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Principal Investigator: Beatrice H Hahn
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2021
Award: $802,998
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Studying Natural SIV Reservoirs and Human Zoonotic Risk, we discovered in the last funding period that
certain strains of SIV infecting Old World monkeys and African apes share unexpected antigenic cross-
reactivity with HIV-1 in the functionally important V1V2 region of the envelope glycoprotein (Env) trimer apex
(44). This antigenic conservation renders these viruses uniquely sensitive to HIV-1 elicited V2 apex broadly
neutralizing antibodies (bNabs) and suggests that SIV Envs, because of their extensive backbone diversity but
highly conserved trimer apex antigenicity, could serve to “immunofocus” B cell responses in humans to this
bNab epitope. Preliminary data in knock-in mice expressing the inferred unmutated common ancestor (UCA) of
the V2 apex bNab CH01 (heavy chain only) provide supporting evidence: Immunization of these mice with a
germline targeting SIVcpz Env SOSIP trimer (MT145.Q171K) elicited antibodies that not only neutralized
viruses containing the autologous SIVcpz Env, but also viruses bearing Envs of heterologous HIV-1 strains
(59). These results suggest that highly divergent SIVcpz (and other SIV) Envs can prime human V2 apex UCA
B cells and induce bNab responses that cross-react with heterologous tier 2 HIV-1 strains (59). Utilizing our
extensive knowledge of the evolutionary history, immunobiology and pathogenicity of the primate precursors of
HIV-1 (summarized in 102 Progress Publications), we propose in this competing renewal of our MERIT award
(R37 AI050529) to systematically explore the potential utility of SIVcpz and other SIV Envs as novel
components of an AIDS vaccine. Our scientific premise is that the quaternary structure of the Env trimer
apex is highly conserved across divergent SIV lineages because it mediates essential functions related to the
biology of the unliganded Env glycoprotein, and that this structural conservation is reflected in conserved
antigenicity. Our hypothesis is that evolutionarily divergent SIVcpz (and other SIV) Envs, when expressed as
chimeric simian-human immunodeficiency viruses (SHIVs), mRNA-encoded cell surface expressed gp160
trimers, and/or virus-like particles (VLPs) in rhesus macaques (RMs), will elicit V2 apex bNabs that cross-react
with HIV-1. To test this hypothesis, we will (i) characterize the extent of the V2 apex antigenic conservation
across Envs from diverse primate lentiviral lineages and elucidate associated structure-function-antigenicity
relationships relevant to vaccine design (Aim #1), (ii) define the potential of primate lentiviral Envs to elicit V2
apex bNabs in the context of SHIV infections (Aim #2), and (iii) determine if primate lentiviral Envs when
delivered as mRNA/LNP or VLP immunogens can immunofocus V2 apex bNab responses in RMs, alone or in
combination with heterologous SHIVs (Aim #3). Our application is timely because the SIVcpz MT145.Q171K
Env SOSIP trimer has been selected by the NIH for GMP production and advancement to Phase 1
clinical testing in humans. The work we propose will provide an important complement and “guidepost” to
the immunogenicity studies planned in humans, and thus inform and accelerate AIDS vaccine development.
Terms: <AIDS><AIDS Vaccines><AIDS Virus><AIDS vaccine><AIDS vaccine development><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immuno-Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Acquired Immunologic Deficiency Syndrome><Affinity><African><Antibodies><Antigenic Determinants><Antigens><Apes><Autologous><Award><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Behavior><Binding><Binding Determinants><Biology><Bionomics><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CH01><CHA-hES-1><Cameroon><Cell Body><Cell surface><Cells><Central Africa><Cercopithecidae><Chimp><Chimpanzee><Clinical Evaluation><Clinical Testing><Collection><Communities><Complement><Complement Proteins><Consensus><Country><Data><Development><Ecology><Environmental Science><Epitopes><Funding><Genetic><Genome><Glycoproteins><Goals><Gorilla gorilla><Gorillas><Grant><HIV><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV env Protein gp120><HIV-1><HIV-1 vaccine><HIV-I><HIV1><HIV1 vaccine><HTLV-III gp120><History><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Immunization><Immunize><Immunobiology><Immunogenetics><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunophysiology><Immunostimulation><In Vitro><KI mice><Kinetics><Knock-in><Knock-in Mouse><Knowledge><LAV-HTLV-III><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca mulatta><Malaria><Maps><Mediating><Messenger RNA><Mice><Mice Mammals><Modern Man><Molecular Epidemiology><Molecular Interaction><Monkeys><Murine><Mus><NIH><National Institutes of Health><Old World Monkeys><P falciparum><P vivax><P. falciparum><P. vivax><P.falciparum><Paludism><Pan Genus><Pan Species><Parasites><Pathogenicity><Pattern><Phase><Plasmodium Infections><Plasmodium falciparum><Plasmodium vivax><Pongidae><Primate Immunodeficiency Viruses><Primate Lentiviruses><Primates><Primates Mammals><Production><Protomer><Public Health><Publications><Recording of previous events><Research><Research Specimen><Rhesus Macaque><Rhesus Monkey><Risk><SHIV><SIV><Scientific Publication><Simian Immunodeficiency Viruses><Specimen><Spinal Column><Spine><Structure><T-Cell Depletion><T-cell depletion therapy><T-lymphocyte depletion therapy><T4 Cells><T4 Lymphocytes><Tail><Testing><Time><Transmission><United States National Institutes of Health><Vaccine Design><Vertebral column><Viral Diseases><Viral Pathogenesis><Viral reservoir><Virus><Virus Diseases><Virus reservoir><Virus-HIV><Virus-like particle><Work><Zoonoses><Zoonotic><Zoonotic Infection><backbone><base><clinical test><cross reactivity><develop a vaccine><development of a vaccine><developmental><gene function><glycoprotein structure><gp120><gp120 ENV Glycoprotein><gp120(HIV)><gp160><great ape><immunogen><immunogenicity><knockin><knockin mice><mRNA><microbial consortia><microbial flora><microbiota><microflora><multispecies consortia><neutralizing antibody><new approaches><novel><novel approaches><novel strategies><novel strategy><pandemic><pandemic disease><pathogen><research clinical testing><response><simian HIV><simian human immunodeficiency virus><transmission process><vaccine development><vaccine formulation><viral infection><virus infection><virus pathogenesis><virus-induced disease><virus-like nanoparticles><viruslike particle>