Carrington M; Conference on Retroviruses and Opportunistic Infections.

Abstr 10th Conf Retrovir Oppor Infect Feb 10 14 2003 Hynes Conv Cent Boston Mass USA Conf Retrovir Oppor Infect 10th 2003 Boston Mass. 2003 Feb 10-14; 10: abstract no. 55.

NCI-Frederick, MD

BACKGROUND: Natural killer (NK) cells are an important component of the innate immune system and provide the first line of defense in the early stages of the immune response against viral infections, by production of cytokines, and direct cytotoxicity. Method: The killer immunoglobulin-like receptors (KIR) on NK cells regulate inhibition and activation of NK cell responses through recognition of HLA class I molecules on target cells. KIR and HLA loci are both highly polymorphic and particular HLA class I products bind and trigger cell surface receptors specified by KIR genes, raising the possibility of an epistatic relationship between KIR and HLA in NK cell mediated immunity.RESULTS: Indeed, we have found that 1 activating KIR allele, KIR3DS1, in combination with HLA-B alleles that encode molecules having isoleucine at position 80 (HLA-B Bw4-80I) resulted in delayed progression to AIDS. In the ence of KIR3DS1, HLA-B Bw4-80I alleles were not associated with any of the AIDS outcomes measured. Conversely, in the ence of HLA-B Bw4-80I alleles, KIR3DS1 is significantly associated with more rapid progression to AIDS. Thus, an additive effect of the 2 unlinked loci would not explain the observed protection in individuals who have both variants, and only a model involving an epistatic interaction between the 2 loci appropriately fits the observations. The synergistic effect of these loci was most apparent on progression to CD4 T-cell depletion, suggesting that a protective response of NK cells involving KIR3DS1 and its HLA class I ligands begins early after HIV-1 infection. Genotypic analysis of families, as well as sequence analyses of KIR haplotypes indicates that the inhibitory KIR3DL1 and the activating KIR3DS1 segregate as alleles of one another. At least 20 additional alleles (all encoding inhibitory molecules) of the KIR3DL1/3DS1 gene have been identified. Some of the variants are not expressed, and others are expressed at either low or high levels, which could affect potential interactions between these KIR molecules and their infected cell targets. It is also possible that the various KIR3DL1/3DS1 molecules might differ in their binding affinity for their HLA ligand, which may in turn influence AIDS progression. Conclusion: We hypothesize that this variation may play a role in AIDS pathogenesis and we have begun to subtype the KIR3DL1/3DS1 alleles in our AIDS cohorts.

Publication Types:

• Meeting Abstracts

Keywords:

• Acquired Immunodeficiency Syndrome
• Alleles
• Disease Progression
• HIV Infections
• HLA Antigens
• HLA-B Antigens
• Haplotypes
• Killer Cells, Natural
• Receptors, Immunologic
• Receptors, KIR
• genetics
• immunology

Other ID:

• GWAIDS0021543

UI: 102261167

From Meeting Abstracts