Mapping a locus for susceptibility to HIV-1-associated nephropathy to mouse chromosome 3

Abstract

HIV-1-associated nephropathy (HIVAN) is a major complication of HIV-1 infection with distinct pathologic features. Introduction of the HIV-1 genome into mice results in a renal disease with all of the histologic and clinical hallmarks of HIVAN on the FVB/N genetic background (TgFVB). We assessed the influence of genetic background on the development or progression of HIVAN by making F1 hybrids of TgFVB with five other inbred strains (CBA, DBA/2, CAST/Ei, C3H/He, BALB/c) and determining phenotypes relevant to renal failure among transgenic offspring (histology, blood urea nitrogen, proteinuria, serum albumin, and serum cholesterol). We found striking variation in phenotypes among F1s, ranging from severe renal disease to no renal disease whatsoever (P<0.001 for ANOVA across all groups). To map genes responsible for this variation, we produced a backcross of TgFVB/CAST F1 x TgFVB. By genome-wide analysis of linkage in 185 heterozygous transgenic backcross mice, we identified a locus on chromosome 3A1-3, HIVAN1, that showed highly significant linkage to renal disease [logarithm of odds (lod) score 4.9 at D3Mit203, accounting for 15% of the variance in renal disease]. Other loci on chromosomes 11, 14, and 16 were suggestive of linkage to renal disease, and a locus on chromosome 9 influenced serum cholesterol but not nephropathy. Interestingly, HIVAN1 is syntenic to human chromosome 3q25-27, an interval showing suggestive evidence of linkage to various nephropathies. These findings demonstrate a strong genetic influence on HIVAN and demonstrate a major renal disease susceptibility locus on mouse chromosome 3A1-3.

Fig. 1.

Renal pathology in transgenic HIV-1 backcross mice. Periodic-acid Schiff-stained kidney sections of HIV-1 transgenic mice at 3 months of age from the TgFVB × TgFVB/CAST backcross are shown. (a and c) A mouse with marked renal disease. (b and d) A mouse with no detectable disease. (a and b) Low-power views. The affected kidney shows microcystic tubular dilatation, tubular casts, interstitial infiltrate, and focal segmental glomerulosclerosis. (c and d) Higher-power magnification of glomeruli. The affected kidney shows a collapsing glomerulopathy reminiscent of human HIVAN.

Fig. 2.

Distribution of phenotypes in F₀, F₁, and backcross cohort of HIV-1 transgenic mice. A TgFVB/CAST F₁ was backcrossed to TgFVB, and the transgene heterozygote progeny were phenotyped as described in Methods. The phenotypic values for each transgene heterozygote mouse in the parental and backcross cohorts are shown as follows: composite score (a), histology score (b), BUN (c), dipstick proteinuria (d), albumin (e), and cholesterol (f). The mean value for each group is indicated by the horizontal bars.

Fig. 3.

Linkage in the backcross cohort. Multipoint lod score plots for phenotypes on chromosomes 3 (a), 11 (b), 14 (c), and 9 (d) for the six primary phenotypes are shown. Map distance is presented in cM. The positions of informative markers genotyped are shown above each plot. The dashed horizontal bar indicates the threshold (3.3) for genome-wide significance for a backcross. The solid bar above the chromosome 3 lod plot indicates the 95% confidence interval for HIVAN1 computed by bootstrap resampling (composite score). The location of the Apoa1/c3/a4/a5 gene cluster is shown above the lod plot for chromosome 9.