Simian-human immunodeficiency virus escape from cytotoxic T-lymphocyte recognition at a structurally constrained epitope.
Virus-specific cytotoxic T lymphocytes (CTL) exert intense selection pressure on replicating simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1) in infected individuals. The immunodominant Mamu-A(*)01-restricted Gag p11C, C-M epitope is highly conserved among all sequenced isolates of SIV and therefore likely is structurally constrained. The strategies used by virus isolates to mutate away from an immunodominant epitope-specific CTL response are not well defined. Here we demonstrate that the emergence of a position 2 p11C, C-M epitope substitution (T47I) in a simian-human immunodeficiency virus (SHIV) strain 89.6P-infected Mamu-A(*)01(+) monkey is temporally correlated with the emergence of a flanking isoleucine-to-valine substitution at position 71 (I71V) of the capsid protein. An analysis of the SIV and HIV-2 sequences from the Los Alamos HIV Sequence Database revealed a significant association between any position 2 p11C, C-M epitope mutation and the I71V mutation. The T47I mutation alone is associated with significant decreases in viral protein expression, infectivity, and replication, and these deficiencies are restored to wild-type levels with the introduction of the flanking I71V mutation. Together, these data suggest that a compensatory mutation is selected for in SHIV strain 89.6P to facilitate the escape of that virus from CTL recognition of the dominant p11C, C-M epitope.
Peyerl
Fred W
FW
Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Barouch
Dan H
DH
Yeh
Wendy W
WW
Bazick
Heidi S
HS
Kunstman
Jennifer
J
Kunstman
Kevin J
KJ
Wolinsky
Steven M
SM
Letvin
Norman L
NL
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D015683:Gene Products, gag / Q000737:chemistry; D015750:Genes, gag; D006678:HIV / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D000882:Haplorhini; D006801:Humans; D008969:Molecular Sequence Data; D017354:Point Mutation; D011446:Prospective Studies; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D017931:DNA Primers; D000939:Epitopes; D015683:Gene Products, gag