HLA-B*35-Px–mediated Acceleration of HIV-1 Infection by Increased Inhibitory Immunoregulatory Impulses
Goedert, James J.
Sundberg, Eric J.
Cung, Thai Duong Hong
Burke, Patrick S.
Martin, Maureen P.
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CitationHuang, Jinghe, James J. Goedert, Eric J. Sundberg, Thai Duong Hong Cung, Patrick S. Burke, Maureen P. Martin, Liliana Preiss, et al. 2009. HLA-B*35-Px–mediated acceleration of HIV-1 infection by increased inhibitory immunoregulatory impulses. The Journal of Experimental Medicine 206(13): 2959-2966.
AbstractA subset of HLA-B*35 alleles, B*35-Px, are strongly associated with accelerated HIV-1 disease progression for reasons that are not understood. Interestingly, the alternative set of B*35 subtypes, B*35-PY, have no detectable impact on HIV-1 disease outcomes, even though they can present identical HIV-1 epitopes as B*35-Px molecules. Thus, the differential impact of these alleles on HIV-1 disease progression may be unrelated to interactions with HIV-1–specific CD8+ T cells. Here, we show that the B*35-Px molecule B*3503 binds with greater affinity to immunoglobulin-like transcript 4 (ILT4), an inhibitory MHC class I receptor expressed on dendritic cells, than does the B*35-PY molecule B*3501, even though these two B*35 molecules differ by only one amino acid and present identical HIV-1 epitopes. The preferential recognition of B*3503 by ILT4 was associated with significantly stronger dendritic cell dysfunction in in vitro functional assays. Moreover, HIV-1–infected carriers of B*3503 had poor dendritic cell functional properties in ex vivo assessments when compared with carriers of the B*3501 allele. Differential interactions between HLA class I allele subtypes and immunoregulatory MHC class I receptors on dendritic cells thus provide a novel perspective for the understanding of MHC class I associations with HIV-1 disease progression and for the manipulation of host immunity against HIV-1.
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