CERTAIN HLA-DR5 AND HLA-DR6 MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-IIALLELES ARE ASSOCIATED WITH A CD8 LYMPHOCYTIC HOST RESPONSE TO HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 CHARACTERIZED BY LOW LYMPHOCYTE VIRAL STRAIN HETEROGENEITY AND SLOW DISEASE PROGRESSION

Either of two structurally related major histocompatibility complex cl ass II alleles, DRB11102, which encodes a DR5 specificity, or DRB1*13 01, which encodes a DR6 specificity, was found in 67% of individuals r esponding to human immunodeficiency virus type 1 (HIV-1) infection wit h a syndrome characterized by persistent circulating and diffusely inf iltrative CD8 lymphocytosis (DILS), slow progression to opportunistic infections, and delayed CD4 T-cell depletion. These alleles were prese nt in only 28% of ethnically matched HIV-positive controls (P = 0.001) . The frequency of DRB11301 was increased in both Blacks and Caucasia ns with this syndrome, while that of DRBI1102 was increased only in B lacks, where 80% had either of these alleles. To investigate whether t he host response associated with these alleles influences the evolutio nary divergence of the HIV-1 genome, sequencing of the envelope V3 loo p was performed. This revealed a significantly diminished lymphocyte v iral heterogeneity com pared with random HIV+ controls matched for CD4 T-cell levels. These results suggest that the immunogenetics of the h ost influence the nature of the immune response to HIV-1, which may le ad to constrained evolution of HIV-1 gene products. Of possible releva nce, the alpha-helical third diversity region common to both the DRB1 1102 and DRB11301 allelic products was noted to have homology with th e C-terminal region of the HIV-1 envelope V3 loop at six of nine conse cutive residues. This suggests the possibility that these alleles may bias the anti-HIV T-cell receptor repertoire through a mimicry mechani sm.