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Principal Investigator: Jose Maria Martinez-Navio
Organization: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
Fiscal Year: 2023
Award: $785,297
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
The poor immunogenicity of the HIV envelope spike and its vast variability represent major obstacles for efficient
elicitation of protective anti-HIV antibodies. One promising strategy is to bypass the immune system and deliver
already known and well-characterized potent and broadly neutralizing antibodies directly to the host. However,
periodic administrations of large amounts of protein would be required for long-term effects. Recombinant adeno-
associated virus (AAV) vectors have been widely used for gene delivery applications because of their safety and
cost-efficiency: one single injection can account for long term expression of the transgene. The use of AAV
vectors would bypass the need for periodic administrations of antibody and, as long as the delivered protein is
viewed as self, it can result in continuous durable expression. Studies in monkeys and in mice have already
shown the extreme promise of AAV for this antibody delivery approach against HIV, and pioneer human trials
have demonstrated its safety and feasibility. However, only antibodies in IgG form (monomeric immunoglobulin)
have been employed in such AAV-antibody delivery applications, while polymeric immunoglobulins (such as
dimeric IgA and pentameric IgM) have been overlooked, despite their desirable characteristics for mucosal
protection. In addition, little is known about what proportion of circulating AAV-delivered antibody gets transferred
to relevant viral entry points such as the rectal or vaginal mucosae and how that correlates with the level of
protection against mucosal exposure that can be achieved. Building up on our previous monkey trials, what we
propose here is to evaluate AAV-mediated delivery of a potent and broadly neutralizing antibody as different
immunoglobulin types and assess the degree of protection that can be achieved to mucosal viral challenge by
each type (Aim 1). We will use the highly relevant macaque model and quantitate in vivo AAV-produced antibody
in circulation and in the relevant mucosae. Our goal is to find what immunoglobulin type shows optimal transfer
of the AAV-delivered antibody to the viral point of entry in mucosae and/or optimal protection against challenge.
Because HIV is mainly transmitted sexually, our findings will be highly relevant in the fight against HIV
transmission. Our overall goal is to inform and guide development of the AAV-antibody concept for its use in
people.
Terms: <19S Gamma Globulin><7S Gamma Globulin><AAV vector><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adeno-Associated Viruses><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Binding Sites><Avidity><Binding Sites><Bioavailability><Biological Availability><Blood Serum><Bypass><Characteristics><Circulation><Clinical Treatment Moab><Clinical Trials><Combining Site><Cost efficiency><Dependoparvovirus><Dependovirus><Development><Dose><Environment><Future><Gene Delivery><Genetic Alteration><Genetic Change><Genetic defect><Goals><HIV><HIV Antibodies><HIV Infections><HIV envelope><HIV envelope protein><HIV-Associated Antibodies><HTLV-III Antibodies><HTLV-III Infections><HTLV-III-LAV Antibodies><HTLV-III-LAV Infections><Half-Life><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Antibodies><Human T-Lymphotropic Virus Type III Infections><IgA><IgG><IgG1><IgM><Immune Globulins><Immune system><Immunoglobulin A><Immunoglobulin G><Immunoglobulin M><Immunoglobulins><Injections><LAV Antibodies><LAV-HTLV-III><Location><Long-Term Effects><Longterm Effects><Lymphadenopathy-Associated Antibodies><Lymphadenopathy-Associated Virus><Macaca><Macaque><Mammalia><Mammals><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Monkeys><Monoclonal Antibodies><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Mutation><Paratopes><Pathogenicity><Periodicals><Peripheral><Persons><Physiologic Availability><Poly-Ig Receptor><Polyimmunoglobulin Receptor><Polymeric Ig Receptor><Polymeric Immunoglobulin Receptors><Polymers><Property><Prophylactic treatment><Prophylaxis><Proteins><Reactive Site><Recombinant adeno-associated virus><Recombinant adeno-associated virus (rAAV)><Rectum><Route><SHIV><SIV><Safety><Secretory Component><Secretory Piece><Serum><Sexual Transmission><Simian Immunodeficiency Viruses><Spinal Column><Spine><Sterility><Surface><Transmission><Transport Piece><Vertebral column><Viral><Virus-HIV><adeno associated virus group><adeno-associated viral vector><adeno-associated virus vector><antibody combining site><antigen binding><antigen bound><backbone><contagion><delivery vector><delivery vehicle><developmental><dimer><experiment><experimental research><experimental study><experiments><fighting><genome mutation><immunogenicity><in vivo><mAbs><model of animal><monoclonal Abs><monomer><neutralizing antibody><periodic><periodical><polymer><polymeric><prophylactic><rAAV><recombinant AAV><rectal><safety and feasibility><sexually transmitted><simian HIV><simian human immunodeficiency virus><sterile><transgene expression><transmission process><vaginal mucosa>