HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells.

HIV protease inhibitors (HIV-PIs) target the HIV aspartyl protease, which cleaves the HIV gag-pol polyprotein into shorter proteins required for the production of new virions. HIV-Pls are a cornerstone of treatment for HIV but have been associated with lipodystrophy and other side effects. In both human and mouse fibroblasts, we show that HIV-Pls caused an accumulation of prelamin A. The prelamin A in HIV-Pl-treated fibroblasts migrated more rapidly than nonfarnesylated prelamin A, comigrating with the farnesylated form of prelamin A that accumulates in ZMPSTE24-deficient fibroblasts. The accumulation of farnesyl-prelamin A in response to HIV-Pl treatment was exaggerated in fibroblasts heterozygous for Zmpste24 deficiency. HIV-Pls inhibited the endoproteolytic processing of a GFP-prelamin A fusion protein. The HIV-Pls did not affect the farnesylation of HDJ-2, nor did they inhibit protein farnesyltransferase in vitro. HIV-Pls also did not inhibit the activities of the isoprenyl-cysteine carboxyl methyltransferase ICMT or the prenyiprotein endoprotease RCE1 in vitro, but they did inhibit ZMPSTE24 (IC₅₀: lopinavir, 18.4 ± 4.6 µM; tipranavir, 1.2 ± 0.4 µM). We conclude that the HIV-Pls inhibit ZMPSTE24, leading to an accumulation of farnesyl-prelamin A. The inhibition of ZMPSTE24 by HIV-Pls could play a role in the side effects of these drugs. [ABSTRACT FROM AUTHOR]