Maternal transmission of human immunodeficiency virus escape mutations subverts HLA-B57 immunodominance but facilitates viral control in the haploidentical infant.
Expression of HLA-B57 is associated with restricted replication of human immunodeficiency virus (HIV), but the mechanism for its protective effect remains unknown. If this advantage depends upon CD8 T-cell recognition of B57-restricted epitopes, mother-to-child transmission of escape mutations within these epitopes could nullify its protective effect. However, if the B57 advantage is largely mediated by selection for fitness-attenuating viral mutations within B57-restricted epitopes, such as T242N in TW10-Gag, then the transmission of such mutations could facilitate viral control in the haploidentical infant. We assessed the consequences of B57-associated mutations on replication capacity, viral control, and clinical outcome after vertical transmission in 13 mother-child pairs. We found that expression of HLA-B57 was associated with exceptional control of HIV during infancy, even when mutations within TW10 and most other B57-restricted epitopes were transmitted, subverting the natural immunodominance of HLA-B57. In contrast, most B57-negative infants born to B57-positive mothers progressed rapidly to AIDS. The presence of T242N led to a reproducible reduction in viral fitness, as demonstrated by in vitro assays using NL4-3 constructs encoding p24 sequences from individual mothers and infants. Associated compensatory mutations within p24-Gag were observed to reverse this impairment and to influence the propensity of T242N to revert after transmission to B57-negative hosts. Moreover, primary failure to control viremia was observed in one infant to whom multiple compensatory mutations were transmitted along with T242N. These parallel in vivo and in vitro data suggest that HLA-B57 confers its advantage primarily by driving and maintaining a fitness-attenuating mutation in p24-Gag.
Schneidewind
Arne
A
Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA.
Tang
Yanhua
Y
Brockman
Mark A
MA
Ryland
Elizabeth G
EG
Dunkley-Thompson
Jacqueline
J
Steel-Duncan
Julianne C
JC
St John
M Anne
MA
Conrad
Joseph A
JA
Kalams
Spyros A
SA
Noel
Francine
F
Allen
Todd M
TM
Christie
Celia D
CD
Feeney
Margaret E
ME
D000595:Amino Acid Sequence; D000818:Animals; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D006678:HIV / Q000235:genetics / Q000254:growth & development* / Q000276:immunology*; D016655:HIV Core Protein p24 / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000635:transmission / Q000821:virology; D015235:HLA-B Antigens / Q000276:immunology*; D006801:Humans; D007223:Infant; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000276:immunology*; D017422:Sequence Analysis, DNA
D016655:HIV Core Protein p24; D015235:HLA-B Antigens; C103707:HLA-B57 antigen