Correlates of spontaneous viral control among long-term survivors of perinatal HIV-1 infection expressing human leukocyte antigen-B57.
OBJECTIVE
We sought to identify immunologic and virologic correlates of spontaneous viral control among long-term survivors of perinatal HIV infection expressing the protective human leukocyte antigen (HLA)-B57 allele.


METHODS
The frequency, epitope specificity, and functional attributes of HIV-specific T cells and sequence variation within B57-restricted epitopes were compared between 'spontaneous controllers' who maintained normal CD4 percentages and viral loads less than 3000 copies/ml without antiretroviral therapy, and 'treated progressors' who had initiated HAART.


METHODS
Recognition of HIV optimal epitopes was assessed by interferon gamma (IFNgamma) enzyme-linked immunosorbent spot. Functional characterization of CD8 cells targeting B57 epitopes was performed by staining for cytokine production (intracellular IFNgamma, interleukin-2, tumor necrosis factor alpha) and degranulation. Sequencing of autologous RNA was performed to determine the prevalence of viral escape mutations within B57-restricted epitopes and associated compensatory mutations.


RESULTS
HLA-B57 remained immunodominant during chronic infection in both controllers and progressors, but controllers recognized fewer epitopes and targeted epitopes within Gag and reverse transcriptase only, whereas progressors demonstrated a broader response targeting additional proteins. No individual epitope was targeted more frequently by spontaneous controllers. CD8 cytokine production patterns were heterogeneous among individuals and even among different epitopes in the same individual and did not correlate with spontaneous viral control. Extensive sequence variation within B57 epitopes was observed in both groups, but only progressors displayed additional capsid mutations that are known to offset the viral fitness cost of B57-driven immune escape.


CONCLUSIONS
Among HLA-B57-positive long-term survivors, spontaneous control of viremia is not associated with a qualitatively or quantitatively superior T-cell response, but with uncompensated fitness-attenuating mutations in the viral capsid.
Ragon Institute of MGH, MIT, Charlestown, Massachusetts, USA.
Yanhua
Y
Tang
Sihong
S
Huang
Jacqueline
J
Dunkley-Thompson
Julianne C
JC
Steel-Duncan
Elizabeth G
EG
Ryland
M Anne
MA
St John
Rohan
R
Hazra
Celia D C
CD
Christie
Margaret E
ME
Feeney
D000293:Adolescent; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002648:Child; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D015235:HLA-B Antigens / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008297:Male; D014766:Viremia
D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; C103707:HLA-B57 antigen; D007371:Interferon-gamma