HIV immune escape at an immunodominant epitope in HLA-B*27-positive individuals predicts viral load outcome.
The CTL response in HLA-B*27(+) HIV-infected individuals is characterized by an immunodominant response to a conserved epitope in gag p24 (aa 263-272, KRWIILGLNK; KK10). Mutations resulting in substitution of the arginine (R264) at position 2 of this epitope have been identified as escape mutations. Nineteen HLA-B*27(+) long-term nonprogressors were identified from an Australian cohort with an average follow-up of 16 y following infection. Viral and host genetic factors impacting on disease progression were determined at multiple time points. Twelve of 19 had wild-type sequences at codon 264 at all time points; 7 of 19 carried CTL escape variants. Median viral load and CD4(+) T cell counts were not significantly different between these groups at enrollment. Viral load, as judged by levels at their last visit (1,700 and 21,000 RNA copies/ml, respectively; p = 0.01) or by time-weighted area under the curve was higher in the escape group (p = 0.02). Escape mutants at other HLA-B*27-restricted epitopes were uncommon. Moreover, host polymorphisms, such as CCR5Δ32, CCR2-64I, and SDF1-3'A, or breadth of TCR repertoire responding to KK10 did not segregate to wild-type or escape groups. Host and viral factors were examined for a relationship to viral load. The only factor to affect viral load was the presence of the R264 escape mutations at the immunodominant epitope. CTL escape at R264 in the KK10 epitope is a major determinant of subsequent viral load in these HLA-B*27(+) individuals.
Immunovirology Laboratory, St Vincent's Centre for Applied Medical Research, Darlinghurst, New South Wales, Australia.
Palanee
P
Ammaranond
David J
DJ
van Bockel
Kathy
K
Petoumenos
Marylin
M
McMurchie
Robert
R
Finlayson
Melanie G
MG
Middleton
Miles P
MP
Davenport
Vanessa
V
Venturi
Kazuo
K
Suzuki
Linda
L
Gelgor
John M
JM
Kaldor
David A
DA
Cooper
Anthony D
AD
Kelleher
D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D001120:Arginine / Q000235:genetics; D003062:Codon / Q000276:immunology; D017124:Conserved Sequence / Q000235:genetics / Q000276:immunology; D018450:Disease Progression; D016655:HIV Core Protein p24 / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D015235:HLA-B Antigens / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D006801:Humans; D057131:Immune Evasion / Q000235:genetics / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology / Q000821:virology; D019562:Viral Load / Q000235:genetics / Q000276:immunology*
D003062:Codon; D016655:HIV Core Protein p24; D015235:HLA-B Antigens; D016056:Immunodominant Epitopes; C514799:p24 protein, Human Immunodeficiency Virus Type 1; D001120:Arginine