All ETDs from UAB

Advisory Committee Chair

Richard A Kaslow

Advisory Committee Members

Jianming Tang

Allan Zajac

Lou Justement

Kui Zhang

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Human leukocyte antigen (HLA) molecules influence the adaptive and innate immune responses through interactions with cytotoxic T lymphocytes and natural killer cells (NK). HLA influence the activation state of NK through direct binding to killer immunoglobulin-like receptors (KIR) and presentation of HLA-derived peptides to NKG2 receptors. Activated NK can kill HIV-infected cells through direct cytolysis and release cytokines that influence other aspects of the immune system. Variations in KIR gene content and allelic variants have been associated with autoimmunity, transplantation success, and infectious diseases such as hepatitis C and HIV/AIDS. We investigated the impact of KIR genes and potential KIR-HLA interactions on heterosexual HIV-1 transmission among 566 discordant couples from Lusaka, Zambia. KIR2DS4*001, the only allele of KIR2DS4 known to encode a full-length (functional) receptor, was associated with relatively high HIV-1 viral load in index (HIV-1 seropositive) partners and with accelerated transmission of HIV-1 to seronegative partners. This association did not rely on interaction with the putative ligand HLA-Cw*04. In addition to interaction with KIR, HLA molecules also influence NK activation through the CD94/NKG2 family of receptors. HLA-E binds peptides from the amino acid residues 3-11 of the signal peptide of HLA-A, -B, -C molecules and presents these to CD94/NKG2 receptors on NK. The inhibitory NKG2A has a higher affinity for HLA-E than the activating NKG2C receptor. HLA-A and HLA-C alleles carry methionine (Met) at anchor position 2 (P2), while those of HLA-B carry Met or threonine (Thr). Because these different P2 residues can alter HLA-E binding to its cognate NKG2 receptors, we examined associations of P2-Thr/Met polymorphisms with acquisition and control of HIV-1 infection. Among Zambian couples (N=566) initially serodiscordant for HIV-1, the presence of P2-Met accelerated acquisition of infection (RH=1.79, p<0.0001). P2-Met also accelerated acquisition among 64 seroconverters from Rwanda (RH=1.83, p=0.048). This dissertation details the novel HLA and KIR polymorphisms that we have discovered to impact HIV-1 transmission, acquisition, and viral load in native Africans.

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