MHC ancestral haplotypes containing HLA-B8 and B35 are associated with different patters of HIV-1 disease progression and complications
Cameron, P.U., Mallal, S.A., Witt, C., French, M.A.H. and Dawkins, R.L. (1995) MHC ancestral haplotypes containing HLA-B8 and B35 are associated with different patters of HIV-1 disease progression and complications. In: 2nd National Conference on Human Retroviruses and Related Infections, 27 January - 2 Feb 1995, Washington DC.
We have determined the effect of MHC genes on the survival of a cohort of 450 HIV infected subjects followed between 1983 and 1992. Among 130 patients whose seroconversion time was known, haplotypes bearing B8 or B35 conferred increased risk for early HIV-1 related death compared to those without these haplotypes [relative hazard 2.5 and 8.1, p=0.03 and 0.0001 respectively]. HLA B8 and the 8.1 ancestral haplotype [A1, B8, C4AQO, C481, BfS, DR3, DQ2] acted early in the disease and was associated with rapid early loss of CD4 cells [p=0.004 log rank test, median time to CD4 less than 20% 19 months compared to 58 months in non HLA B8s] but did not affect survival after the CD4 T cells count fell below 20% [p=0.39, median survival=55 months compared to 46 months in non HLA B8s]. Analysis of the phenotypes for the presence of parts of the 8.1 Ancestral Haplotype mapped the effect to the central MHC between HLA-B and complement C4, a region known to contain the TNF gene family. In contrast the haplotypes carrying B35 were found to effect B35 were found to effect survival in seroconverters by markedly reducing late survival. Early loss of CD4 cells was no greater in those with B35 than in those without this antigen [p=0.83]. Survival was reduced after the CD4 cell count had fallen below 20% [p=0.003, median survival =42 months compared to 74 months in non HLA B35s]. Several late complications of HIV-1 infection accounted for this difference, including an increase CD4 adjusted risk for cryptococcal meningitis [RH=3.1, p=0.017] and HIV encephalopathy [RH=2.1, p=0.03]. Disseminated MAC infection was also more frequent in these subjects [CD4 adjusted RH=2.9, p=0.002], such that the estimated probability of MAC infection in individuals with HLA B35 approached 100% as the CD4 count fell below 10 x 10(6)/L. In Cox proportional hazards survival models the effect of the 8.1AH was completely lost when CD4 T cells were included in the model but the influence of haplotypes containing HLA B35 was independent of blood CD4 cells or serum IgA levels. These data suggest the 8.1AH acts early in HIV-1 by affecting the rate of loss of CD4 cells, but the B35 containing haplotypes are associated with reduced survival as a result of a late CD4 independent effect predisposing to infection by intracellular pathogens.
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