Treatment strategies for HTLV-1 infection: gene editing and immune modulation in non-human primate cells

• Grant number: 23/14320-9
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): March 01, 2024
• Effective date (End): March 31, 2027
• Field of knowledge: Biological Sciences - Immunology - Immunogenetics
• Principal Investigator: Jorge Simao do Rosario Casseb
• Grantee: Víctor Ângelo Folgosi
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

STLV-1, Simian T-Cell Lymphotropic Virus type 1, shares genomic similarity with HTLV-1, making it a relevant model for genome editing studies. CRISPR-Cas9 technology has been crucial in genetic editing of HIV-1, but there is a scarcity of studies applying this strategy to the HTLV-1 genome. Furthermore, investigating cGAS/STING activation pathways can provide insights into inflammation and cellular senescence mechanisms. This study aims to create CRISPR-Cas9 systems to target and remove specific parts of the tax gene from STLV-1 proviral DNA. Subsequently, we seek to assess how STING gene activation can bolster immunity against cellular senescence and induce a more effective antiviral response against the remaining proviral DNA. Blood samples will be collected from 54 non-human primates of the Cercopithecus aethiops species to detect STLV-1 infection. From the positive samples, DNA will be extracted from PBMC and then subjected to PCR and gene sequencing. CRISPR-Cas guide RNAs will be designed based on these sequences and those deposited in genomic banks. Finally, after using the CRISPR-CAS system, experiments with cGAS/STING agonists, which modulate the immune response against viral infections, will also be conducted. Statistical analysis, including ANOVA and post-hoc tests, will be used for group comparisons. The goal is to develop an effective genetic editing and immunomodulation system to disrupt viral production, influence gene expression, and provide an innovative therapeutic tool for STLV-1 infection and consequently, HTLV-1 infection.