Document text
Principal Investigator: Rajesh Thippeshappa
Organization: TEXAS BIOMEDICAL RESEARCH INSTITUTE
Fiscal Year: 2023
Award: $378,000
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract/Summary:
Commonly used animal models of HIV-1 include infection of macaques with Simian Immunodeficiency Virus
(SIV) or Simian-Human Immunodeficiency Virus (SHIV) containing HIV envelope (Env) or reverse transcriptase.
These animal models have been extremely useful in understanding HIV pathogenesis and disease progression,
as well as understanding the efficacy of vaccines and drugs. However, the genetic difference between HIV-1
and SIV, and the absence of other HIV-1 genes such as gag, pol, vif, vpr, and nef in SHIV limits the utility of
these models in vaccine studies. Ideally, good animal model of HIV-1 infection/AIDS would be infection of
macaques with HIV-1. However, HIV-1 does not replicate in macaque cells due to the presence of retroviral
restriction factors. HIV-1 can be made to replicate by substituting its accessory genes with SIV genes such as
vif, vpx, vpr, and nef, which can counteract interferon-induced restriction factors in macaque cells. Indeed, we
have previously reported that Human-Simian Immunodeficiency Virus generated by substitution of HIV-1NL4-3 vif
with SIV substitution (named HSIV-vifNL4-3) can replicate persistently in pigtail macaques (PTMs). However,
infection did not result in high peak viremia and setpoint viral loads as observed during SIV or Simian-Human
Immunodeficiency virus (SHIV) infection of macaques. To further adapt HSIV, we performed serial in vivo
passaging to enhance infectivity or replicative capacity. We conducted animal-to-animal transfer of infected blood
in 3 immunocompetent PTMs with starting initial inoculum containing a mixture of CXCR4- (HSIV-vifNL4-3
recovered from previously infected macaque) and CCR5-tropic HSIV (HSIV-vif derivative based on pNL-AD8
and Bru-Yu2). Interestingly, all the macaques showed peak viremia close to or above 105 copies/ml and virus
replication persisted for more than 20 weeks. We have recovered three CXCR4-tropic infectious molecular
clones (IMCs) from passage 3 macaque (HSIV-P3 IMCs) with interesting mutations throughout the genome,
perhaps suggesting adaptation to PTMs. We hypothesize that further in vivo passaging of HSIV-P3 IMCs will
generate pathogenic variants with enhanced replication capacity. We propose to conduct serial in vivo
passaging in older PTMs, which may support better virus replication compared to juvenile/younger macaques.
Since we recovered only CXCR4-tropic HSIV, we also propose to use HSIV-P3 IMCs as backbones to develop
CCR5-tropic HSIV. The results from this study will provide valuable insights into development of biologically
relevant animal model of HIV-1 infection for preclinical evaluation of vaccine prevention of HIV transmission.
Terms: <(IFN) α><(IFN)-α><(IFN)α><AIDS><AIDS Virus><AIDS prevention><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><Adolescent><Adolescent Youth><Alferon><Animal Model><Animal Models and Related Studies><Animals><Anti-Retroviral Agents><Antibody Response><Antiretroviral Agents><Autopsy><Blood><Blood Plasma><Blood Reticuloendothelial System><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><CHEMR13><CHEMR13 Gene><CKR-5><CKR-5 Gene><CKR5><CKR5 Gene><CKR5 Receptors><CMKBR5><CMKBR5 Gene><CXC-R4><CXCR-4><CXCR4><CXCR4 gene><Cell Body><Cell Count><Cell Number><Cells><Chemokine (C-C Motif) Receptor 5><Chemokine (C-C) Receptor 5><Chemokine (C-C) Receptor 5 Gene><Co-culture><Cocultivation><Coculture><Coculture Techniques><D2S201E><DNA><Deoxyribonucleic Acid><Development><Disease><Disease Progression><Disorder><Drugs><EC 2.7.7.49><Evolution><FB22><Generations><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genome><Goals><HIV><HIV Prevention><HIV envelope><HIV envelope protein><HIV-1><HIV-1 Fusion Co-Receptor><HIV-1 Fusion Co-Receptor Gene><HIV-I><HIV/AIDS prevention><HIV1><HM89><HSY3RR><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><IFN><IFN Alpha><IFN α><IFN-α><IFNa><IFNα><Immunocompetent><In Vitro><Infection><Interferon Alfa-n3><Interferon alpha><Interferon-α><Interferons><LAP3><LAV-HTLV-III><LCR1><LESTR><Leukocyte Interferon><Lymphadenopathy-Associated Virus><Lymphoblast Interferon><Lymphoblastoid Interferon><M nemestrina><M. nemestrina><Macaca><Macaca nemestrina><Macaque><Measures><Medication><Messenger RNA><Modeling><Molecular Cloning><Mutation><NPY3R><NPYR><NPYRL><NPYY3R><Names><ORFs><Open Reading Frames><PBMC><Pathogenesis><Pathogenicity><Peripheral Blood Mononuclear Cell><Pharmaceutic Preparations><Pharmaceutical Preparations><Pigtail Macaque><Pigtail Monkey><Plasma><Plasma Serum><Play><Protein Coding Region><Protein Family><Proteins><R-Series Research Projects><R01 Mechanism><R01 Program><RNA Splicing><RNA Transcriptase><RNA-Dependent DNA Polymerase><RNA-Directed DNA Polymerase><Reporting><Research Grants><Research Project Grants><Research Projects><Research Resources><Resistance><Resources><Reticuloendothelial System, Serum, Plasma><Reverse Transcriptase><Revertase><SHIV><SIV><Simian Immunodeficiency Viruses><Site><Spinal Column><Spine><Splicing><T4 Cells><T4 Lymphocytes><Time><Tissues><Transmission><Variant><Variation><Vertebral column><Viral><Viral Burden><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Load><Viral Load result><Viral Proteins><Viremia><Virus><Virus Diseases><Virus Replication><Virus-HIV><anti-retroviral><antiretroviral><backbone><developmental><drug/agent><efficacy study><evaluate vaccines><experiment><experimental research><experimental study><experiments><genome mutation><human model><immune competent><in vivo><insight><juvenile><juvenile human><mRNA><model of animal><model of human><name><named><naming><necropsy><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><non-human primate><nonhuman primate><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pig-tailed macaque><postmortem><pre-clinical evaluation><preclinical evaluation><prevent><preventing><resistant><simian HIV><simian human immunodeficiency virus><therapeutic vaccine><transmission process><treatment vaccines><vaccination study><vaccination trial><vaccine efficacy><vaccine evaluation><vaccine for the treatment><vaccine for treatment><vaccine screening><vaccine study><vaccine testing><vaccine trial><viraemia><viral RNA><viral infection><viral multiplication><viral replication><viral sepsis><virus RNA><virus infection><virus multiplication><virus protein><virus-induced disease><virusemia>