Refinement of the HIVAN1 Susceptibility Locus on Chr. 3A1-A3 via Generation of Sub-Congenic Strains

Abstract

HIV-1 transgenic mice on the FVB/NJ background (TgFVB) represent a validated model of HIV-associated nephropathy (HIVAN). A major susceptibility locus, HIVAN1, was previously mapped to chromosome 3A1-A3 in a cross between TgFVB and CAST/EiJ (CAST) strains, and introgression of a 51.9 Mb segment encompassing HIVAN1 from CAST into TgFVB resulted in accelerated development of nephropathy. We generated three sub-congenic strains carrying CAST alleles in the proximal or distal regions of the HIVAN1 locus (Sub-II, 3.02–38.93 Mb; Sub-III, 38.45–55.1 Mb and Sub-IV, 47.7–55.1 Mb, build 38). At 5–10 weeks of age, histologic injury and proteinuria did not differ between HIV-1 transgenic Sub-II and TgFVB mice. In contrast, HIV-1 transgenic Sub-III and Sub-IV mice displayed up to 4.4 fold more histopathologic injury and 6-fold more albuminuria compared to TgFVB mice, similar in severity to the full-length congenic mice. The Sub-IV segment defines a maximal 7.4 Mb interval for HIVAN1, and encodes 31 protein coding genes: 15 genes have missense variants differentiating CAST from FVB, and 14 genes show differential renal expression. Of these, Frem1, Foxo1, and Setd7 have been implicated in the pathogenesis of nephropathy. HIVAN1 congenic kidneys are histologically normal without the HIV-1 transgene, yet their global transcriptome is enriched for molecular signatures of apoptosis, adenoviral infection, as well as genes repressed by histone H3 lysine 27 trimethylation, a histone modification associated with HIV-1 life cycle. These data refine HIVAN1to 7.4 Mb and identify latent molecular derangements that may predispose to nephropathy upon exposure to HIV-1.

HIV-Associated Nephropathy in Africa: Pathology, Clinical Presentation and Strategy for Prevention

“…Experimental studies mapped a major HIVAN susceptibility locus (HIVAN1) to chromosome 3A1-A3 in a cross between HIV-1 transgenic mice on the FVB/NJ background (TgFVB) which is a documented model of HIVAN and CAST/EiJ (CAST) strains, and introgression of a 51.9 Mb segment covering HIVAN1 from CAST into TgFVB caused enhanced progress of nephropathy. So, dormant molecular disorders may lead to nephropathy when exposed to HIV-1 [ 34 ].…”

GWAS in Mice Maps Susceptibility to HIV-Associated Nephropathy to the Ssbp2 Locus

“…Kidney histology was scored by a renal pathologist (VDD) who was blinded to the genotype on the basis of analysis of ≥200 glomeruli per mouse in whole kidney cross-sections of cortex and medulla. The percentage of glomeruli with segmental and global sclerosis, the percentage of tubules with casts and cystic dilation, the percentage of the cortical area with tubular atrophy/interstitial fibrosis, and the percentage of the cortical area with interstitial inflammation were quantified as previously described 37 – 39 , 44 . Proteinuria and hematuria in the urine were determined using the Chemstrip 10 UA (Roche) according to manufacturer’s instructions and were scored by a single investigator (ND).…”

“…These mice were crossed with the HIV-1 transgenic mouse line TgN(pNL43d14) Lom26 (TgFVB) maintained on the inbred FVB/NJ background. 39 Animals were euthanized at 8 weeks of age. A final urine collection was completed, serum was collected via cardiac puncture, and kidneys were collected for phenotypic studies and for comparisons between the different strains.…”

“…F1 hybrids between HIV-1 transgenic FVB/NJ (TgFVB) and other inbred strains showed that C57BL/6J, CAST/EiJ, and BALB/cJ backgrounds conferred resistance compared with CBA/J, DBA/2J, and C3H/HeJ backgrounds. [37][38][39][40] Using traditional mapping crosses between strains with contrasting susceptibility, we previously localized four quantitative trait loci (QTLs) for nephropathy in this mouse model. [37][38][39][40][41] However, classic mapping crosses between two inbred strains have very low resolution, complicating identification of underlying susceptibility genes.…”

“…We have previously reported that the severity of HIVAN in HIV-1 transgenic mice varied on the basis of genetic background. F1 hybrids between HIV-1 transgenic FVB/NJ (TgFVB) and other inbred strains showed that C57BL/6J, CAST/EiJ, and BALB/cJ backgrounds conferred resistance compared with CBA/J, DBA/2J, and C3H/HeJ backgrounds 37 – 40 . Using traditional mapping crosses between strains with contrasting susceptibility, we previously localized four quantitative trait loci (QTLs) for nephropathy in this mouse model 37 – 41 .…”