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Principal Investigator: Michael R. Farzan
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $884,320
Funding agency: National Institute of Allergy and Infectious Diseases
eCD4-Ig is a potent and exceptionally broad fusion of the first two domains of CD4 to an antibody Fc
domain and a short tyrosine-sulfated coreceptor-mimetic peptide. In rhesus macaques, adeno-associated
virus (AAV)-expressed eCD4-Ig mediates consistent and very effective long-term protection against SHIV-
AD8 and SIVmac239. eCD4-Ig also has properties that make it especially useful for establishing a
functional cure in rhesus macaques and perhaps in humans. These include its potency, breadth, difficulty-
of-escape, low immunogenicity when expressed by AAV, consistent expression by AAV, potent intrinsic
ADCC activity, and collaboration with serum antibodies to mediate ADCC. These properties allow eCD4-
Ig to circumvent two major problems associated with using AAV-expressed antibodies to establish
functional cures, namely immune clearance and viral escape.
In the forthcoming award period, we will improve the technologies allowing AAV-mediated delivery of
eCD4-Ig by optimizing its expression as an AAV transgene, by eliminating residual antibody responses to
AAV-delivered eCD4-Ig, and by assessing the role of the eCD4-Ig Fc domain in anti-eCD4-Ig antibody
responses and in control an established SIVmac239 infection. These efforts will develop technologies that
can be applied to the ongoing efforts by many laboratories to prevent new infections, to provide long-
acting alternatives to combined antiretroviral therapies, and to reduce the scale of the viral reservoir.
Terms: <AAV delivered><AAV delivery><AAV vector><AAV-based delivery><AAV-based vector><AAV-based viral delivery><AAV-mediated delivery><Adeno-Associated Viruses><Adeno-associated-virus-based delivery><Adverse Experience><Adverse event><Antibodies><Antibody Response><Antigen-Antibody Complex><Award><Blood Serum><CD16><CD16B><Cell Culture Techniques><Chimera><Chimera organism><Collaborations><Communities><Dependoparvovirus><Dependovirus><Ensure><FCGR3B><FCGR3B gene><Fc Receptor III-1><Fc domain><Fc gamma IIIb receptor><Fc-Gamma RIII-Beta><Fc-Gamma RIIIB><FcRIIIB><Foundations><Funding><Funding Mechanisms><Future><Genetic Alteration><Genetic Change><Genetic defect><Goals><HIV-1><HIV-I><HIV1><Human><Human Immunodeficiency Virus Type 1><Human immunodeficiency virus 1><IgG Fc Receptor IIIB><IgG1><IgG2><Immune Cell Activation><Immune Complex><Immune response><Immunological response><Infection><Laboratories><Low Affinity IgG Fc Receptor IIIB><Low Affinity Immunoglobulin Gamma Fc Region Receptor III-B><M mulatta><M. mulatta><Macaca><Macaca mulatta><Macaque><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Mutation><Patients><Persons><Property><Proteins><Receptor Protein><Residual><Residual state><Rhesus><Rhesus Macaque><Rhesus Monkey><Role><SHIV><SIV><Serum><Simian Immunodeficiency Viruses><System><T cell response><Technology><Therapeutic Uses><Transgenes><Variant><Variation><Viral><Viral reservoir><Virus><Virus Replication><Virus reservoir><Work><adeno associated virus group><adeno-associated viral vector><adeno-associated viral vector delivery><adeno-associated virus delivery><adeno-associated virus mediated delivery><adeno-associated virus vector><adenovirus mediated delivery><antiretroviral therapy><antiretroviral treatment><cell culture><cell cultures><chimeras><collaboratory><cost><delivered with AAV><delivery with AAV><genome mutation><host response><immune activation><immune clearance><immune elimination><immune system response><immunogenicity><immunoresponse><improved><inhibitor><non-human primate><nonhuman primate><peptide mimetic><peptide mimic><peptidomimetics><prevent><preventing><receptor><response><simian HIV><simian human immunodeficiency virus><social role><sulfotyrosine><timeline><transgene><tyrosine O-sulfate><tyrosine sulfate><vector><viral multiplication><viral replication><virus multiplication>