Document text
Principal Investigator: Rajesh Thippeshappa
Organization: TEXAS BIOMEDICAL RESEARCH INSTITUTE
Fiscal Year: 2024
Award: $99,000
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. Human-Simian
Immunodeficiency Virus (HSIV) is an HIV-1NL4-3 derivative with SIV vif gene substitution (named HSIV-vifNL4-3)
that can replicate persistently in pigtail macaques (PTMs). However, infection did not result in high peak viremia
and setpoint viral loads as observed during SIV infection of macaques. Serial in vivo passaging in PTMs was
performed to enhance infectivity or replicative capacity of HSIV. Three rounds of 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) was conducted to generate pathogenic variants. Interestingly, all the macaques showed peak
viremia close to or above 105 copies/ml and virus replication persisted for more than 20 weeks. Following in vivo
passaging, three infectious molecular clones (IMCs) were recovered from passage 3 macaque (HSIV-P3 IMCs).
Sequencing of HSIV-P3 IMCs showed several interesting mutations throughout the genome, perhaps suggesting
adaptation to PTMs. These mutations could help the virus in overcoming restriction factors, or better utilization
of host dependency factors, or they could help the virus escape host immune responses. Focus of this grant
application is to determine the functional significance of mutations observed in envelope gene. The results from
this study will provide valuable insights into the role of envelope gene in cross-species transmission of HIV-1 to
pigtailed macaques.
Terms: <AIDS><AIDS Virus><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Animal Model><Animal Models and Related Studies><Animals><Antibody Response><Applications Grants><Assay><Binding><Bioassay><Biological Assay><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Serum><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><Cells><Chemokine (C-C Motif) Receptor 5><Chemokine (C-C) Receptor 5><Chemokine (C-C) Receptor 5 Gene><Cloning><D2S201E><Dependence><Development><Disease Progression><Drugs><EC 2.7.7.49><Envelope Protein><FB22><G24 protein><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genome><Grant Proposals><HIV><HIV Viral Protein R><HIV envelope><HIV envelope protein><HIV vpr Gene Product><HIV-1><HIV-1 Fusion Co-Receptor><HIV-1 Fusion Co-Receptor Gene><HIV-1 vpr Gene Products><HIV-I><HIV1><HM89><HSY3RR><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><IFN><Immune response><Immunocompetent><Immunological response><Infection><Interferons><LAP3><LAV-HTLV-III><LCR1><LESTR><Lymphadenopathy-Associated Virus><M nemestrina><M. nemestrina><Macaca><Macaca nemestrina><Macaque><Medication><Messenger RNA><Modeling><Modification><Molecular Cloning><Molecular Interaction><Mutation><NPY3R><NPYR><NPYRL><NPYY3R><Names><ORFs><Open Reading Frames><PBMC><Pathogenesis><Pathogenicity><Peripheral Blood Mononuclear Cell><Pharmaceutical Preparations><Phenotype><Pigtail Macaque><Pigtail Monkey><Plasma><Plasma Serum><Predisposition><Protein Coding Region><Protein Family><Q Genes><R Gene Products><RNA Splicing><RNA Transcriptase><RNA-Dependent DNA Polymerase><RNA-Directed DNA Polymerase><Resistance><Reticuloendothelial System, Serum, Plasma><Reverse Transcriptase><Revertase><Role><SHIV><SIV><Sampling><Serum><Simian Immunodeficiency Viruses><Site><Splicing><Standardization><Susceptibility><T4 Cells><T4 Lymphocytes><Testing><Variant><Variation><Viral Burden><Viral Diseases><Viral Load><Viral Load result><Viremia><Virion><Virus><Virus Diseases><Virus Particle><Virus Replication><Virus-HIV><beta lactam hydrolase><beta-Lactamase><beta-Lactamhydrolase><cross-species spillover><cross-species transmission><developmental><drug/agent><env Antigens><env Gene Products><env Polyproteins><env Protein><experiment><experimental research><experimental study><experiments><genome mutation><host jump><host response><host switching><immune competent><immune system response><immunoresponse><improved><in vivo><insight><interspecies transmission><mRNA><model of animal><name><named><naming><neutralizing antibody><non-human primate><non-synonymous mutation><nonhuman primate><nonsynonymous mutation><novel><pig-tailed macaque><prevent><preventing><rap Gene Products><resistant><simian HIV><simian human immunodeficiency virus><social role><sor Gene Products><sor Genes><transmission across species><transmission between species><transmitted across species><transmitted between species><transmitted cross-species><vaccination study><vaccination trial><vaccine efficacy><vaccine study><vaccine trial><vif Gene Products><vif Genes><vif Protein><viraemia><viral infection><viral multiplication><viral replication><viral sepsis><virus infection><virus multiplication><virus-induced disease><virusemia><vpr Gene Products><vpr Protein><β-Lactamase>