TY - JOUR
T1 - HIV-1 protease evolvability is affected by synonymous nucleotide recoding
AU - Nevot, Maria
AU - Jordan-Paiz, Ana
AU - Martrus, Glòria
AU - Andrés, Cristina
AU - García-Cehic, Damir
AU - Gregori, Josep
AU - Franco, Sandra
AU - Quer, Josep
AU - Martinez, Miguel Angel
N1 - Funding information:
This study was supported by the Spanish Ministry of Economy and Competitiveness (grant SAF2016-75277-R), the Instituto de Salud Carlos III (grant PI16/00337), and the European Regional Development Fund (ERDF). M.N. was supported by the Instituto de Salud Carlos III through the Spanish AIDS Network (grant RD16/0025/0041). A.J.-P. was supported by a contract from the Spanish Ministry of Economy and Competitiveness (grant BES-2014-069931).
Publisher Copyright:
© 2018 American Society for Microbiology.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - ABSTRACT One unexplored aspect of HIV-1 genetic architecture is how codon choice influences population diversity and evolvability. Here we compared the levels of development of HIV-1 resistance to protease inhibitors (PIs) between wild-type (WT) virus and a synthetic virus (MAX) carrying a codon-pair-reengineered protease sequence including 38 (13%) synonymous mutations. The WT and MAX viruses showed indistinguishable replication in MT-4 cells or peripheral blood mononuclear cells (PBMCs). Both viruses were subjected to serial passages in MT-4 cells, with selective pressure from the PIs atazanavir (ATV) and darunavir (DRV). After 32 successive passages, both the WT and MAX viruses developed phenotypic resistance to PIs (50% inhibitory concentrations [IC50s] of 14.6 ± 5.3 and 21.2 ± 9 nM, respectively, for ATV and 5.9 ± 1.0 and 9.3 ± 1.9, respectively, for DRV). Ultradeep sequence clonal analysis revealed that both viruses harbored previously described mutations conferring resistance to ATV and DRV. However, the WT and MAX virus proteases showed different resistance variant repertoires, with the G16E and V77I substitutions observed only in the WT and the L33F, S37P, G48L, Q58E/K, and L89I substitutions detected only in the MAX virus. Remarkably, the G48L and L89I substitutions are rarely found in vivo in PI-treated patients. The MAX virus showed significantly higher nucleotide and amino acid diversity of the propagated viruses with and without PIs (P < 0.0001), suggesting a higher selective pressure for change in this recoded virus. Our results indicate that the HIV-1 protease position in sequence space delineates the evolution of its mutant spectrum. Nevertheless, the investigated synonymously recoded variant showed mutational robustness and evolvability similar to those of the WT virus.
AB - ABSTRACT One unexplored aspect of HIV-1 genetic architecture is how codon choice influences population diversity and evolvability. Here we compared the levels of development of HIV-1 resistance to protease inhibitors (PIs) between wild-type (WT) virus and a synthetic virus (MAX) carrying a codon-pair-reengineered protease sequence including 38 (13%) synonymous mutations. The WT and MAX viruses showed indistinguishable replication in MT-4 cells or peripheral blood mononuclear cells (PBMCs). Both viruses were subjected to serial passages in MT-4 cells, with selective pressure from the PIs atazanavir (ATV) and darunavir (DRV). After 32 successive passages, both the WT and MAX viruses developed phenotypic resistance to PIs (50% inhibitory concentrations [IC50s] of 14.6 ± 5.3 and 21.2 ± 9 nM, respectively, for ATV and 5.9 ± 1.0 and 9.3 ± 1.9, respectively, for DRV). Ultradeep sequence clonal analysis revealed that both viruses harbored previously described mutations conferring resistance to ATV and DRV. However, the WT and MAX virus proteases showed different resistance variant repertoires, with the G16E and V77I substitutions observed only in the WT and the L33F, S37P, G48L, Q58E/K, and L89I substitutions detected only in the MAX virus. Remarkably, the G48L and L89I substitutions are rarely found in vivo in PI-treated patients. The MAX virus showed significantly higher nucleotide and amino acid diversity of the propagated viruses with and without PIs (P < 0.0001), suggesting a higher selective pressure for change in this recoded virus. Our results indicate that the HIV-1 protease position in sequence space delineates the evolution of its mutant spectrum. Nevertheless, the investigated synonymously recoded variant showed mutational robustness and evolvability similar to those of the WT virus.
KW - Evolutionary biology
KW - Human immunodeficiency virus
KW - Proteases
KW - Synonymous recoding
KW - Evolutionary biology
KW - Human immunodeficiency virus
KW - Proteases
KW - Synonymous recoding
KW - Evolutionary biology
KW - Human immunodeficiency virus
KW - Proteases
KW - Synonymous recoding
UR - http://www.scopus.com/inward/record.url?scp=85050823653&partnerID=8YFLogxK
U2 - 10.1128/JVI.00777-18
DO - 10.1128/JVI.00777-18
M3 - Article
C2 - 29875244
AN - SCOPUS:85050823653
SN - 0022-538X
VL - 92
JO - Journal of Virology
JF - Journal of Virology
IS - 16
M1 - e00777-18
ER -