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Principal Investigator: Afamefuna Okoye
Organization: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2023
Award: $840,477
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Although the advent of combination antiretroviral therapy (cART) has dramatically improved the prognosis of
people living with human immunodeficiency virus (HIV), cART alone cannot eradicate the infection and,
therefore, daily treatment must be maintained for life to prevent relapse of uncontrolled viral replication and
resumption of disease progression. However, lifelong treatment entails both health risks to treated individuals
and a significant economic burden to society. As such, there is a pressing need to develop novel therapeutic
interventions to cure HIV. Since most examples of stringent, long-term, spontaneous and vaccine-associated
immune control of HIV and simian immunodeficiency virus (SIV) infection are either known, or strongly suspected
to be CD8+ T cell-mediated, therapeutic strategies designed to exploit CD8+ T cell immunity hold great promise
for achieving durable control of virus replication in the absence of cART, often referred to as a “functional cure”.
However, in most people, naturally occurring CD8+ T cell responses induced by HIV infection are often
ineffective at controlling the virus. As such, any HIV cure strategy based on enhancing CD8+ T cell immunity
would need to elicit immune responses that are qualitatively and/or quantitatively different from those that
emerge during primary infection and are subsequently maintained during cART. In addition, in the setting of cure
where the rebound-competent viral reservoir is systemically distributed, having high frequencies of effector-
differentiated and functionally potent anti-viral CD8+ T cell responses pre-positioned in sites of potential viral
rebound (even in immune privileged sites such as B cell follicles) at the time of cART cessation is likely to be
critical for achieving durable post-cART viral control. In this project, we will determine whether a therapeutic
vaccination strategy that utilizes the messenger ribonucleic acid (mRNA)-based vaccine platform RNActive,
can enhance cellular immunity in SIV-infected rhesus macaques (RM) on cART and establish high-level, long-
term control of SIV replication after cART cessation. The choice of this vector is based on preliminary data
demonstrating RNActivevaccines with SIV gene inserts (mRNA/SIV) are highly immunogenic in RM, with the
capacity to elicit potent, systemically distributed, SIV-specific CD8+ T cells with broad epitope recognition. Here
we will assess whether mRNA/SIV vaccination alone or in combination with anti-CD20 B cell depletion (to disrupt
B cell follicles) can facilitate immediate interception of rebounding viral reservoirs to facilitate durable control of
SIV replication after cART cessation. Any finding of vaccine efficacy in this project will provide strong impetus
for clinical assessment of the RNActiveplatform in cART-suppressed HIV+ patients and potentially lead to a
clinically translatable therapeutic approach to achieve HIV infection remission off cART.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute><Address><Anti-CD20 Antibody><Antigenic Determinants><Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><Blood><Blood Plasma><Blood Reticuloendothelial System><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cell Mediated Immunology><Cell-Mediated Immunity><Cellular Immunity><Clinical><Clinical Research><Clinical Study><Clinical assessments><Collaborations><DNA><Data><Deoxyribonucleic Acid><Development><Disease Progression><Disease remission><Dose><Economic Burden><Ensure><Epitope Mapping><Epitopes><Frequencies><GAG><GAG Gene><Generations><Genes><Germany><Goals><HIV><HIV Infections><HIV vaccine><HIV/AIDS Vaccines><HTLV-III Infections><HTLV-III-LAV Infections><Health><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Immune><Immune response><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Individual><Infection><Injections><LAV-HTLV-III><Life><Life Expectancy><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphadenopathy-Associated Virus><Lymphatic Tissue><Lymphatic nodes><Lymphoid Tissue><M mulatta><M. mulatta><Macaca mulatta><Measurable><Mediating><Messenger RNA><MoAb Anti-B1><Modern Man><Molecular Interaction><Monoclonal Antibody Anti-B1><Non-Polyadenylated RNA><Patients><Peptides><Persons><Plasma><Plasma Serum><Position><Positioning Attribute><Primary Infection><Prognosis><RNA><RNA Gene Products><RNA vaccine><RNA-based vaccine><Recrudescences><Regimen><Remission><Reticuloendothelial System, Serum, Plasma><Rhesus Macaque><Rhesus Monkey><Ribonucleic Acid><Risk><Route><SIV><SIV Vaccines><Simian Immunodeficiency Viruses><Site><Societies><Specificity><Staining method><Stains><T cell response><T-Cell Epitopes><T-Lymphocyte Epitopes><T8 Cells><T8 Lymphocytes><Technology><Therapeutic><Time><VAC-TX><Vaccinated><Vaccination><Vaccine Design><Vaccine Therapy><Vaccines><Viral><Viral Burden><Viral Diseases><Viral Load><Viral Load result><Viral reservoir><Virus><Virus Diseases><Virus Replication><Virus reservoir><Virus-HIV><Withdrawal><anti-B1><anti-CD20><anti-retroviral therapy><anti-retroviral treatment><anti-viral immunity><antiretroviral therapy><antiretroviral treatment><antiviral immunity><biopharmaceutical company><biopharmaceutical industry><clinical translation><clinically translatable><cohort><cytokine><design><designing><developmental><disease recurrence prevention><experiment><experimental research><experimental study><experiments><host response><human immunodeficiency virus vaccine><immune system response><immunization strategy><immunogen><immunogenic><immunoresponse><improved><intervention design><lymph gland><lymph nodes><lymphnodes><mRNA><mRNA vaccine><mRNA-based vaccine><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><plasmid vaccine><prevent><prevent relapse><preventing><recurrence prevention><relapse prevention><response><safety and feasibility><simian immunodeficiency virus vaccines><therapeutic vaccination><therapeutic vaccine><therapy design><tool><tositumomab><treatment design><treatment vaccines><vaccination protocol><vaccination schedule><vaccination strategy><vaccine efficacy><vaccine for the treatment><vaccine for treatment><vaccine platform><vaccine protocol><vector><vector control><vector vaccine><viral infection><viral multiplication><viral rebound><viral replication><virus infection><virus multiplication><virus rebound><virus-induced disease>