Cell Type-Dependent Escape of Capsid Inhibitors by Simian Immunodeficiency Virus SIVcpz

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Pandemic human immunodeficiency virus type 1 (HIV-1) emerged from simian immunodeficiency virus (SIV) in chimpanzees (SIVcpzPtt).
• A related SIV (SIVcpzPts) from another chimpanzee subspecies did not transmit to humans.
• Small-molecule capsid inhibitors target a groove in the viral capsid, also used by host protein CPSF6.

Purpose of the Study:

• To investigate the susceptibility of HIV-1, SIVcpzPtt, and SIVcpzPts to capsid inhibitors.
• To understand the role of cellular cofactors, such as cyclophilin A (CYPA) and CPSF6, in the antiviral activity of capsid inhibitors.
• To elucidate the molecular basis of SIVcpzPts resistance and its implications for understanding SIV zoonosis.

Main Methods:

• Testing HIV-1, SIVcpzPtt, and SIVcpzPts sensitivity to capsid inhibitors (PF57, PF74, GS-CA1) in various cell lines and primary cells.
• Utilizing homology modeling and binding energy estimates to analyze capsid-protein interactions.
• Investigating the effect of modulating cyclophilin A (CYPA) levels or binding on SIVcpzPts resistance to PF74.

Main Results:

• HIV-1 was sensitive to capsid inhibitors, while SIVcpzPtt showed mixed sensitivity.
• SIVcpzPts exhibited cell type-specific resistance to PF74, being resistant in HeLa cells and PBMCs but sensitive in HOS cells.
• Modulating CYPA levels or its binding to the capsid overcame SIVcpzPts resistance to PF74 in HeLa cells, indicating a crucial role for CYPA.

Conclusions:

• The antiviral efficacy of PF74 is modulated by CYPA in a virus- and cell type-specific manner.
• SIVcpz viruses can employ infection pathways that evade PF74 activity, suggesting dependence on cellular cofactors.
• Understanding SIVcpzPts-host interactions is vital for comprehending SIV zoonosis and developing effective antiviral strategies.