Compensatory substitutions restore normal core assembly in simian immunodeficiency virus isolates with Gag epitope cytotoxic T-lymphocyte escape mutations.
The evolution of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) as they replicate in infected individuals reflects a balance between the pressure on the virus to mutate away from recognition by dominant epitope-specific cytotoxic T lymphocytes (CTL) and the structural constraints on the virus' ability to mutate. To gain a further understanding of the strategies employed by these viruses to maintain replication competency in the face of the intense selection pressure exerted by CTL, we have examined the replication fitness and morphological ramifications of a dominant epitope mutation and associated flanking amino acid substitutions on the capsid protein (CA) of SIV/simian-human immunodeficiency virus (SHIV). We show that a residue 2 mutation in the immunodominant p11C, C-M epitope (T47I) of SIV/SHIV not only decreased CA protein expression and viral replication, but it also blocked CA assembly in vitro and virion core condensation in vivo. However, these defects were restored by the introduction of upstream I26V and/or downstream I71V substitutions in CA. These findings demonstrate how flanking compensatory amino acid substitutions can facilitate viral escape from a dominant epitope-specific CTL response through the effects of these associated mutations on the structural integrity of SIV/SHIV.
Yeh
Wendy W
WW
Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Research East Room 113, 330 Brookline Ave., Boston, MA 02215, USA.
Cale
Evan M
EM
Jaru-Ampornpan
Pimkwan
P
Lord
Carol I
CI
Peyerl
Fred W
FW
Letvin
Norman L
NL
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002213:Capsid / Q000378:metabolism / Q000648:ultrastructure; D036022:Capsid Proteins / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000235:genetics*; D019143:Evolution, Molecular; D015683:Gene Products, gag / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D017354:Point Mutation; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000648:ultrastructure; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019065:Virus Assembly / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics
D036022:Capsid Proteins; D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag