Human immunodeficiency virus type 1 capsid mutation N74D alters cyclophilin A dependence and impairs macrophage...

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• CPSF6-358 is an antiviral factor that inhibits human immunodeficiency virus type 1 (HIV-1) nuclear entry.
• The N74D mutation in the HIV-1 capsid (CA) confers resistance to CPSF6-358 by altering the viral nuclear entry pathway.

Purpose of the Study:

• To investigate the phenotypic consequences of the N74D mutation in HIV-1, particularly concerning its interaction with antiviral factors and its replication in different cell types.
• To elucidate the early events in the HIV-1 lifecycle affected by the N74D mutation.

Main Methods:

• Comparative analysis of wild-type (WT) HIV-1 and N74D HIV-1.
• Assessment of drug sensitivity (cyclosporine, nevirapine).
• Evaluation of viral replication efficiency in macrophages and transformed cells, focusing on pre-reverse transcription steps.

Main Results:

• N74D HIV-1 exhibits increased sensitivity to cyclosporine and nevirapine compared to WT HIV-1.
• N74D HIV-1 infection is impaired in macrophages prior to reverse transcription.
• Replication of N74D HIV-1 in transformed cells requires cyclophilin A, but macrophage infection relies on different interactions.

Conclusions:

• The N74D mutation creates distinct phenotypes in HIV-1, affecting its interaction with host factors and drug susceptibility early in infection.
• These findings highlight differences in the N74D reverse transcription complex and its pathway, independent of nuclear pore interactions.
• HIV-1 replication strategies vary between cell types, with N74D HIV-1 demonstrating differential dependencies on host factors like cyclophilin A in macrophages versus transformed cells.