Document text
Principal Investigator: James A Hoxie
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2020
Award: $752,353
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
In pathogenic HIV and SIV infection innate and adaptive immune responses fail to control viral replication and,
coupled with persisting immune activation, lead to the progressive depletion of CD4+/CCR5+ T cells and AIDS.
Numerous HIV and SIV vaccines have also failed to elicit immune responses that can broadly prevent or
control infection. Although immune control of HIV and SIV can occur, the determinants are unclear, as is the
ability to induce these responses with vaccines. There is thus, an urgent need to identify and understand
immune responses that can broadly prevent or control HIV/SIV infection and to elicit these responses with
vaccines. A model is described in which deletion of a Gly and Tyr within a highly conserved trafficking motif in
the SIVmac239 envelope (Env) cytoplasmic tail produces a virus (∆GY) that in pigtail macaques (PTM)
replicates acutely to wildtype levels, but becomes highly controlled by cellular immune responses in the
absence of neutralizing antibodies. Remarkably, animals that control ∆GY infection are able to prevent or
control diverse challenges with homologous SIVmac239, heterologous SIVsmE660 and SHIV-SF162P3N,
which are all highly pathogenic in PTM. Recent studies of mutations acquired in rare ∆GY animals that
progressed to AIDS and of viral evolution in PTM depleted of CD8 cells prior to ∆GY infection, have implicated
the loss of polarized trafficking of Env in infected cells as a driver for ∆GY's altered pathogenesis. These
findings have suggested that Env trafficking plays a critical dual role in promoting both cell-cell spread of virus
in tissues and in evading CD8 cellular immune responses. As these events are mediated by virologic and
immunologic synapses, respectively, we hypothesize that this motif is critical in vivo in promoting infectivity and
modulating viral susceptibility to cellular immune attack. Findings with the ∆GY model suggest that disrupting
this motif can not only alter pathogenesis but also enable potent and broadly protective immune responses to
occur. This testable hypothesis and its implications for vaccines will be assessed in 4 Aims: 1) To
identify the immune correlates of ∆GY control and responses that are shared during control of diverse
challenges; 2) To provide a mechanistic understanding of this model by characterizing differences in virologic
and immunologic synapses during ∆GY and SIVmac239 infection; 3) To assess the impact of alterations in Env
trafficking on immunogenicity in the context of a novel mRNA vaccine; and 4) To extend findings for the
immunomodulatory role of this conserved trafficking motif in SIV to an HIV-1 Env. These highly novel
observations are positioned to provide new insights into protective immunity for the SIV and HIV vaccine fields.
Terms: <AIDS><AIDS Virus><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><Acute><Anatomic><Anatomic Sites><Anatomic structures><Anatomical Sciences><Anatomy><Animals><Antigenic Determinants><Antiviral Agents><Antiviral Drugs><Antivirals><Assay><Binding Determinants><Bioassay><Biologic Assays><Biological><Biological Assay><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood monocyte><Body Tissues><C-C CKR-5><C-C CKR-5 Gene><C-C Chemokine Receptor Type 5><C-C Chemokine Receptor Type 5 Gene><CC Chemokine Receptor 5><CC-CKR-5><CC-CKR-5 Gene><CC-CKR5><CCCKR5><CCCKR5 Gene><CCR-5><CCR-5 Gene><CCR5><CCR5 Protein><CCR5 Receptors><CCR5 gene><CD195 Antigen><CD195 Antigen Gene><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><CHEMR13><CHEMR13 Gene><CKR-5><CKR-5 Gene><CKR5><CKR5 Gene><CKR5 Receptors><CMKBR5><CMKBR5 Gene><Cell Body><Cell Communication and Signaling><Cell Line><Cell Signaling><CellLine><Cells><Chemokine (C-C Motif) Receptor 5><Chemokine (C-C) Receptor 5><Chemokine (C-C) Receptor 5 Gene><Chronic><Code><Coding System><Control Animal><Coupled><Cytoplasmic Domain><Cytoplasmic Tail><Data><Disease><Disorder><Epitopes><Event><Evolution><Exhibits><Future><Genetic Alteration><Genetic Change><Genetic defect><Gut associated lymphoid tissue><HIV><HIV vaccine><HIV-1><HIV-1 Fusion Co-Receptor><HIV-1 Fusion Co-Receptor Gene><HIV-I><HIV/AIDS Vaccines><HIV/SIV vaccine><HIV1><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Image><Immune><Immune Cell Activation><Immune response><Immunes><Immunity><Immunocompetence><Immunologic Competence><Immunological Competence><Immunological response><Immunomodulation><Impairment><In Vitro><Infection><Infection Control><Intervention><Intervention Strategies><Intracellular Communication and Signaling><LAV-HTLV-III><LYT3><Lead><Lymphadenopathy-Associated Virus><M nemestrina><M. nemestrina><Macaca nemestrina><Maps><Marrow monocyte><Mediating><Messenger RNA><Modeling><Molecular Cloning><Mutation><Outcome><Pathogenesis><Pathogenicity><Pb element><Pigtail Macaque><Pigtail Monkey><Plasma><Plasma Serum><Play><Position><Positioning Attribute><Predisposition><RNA vaccine><Reticuloendothelial System, Serum, Plasma><Role><SHIV><SIV><SIV Vaccines><Signal Transduction><Signal Transduction Systems><Signaling><Simian Immunodeficiency Viruses><Sorting - Cell Movement><Strains Cell Lines><Susceptibility><T cell response><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Testing><Tissues><Vaccines><Viral><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Virus Diseases><Virus Replication><Virus-HIV><adaptive immune response><anti-viral agents><anti-viral drugs><anti-virals><base><biological signal transduction><cellular targeting><cultured cell line><genome mutation><heavy metal Pb><heavy metal lead><host response><human immunodeficiency virus vaccine><imaging><immune activation><immune modulation><immune regulation><immune regulator><immunogenicity><immunologic reactivity control><immunological synapse><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><in vivo><insight><interventional strategy><mRNA><mRNA vaccine><macrophage><monocyte><nef Protein><neutralizing antibody><new vaccines><next generation vaccines><non-human primate><nonhuman primate><novel><novel vaccines><prevent><preventing><regenerative><response><simian HIV><simian human immunodeficiency virus><simian immunodeficiency virus vaccines><social role><sorting><synapse formation><synaptogenesis><thymus derived lymphocyte><trafficking><viral RNA><viral infection><viral multiplication><viral replication><viral transmission><virological synapse><virus RNA><virus infection><virus multiplication><virus protein><virus transmission><virus-induced disease>