Role for HLA class II molecules in HIV-1 suppression and cellular immunity following antiretroviral treatment
Uma Malhotra, … , Lawrence Corey, M. Juliana McElrath
Uma Malhotra, … , Lawrence Corey, M. Juliana McElrath
Published February 15, 2001
Citation Information: J Clin Invest. 2001;107(4):505-517. https://doi.org/10.1172/JCI11275.
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Article

Role for HLA class II molecules in HIV-1 suppression and cellular immunity following antiretroviral treatment

Abstract

HIV-1–infected patients treated early with combination antiretrovirals respond favorably, but not all maintain viral suppression and improved HIV-specific Th function. To understand if genetic factors contribute to this variation, we prospectively evaluated over 18 months 21 early-treated patients stratified by alleles of class II haplotypes. All seven subjects with the DRB1*13-DQB1*06 haplotype, but only 21% of other subjects, maintained virus suppression at every posttreatment measurement. Following HIV-1 p24 antigen stimulation, PBMCs from patients with this haplotype demonstrated higher mean lymphoproliferation and IFN-γ secretion than did cells from patients with other haplotypes. Two DRB1*13-restricted Gag epitope regions were identified, a promiscuous one that bound its putative restriction element with nanomolar affinity, and another that mapped to a highly conserved region. These findings suggest that class II molecules, particularly the DRB1*13 haplotype, have an important impact on virologic and immunologic responses. The advantage of the haplotype may relate to selection of key HIV-1 Th1 epitopes in highly conserved regions with avid binding to class II molecules. Eliciting responses to the promiscuous epitope region may be beneficial in vaccine strategies.

Authors

Uma Malhotra, Sarah Holte, Sujay Dutta, M. Michelle Berrey, Elizabeth Delpit, David M. Koelle, Alessandro Sette, Lawrence Corey, M. Juliana McElrath

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Figure 5

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HIV-1 p24-specific CD4+ T-cell clones from subject 1243 map to two epito...
HIV-1 p24-specific CD4+ T-cell clones from subject 1243 map to two epitopes between aa 251–270 (Gag 26) and have a Th1 phenotype. (a) Clone number 14 proliferates when stimulated with peptides spanning HIV-1 p24 sequential aa 251–270 (TNNPPIPVGEIYKRWIILGL) and aa 261–280 (IYKRWIILGLNKIVRMYSPT). Clone number 64 proliferates when stimulated with HIV-1 p24 peptide spanning aa 251–270 (TNNPPIPVGEIYKRWIILGL), but not with HIV-1 p24 peptide spanning aa 261–280 (IYKRWIILGLNKIVRMYSPT). Data are expressed as Δ cpm, equal to mean cpm in antigen-stimulated cultures minus the mean cpm in medium alone, which was less than 500 cpm in each case. (b) Clone number 14 secretes high levels of IFN-γ when stimulated with peptides spanning HIV-1 p24 sequential aa 251–270 (TNNPPIPVGEIYKRWIILGL) and aa 261–280 (IYKRWIILGLNKIVRMYSPT). Clone number 64 secretes high levels of IFN-γ when stimulated with HIV-1 p24 peptide spanning aa 251–270 (TNNPPIPVGEIYKRWIILGL), but not with HIV-1 p24 peptide aa 261–280 (IYKRWIILGLNKIVRMYSPT). IFN-γ secretion (picograms per milliliter) is depicted as the amount secreted in antigen-stimulated cultures minus the amount in medium alone, which was less than 50 pg/ml. (c) Clone number 14 maps to epitope spanning aa 260–269. Proliferative responses were measured to 20-mer peptides spanning HIV-1 p24 sequential aa 251–270 and 261–280 and 10-mer peptides spanning aa 254–274 at 1 μM. The 10-mer peptide aa 260–269 was used at tenfold serial dilutions between 1.0 μM and 0.001 μM. Data are expressed as Δ cpm, equal to mean cpm in antigen-stimulated cultures minus the mean cpm in medium alone, which was less than 500 cpm in each case.