Role for HLA class II molecules in HIV-1 suppression and cellular immunity following antiretroviral treatment.
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-gamma 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.
Malhotra
U
U
Program in Infectious Diseases, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D3-100, Seattle, WA 98109, USA.
Holte
S
S
Dutta
S
S
Berrey
M M
MM
Delpit
E
E
Koelle
D M
DM
Sette
A
A
Corey
L
L
McElrath
M J
MJ
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology; D018791:CD4 Lymphocyte Count; D016207:Cytokines / Q000096:biosynthesis; D004359:Drug Therapy, Combination; D015683:Gene Products, gag / Q000276:immunology; D005802:Genes, MHC Class II / Q000502:physiology*; D015497:HIV-1 / Q000187:drug effects*; D006683:HLA-DQ Antigens / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D008969:Molecular Sequence Data; D011446:Prospective Studies
D019380:Anti-HIV Agents; D016207:Cytokines; D015683:Gene Products, gag; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains