Escape and compensation from early HLA-B57-mediated cytotoxic T-lymphocyte pressure on human immunodeficiency virus type 1 Gag alter capsid interactions with cyclophilin A.
Certain histocompatibility leukocyte antigen (HLA) alleles are associated with improved clinical outcomes for individuals infected with human immunodeficiency virus type 1 (HIV-1), but the mechanisms for their effects remain undefined. An early CD8(+) T-cell escape mutation in the dominant HLA-B57-restricted Gag epitope TW10 (TSTLQEQIGW) has been shown to impair HIV-1 replication capacity in vitro. We demonstrate here that this T(242)N substitution in the capsid protein is associated with upstream mutations at residues H(219), I(223), and M(228) in the cyclophilin A (CypA)-binding loop in B57(+) individuals with progressive disease. In an independent cohort of epidemiologically linked transmission pairs, the presence of these substitutions in viruses encoding T(242)N was associated with significantly higher plasma viremia in donors, further suggesting that these secondary mutations compensated for the replication defect of T(242)N. Using NL4-3 constructs, we illustrate the ability of these CypA loop changes to partially restore replication of the T(242)N variant in vitro. Notably, these mutations also enhanced viral resistance to the drug cyclosporine A, indicating a reduced dependence of the compensated virus on CypA that is normally essential for optimal infectivity. Therefore, mutations in TW10 allow HIV-1 to evade a dominant early CD8(+) T-cell response, but the benefits of escape are offset by a defect in capsid function. These data suggest that TW10 escape variants undergo a postentry block that is partially overcome by changes in the CypA-binding loop and identify a mechanism for an HIV-1 fitness defect that may contribute to the slower disease progression associated with HLA-B57.
Brockman
Mark A
MA
Partners AIDS Research Center, Massachusetts General Hospital-East, CNY 6625, Charlestown, MA 02129, USA.
Schneidewind
Arne
A
Lahaie
Matthew
M
Schmidt
Aaron
A
Miura
Toshiyuki
T
Desouza
Ivna
I
Ryvkin
Faina
F
Derdeyn
Cynthia A
CA
Allen
Susan
S
Hunter
Eric
E
Mulenga
Joseph
J
Goepfert
Paul A
PA
Walker
Bruce D
BD
Allen
Todd M
TM
D000595:Amino Acid Sequence; D002213:Capsid / Q000737:chemistry / Q000276:immunology*; D021984:Cyclophilin A / Q000378:metabolism; D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015235:HLA-B Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019562:Viral Load; D014771:Virion; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
D015235:HLA-B Antigens; C103707:HLA-B57 antigen; D016056:Immunodominant Epitopes; D054301:gag Gene Products, Human Immunodeficiency Virus; D021984:Cyclophilin A