Human immunodeficiency virus type 1 replication is modulated by host cyclophilin A expression levels

Area of Science:

• Virology
• Molecular Biology
• Cell Biology

Background:

• The Human Immunodeficiency Virus type 1 (HIV-1) Gag protein interacts with cellular cyclophilin A (CypA).
• This Gag-CypA complex is essential for the integrity and infectivity of HIV-1 virions.
• Disrupting this interaction or altering CypA levels affects viral replication.

Purpose of the Study:

• To investigate the role of cyclophilin A stoichiometry in HIV-1 virion infectivity.
• To understand how varying host cell cyclophilin A expression impacts HIV-1 replication and Gag mutant virus behavior.

Main Methods:

• Utilized Gag mutants with altered cyclophilin A affinity.
• Assessed HIV-1 replication in different T cell lines (Jurkat and H9) with varying CypA expression levels.
• Employed cyclosporine, a competitive inhibitor of CypA, to modulate the Gag-CypA interaction.

Main Results:

• Virions with Gag mutants showing reduced CypA affinity or produced with cyclosporine exhibited lower infectivity.
• An A224E Gag mutant, which doesn't affect CypA affinity, conferred cyclosporine resistance in Jurkat cells but was non-infectious in H9 cells.
• H9 cells, expressing higher CypA levels, packaged more CypA into virions, disrupting the A224E mutant core and rescuing its replication in the presence of cyclosporine.
• Conversely, Gag mutants with low CypA affinity were non-infectious in Jurkat cells but replicated in H9 cells.

Conclusions:

• HIV-1 virion infectivity is highly sensitive to the precise stoichiometry of cyclophilin A within the virion core.
• Host cell cyclophilin A expression levels play a critical role in modulating HIV-1 replication and virion assembly.
• The Gag-cyclophilin A interaction is a finely tuned process essential for maintaining viral infectivity across different cellular environments.