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Elevated serum levels of heat shock protein 70 precede the development of AIDS-non-Hodgkin lymphoma in carriers of the common and highly conserved HLA-B8-DR3 haplotype
Infectious Agents and Cancervolume 5, Article number: A25 (2010)
Polymorphisms in the tumor necrosis factor (TNF) and lymphotoxin alpha (LTA) genes, by themselves or in combination with nearby specific human leukocyte antigen (HLA) loci, have been associated with classical and AIDS-related non-Hodgkin lymphoma (NHL). However, whether those gene variants represent true etiologic factors remains uncertain because they are part of the conserved and extended HLA-B*08-containing AH8.1. Building on recent observations linking the MHC-encoded heat shock protein 70 (Hsp70) to lymphomagenesis, we hypothesized that concomitant carriage of presumably high TNF and Hsp70 producing gene variants on AH8.1 may predispose HIV-infected individuals to AIDS-NHL. To test this hypothesis, we have compared Hsp70 serum levels in the years preceding the diagnosis of AIDS-NHL in carriers vs. non-carriers of AH8.1.
Materials and methods
A Caucasian case-control sample (n=169 pairs) was nested in the Multicenter AIDS Cohort Study (MACS). Cases are participants diagnosed with AIDS-NHL prior to April 2002, matched 1:1 with HIV+ NHL-free controls on duration of HIV infection and availability of serum samples at time points 3-5 years; 1-3 years; and <1 year prior to NHL diagnosis. Typed loci are HLA-B, HLA-DRB1, and 6 MHC class III single nucleotide polymorphisms (SNPs) from TNF and complement factor gene clusters. Hsp70 levels were measured by an ultra-sensitive ELISA. Extended MHC haplotypes were estimated via the EM-algorithm and were modeled as fixed main and interaction (with time) effects in a mixed linear model with adjustment for the CD4+ counts at the time of NHL diagnosis separately in cases and controls. A random model was fitted to account for the different levels of Hsp70 at the earliest time point.
No MHC haplotype was associated with a change in Hsp70 levels in cases or controls during the 5 years preceding NHL. However, when the study was restricted to the subset of cases who developed NHL as their AIDS-defining condition (vs. NHL subsequent to another AIDS-defining condition), carriage of AH8.1 haplotypes was significantly (p=0.0002-0.006) associated with increasing Hsp70 levels in the cases but not in the matched controls. Conversely, the common HLA-B7-DR15 haplotype appears to be protective and associated with decreasing Hsp70 levels.
An altered level of Hsp70 may be a component of the AH8.1-mediated pathogenetic pathway in AIDS NHL, perhaps through the action of Hsp70 as a B-cell stimulatory molecule. Investigation of Hsp70 promoter variants in AIDS-NHL is a worthy undertaking, especially if the association can be replicated in larger studies.
This article has been published as part of Infectious Agents and Cancer Volume 5 Supplement 1, 2010: Proceedings of the 12th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI).The full contents of the supplement are available online at http://www.biomedcentral.com/1750-9378/5?issue=S1.