HIV-1 Peptides, Nucleic Acids, and Compositions and Uses Thereof

Abstract

This invention features polypeptides, variants thereof, and fragments thereof useful in eliciting an immune response (e.g., neutralizing antibodies) against abroad spectrum of HIV-I isolates. The polypeptides, variants, and fragments include a portion of the gp120 V2 domain of HIV-I. The polypeptides, variants, and fragments display an epitope that is recognized by at least one antibody which neutralizes at least one HIV-I primary isolate. This invention also features nucleic acid sequences encoding those polypeptides. In addition, the invention provides methods of screening for inhibitors of HIV-I entry into cells, as well as methods of treatment using the inhibitors.

Description

CLAIM OF PRIORITY[0001]This application claims benefit of U.S. Provisional Patent Application No. 60 / 830,044, filed Jul. 10, 2006, incorporated herein by reference.STATEMENT AS TO FEDERALLY FUNDED RESEARCH[0002]Funds used to support some of the studies disclosed herein were provided by grant numbers AI46283 and AI50452, awarded by the U.S. Public Health Service. Therefore, the U.S. Government may have certain rights to the invention.TECHNICAL FIELD[0003]This invention relates to Human Immunodeficiency virus 1 (HIV-1) polypeptides and, in particular, HIV-1 polypeptides useful in eliciting cross-neutralizing antibodies.BACKGROUND OF THE INVENTION[0004]Despite much progress in recent years towards the characterization of functional regions of HIV-1 Envelope protein (Env) and in defining major neutralizing epitopes, progress towards an HIV-1 vaccine capable of inducing a protective humoral response has been limited (Zolla-Pazner et al. (2004) Nat. Rev. Immunol. 4(3):199-210; Burton et a...

AI Technical Summary

Benefits of technology

[0027]Also provided herein is a method of identifying a compound that binds to the V2-CND region of HIV-1 gp120 and neutralizes more than one strain of HIV-1. The method includes the steps of (i) contacting any of the V2-CND polypeptides or fragments thereof described herein with a candidate compound; and (ii) detecting whether binding of the candidate compound and the V2-CND polypeptide has occurred. The detecting step can also include measuring the binding of the candidate compound and the V2-CND polypeptide. Candidate compounds that can bind to a V2-CND polypeptide can include, for example, small molecules, antibodies or antigen-binding fragments thereof, peptides, peptidomimetics, or aptamers. This invention also encompasses a compound identified by the above method to be one that binds to the V2-CND region of HIV-1 gp120.

[0028]Another aspect of the invention is a method of inhibiting infection of a cell by HIV-1. The method includes contacting in vitro a cell and / or an HIV-1 virus with any compound described herein (e.g., a compound that binds to the V2-CND region of HIV-1 gp120, or a compound found to inhibit infection of a cell by an HIV-1 virus). The cell can be a mammalian cell (e.g., a mouse, rat, cat, dog, cow, horse, monkey, or a human cell). The HIV-1 virus can be of any clade, and can be a complete virion or an incomplete virion (e.g., a pseudovirus or an empty viral particle).

[0029]Herein is also provided a method of treating a subject having been, or likely to have been, infected with an HIV-1 virus. The method includes delivering to a subject a composition containing a compound that was determined through any of the above described methods to (a) bind to the V2-CND region of HIV-1 gp120 and to (b) inhibit the infection of a cell by HIV-1. The composition of the method can also be delivered with a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can be a part of the composition or delivered to the subject as a separate composition. The subject can be a mammalian subject, preferably the subject is a human subject (e.g., a human patient).

[0030]The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. All cited patents, patent applications, and references (including references to public sequence database entries) are incorporated by reference in their entireties for all purposes.

[0031]In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Problems solved by technology

Despite much progress in recent years towards the characterization of functional regions of HIV-1 Envelope protein (Env) and in defining major neutralizing epitopes, progress towards an HIV-1 vaccine capable of inducing a protective humoral response has been limited (Zolla-Pazner et al.

The limited number of known neutralization targets that are insensitive to such masking, are poorly immunogenic.

However, these mAbs possess unusual structures, including unusually large CDR3 regions or have autoreactive properties (Haynes et al., (2005) Science 308(5730):1906-1908), and antibodies against these epitopes are rarely produced in immunized or infected individuals.

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