Modulation of HIV-1 Gag NC/p1 cleavage efficiency affects protease inhibitor resistance and viral replicative capacity

0377476 - ÚOCHB 2013 RIV GB eng J - Článek v odborném periodiku
Maarseveen van, N. M. - Andersson, Dan - Lepšík, Martin - Fun, A. - Schipper, P. J. - Jong de, D. - Boucher, Ch. A. B. - Nijhuis, M.
Modulation of HIV-1 Gag NC/p1 cleavage efficiency affects protease inhibitor resistance and viral replicative capacity.
Retrovirology. Roč. 9, č. 29 (2012), s. 1-7. E-ISSN 1742-4690
GRANT EU: European Commission(XE) 37693 - HIV PI RESISTANCE
Grant ostatní: Dutch AIDS Fund(XE) 2006028; (NWO) VIDI(XE) 91796349
Výzkumný záměr: CEZ:AV0Z40550506
Klíčová slova: HIV-1 * protease * Gag * resistance * cleavage
Kód oboru RIV: CE - Biochemie
Impakt faktor: 5.657, rok: 2012

Mutations in the substrate of the HIV-1 protease, especially changes in the NC/p1 cleavage site, can act not only as compensatory mutations but can also directly contribute to protease inhibitor (PI) resistance. These NC/p1 changes bring about PI resistance by causing an enhanced processing of the Gag protein. To investigate the capacity of HIV to modulate Gag cleavage and its consequences for protease inhibitor resistance and replicative capacity (RC), we performed a detailed enzymatic and virological analysis using a set of PI resistant NC/p1 variants (HXB2436E+437T, HXB2437T, HXB2437V and HXB2431V). Here we demonstrate that single NC/p1 mutants, which displayed only a slight increase in PI resistance didn’t show an obvious change in RC. In contrast, the double NC/p1 mutant, which displayed a clear increase in processing efficiency and PI resistance, also demonstrated a clear reduction in RC. Evolution experiments revealed that this decrease in RC could be (partially) restored by either reversion of the 436E change or by the acquisition of additional changes at codon 435 or 438. Furthermore, these changes also normalized Gag processing efficiency and returned PI susceptibility in the direction of wild type level. The results of this study demonstrate that when enhanced Gag processing due to PI resistance mutations in NC/p1 reduces RC, HIV-1 can modulate the NC/p1 sequence to restore RC and Gag cleavage to an optimal rate.
Trvalý link: http://hdl.handle.net/11104/0209622