproteins. By keeping Factor H away from the viral surface, HIV resistance against human complement is weakened, enabling human complement to function.

Problems solved by technology

Immunosuppressive diseases are medically challenging because, among other things, they attack the ability of the host to defend against viral invasion.

If the immune response is suppressed, then the individual becomes susceptible to opportunistic infections.

Some retroviruses that attack the immune system, such as HIV-1, are variable and mutate readily, creating many strains of varying genetic composition that hamper efforts to develop effective treatment.

However, variations in evolutionary rate can produce differences among mutations even within a subtype.

Further, the tendency of retroviruses to recombine with related retroviruses complicate the viral genome.

To date, research has not found a vaccine that would foster an effective immune response against the immunosuppressive retrovirus HIV-1.

Sialic acids are typically found on host proteins and cellular structures; high sialic acid content on a virus, even if the virus is inactivated, would limit the host's ability to recognize the virus and respond properly.

The high rate of mutation of HIV is believed to complicate further the selection of appropriate neutralizing antibodies.

In addition, a substance known as Human Complement Factor H impedes or disrupts the immune response complement cascade.

Any one of the aforementioned can reduce the effectiveness of the complement system.

But to date, there has been no indication of how to implement this growing knowledge of the relationship of HIV and Factor H of the human complement system.

One is the incorporation of sialic acid into its external glycoproteins which interferes with the complement system.

HIV and HIV-infected cells are resistant to the potentially destructive effects of human complement, but are readily destroyed by other animal sera.

Indeed, HIV activates complement in most animal models rendering them unsuitable models for some forms of study.

Because of the central role of C3 in the complement cascade, auto-antibodies against C3 which are detectable in HIV-positive sera, adversely affect complement-mediated immune responses.

This distorts or destroys basic lymph node architecture and function.

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