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Principal Investigator: Morgan Meissner
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2020
Award: $38,509
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
Human immunodeficiency virus (HIV) infects 37 million people globally and has killed over 39 million since its
emergence in the human population. There are two different types of HIV: type 1 (HIV-1) and type 2 (HIV-2),
with the latter exhibiting an attenuated disease phenotype that has been recognized for decades. A high rate of
mutation is a hallmark feature of HIV-1 disease progression and drives immune evasion as well as the
emergence of drug resistance. While the majority of viral mutagenesis is thought to be driven by the low fidelity
of the virally-encoded reverse transcriptase (RT), restrictions factors that act during reverse transcription can
contribute to viral mutation as well. For example, the apolipoprotein B mRNA-editing enzyme catalytic
polypeptide-like 3 (APOBEC3; A3) family of proteins has been identified as a driver of G-to-A mutations in HIV-
1 through deamination of cytosines to uracils during reverse transcription. Another host factor, sterile α motif
domain and histidine-aspartic domain-containing protein 1 (SAMHD1), restricts viral replication by depleting
cellular dNTP pools, and could drive viral mutagenesis as well. How these factors impact HIV-2 mutagenesis
has, to date, been uncharacterized. This proposal seeks to investigate cellular sources of HIV-2 mutagenesis
relative to that of HIV-1, and correlate this with differences in virus infectivity. Levels of restriction by A3
proteins will be evaluated by defining the restrictive capacity of the human A3 repertoire against HIV-2, as well
differences in the effectiveness of the HIV accessory protein Vif. The contribution of SAMHD1 to HIV-1 and
HIV-2 mutagenesis will be determined using high-throughput Illumina sequencing of WT HIV-1 and HIV-2
viruses in monocytic cell lines, as well as with Vpx-deficient HIV-2. Viral mutagens and inhibitors of
ribonucleotide reductase will be used to correlate mutagenesis with viral infectivity in order to shed light on how
tolerance to mutations impacts viral mutagenesis and infectivity. Taken together, these experiments will serve
to determine the relative impact of cellular restriction factors HIV-2 mutagenesis compared to HIV-1
mutagenesis. These comparative studies should provide new insights into the host determinants of HIV
mutagenesis.
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><Anti-viral Drug Resistance><Anti-viral Drug Resistant><Antiviral Drug Resistance><Antiviral Drug Resistant><Attenuated><Blood monocyte><Cell Body><Cell Line><CellLine><Cells><Comparative Study><Cytosine><Cytosine Aminohydrolase><Cytosine deaminase><Deamination><Disease Progression><Drug resistance><EC 2.7.7.49><Effectiveness><Evolution><Exhibits><Frequencies><Genetic Alteration><Genetic Change><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic defect><Genetics-Mutagenesis><Genotoxins><HIV><HIV-1><HIV-2><HIV-I><HIV-II><HIV1><HIV2><HTLV-IV><Histidine><Host Factor><Host Factor Protein><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Virus Type 2><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type IV><Human immunodeficiency virus 1><Human immunodeficiency virus 2><Immune Evasion><Immunoblotting><Induced DNA Alteration><Induced Mutation><Induced Sequence Alteration><Infection><Integration Host Factors><LAV-2><LAV-HTLV-III><Lead><Light><Lymphadenopathy-Associated Virus><Marrow monocyte><Mediating><Modern Man><Mutagenesis><Mutagenesis Molecular Biology><Mutagens><Mutation><Mutation Fixation><Mutation Spectra><Pb element><Photoradiation><Population><Protein Family><Proteins><RNA Transcriptase><RNA-Dependent DNA Polymerase><RNA-Directed DNA Polymerase><Recombinant DNA Technology><Research><Resistance development><Resistant development><Reverse Transcriptase><Reverse Transcription><Revertase><Ribonucleotide Reductase Inhibitor><Source><Sterility><Strains Cell Lines><Testing><Uracil><Viral><Viral Burden><Viral Drug Resistance><Viral Load><Viral Load result><Viral Pathogenesis><Virion><Virus><Virus Particle><Virus Replication><Virus-Cell Interaction><Virus-Cell Membrane Interaction><Virus-HIV><apo B mRNA editing protein><apolipoprotein B mRNA editing enzyme><base><comparative><cultured cell line><develop a vaccine><developing resistance><development of a vaccine><disease phenotype><drug resistant><experience><experiment><experimental research><experimental study><genetically engineered><genome mutation><genotoxic agent><heavy metal Pb><heavy metal lead><insight><knock-down><knockdown><monocyte><mutant><polypeptide><resistance to Drug><resistance to anti-viral><resistance to antiviral><resistant to Drug><resistant to anti-viral><resistant to antiviral><small molecule><sor Gene Products><sterile><trend><vaccine development><vaccine formulation><vector><vif Gene Products><vif Protein><viral multiplication><viral replication><virus multiplication><virus pathogenesis>