Coreceptor Switch of [MLV(SIVagm)] pseudotype vectors by V3-loop exchange

Area of Science:

• Virology
• Gene Therapy
• Immunology

Background:

• Murine leukemia virus (MLV) vectors are utilized for gene delivery.
• Simian immunodeficiency virus (SIVagm) envelope glycoproteins (Env) offer alternative tropism.
• HIV-1 entry into human cells depends on CD4 and coreceptors like CXCR4.

Purpose of the Study:

• To engineer MLV-based vectors with altered coreceptor usage for targeting human lymphocytes.
• To investigate the functional equivalence of SIVagm and HIV-1 V3-loops in vector-mediated cell entry.
• To assess the potential of these modified vectors for gene therapy applications, including HIV-1 infection.

Main Methods:

• Pseudotyping MLV vectors with a modified SIVagm Env, incorporating the HIV-1 BH10 V3-loop.
• Evaluating vector transduction of CD4/CXCR4-positive cell lines and primary human lymphocytes.
• Assessing vector resistance to neutralization by sera from HIV-1-infected individuals.

Main Results:

• The engineered [MLV(SIVagm-X4)] vectors specifically transduced CD4/CXCR4-positive cells.
• The SIVagm-based vector demonstrated efficient cell entry and CXCR4 coreceptor usage, similar to HIV-1.
• These vectors successfully transduced primary human lymphocytes and were resistant to HIV-1 neutralizing antibodies.

Conclusions:

• The V3-loop substitution effectively redirected MLV vector tropism to utilize the CXCR4 coreceptor.
• [MLV(SIVagm-X4)] vectors represent a viable tool for gene therapy, particularly for targeting HIV-1 infection.
• The resistance to neutralization suggests potential for therapeutic applications in the context of HIV-1 infection.