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.
Highlights
HIV-1 associated nephropathy (HIVAN) is a major complication of HIV-1 infection, and results in end-stage renal disease without antiviral treatment [1, 2]
Mice do not have an APOL1 ortholog, transgenic expression of a replication deficient HIV-1plasmid that contains all the structural viral proteins except Gag and Pol reproduces characteristic lesions of HIVAN in the FVB/NJ genetic background (TgFVB strain) [4,5,6]. This finding indicates that perturbations in alternative biological pathways, in the absence of APOL1, can produce HIVAN in the mammalian kidney, and analysis of mouse models of HIVAN may inform the pathogenesis of human disease
Mice do not have an APOL1 ortholog, the TgFVB mice recapitulates all of the clinical and molecular features of HIVAN [4,5,6], providing a model enabling for studying molecular mechanisms of glomerulosclerosis independent or downstream of APOL1
Summary
HIV-1 associated nephropathy (HIVAN) is a major complication of HIV-1 infection, and results in end-stage renal disease without antiviral treatment [1, 2]. Mice do not have an APOL1 ortholog, transgenic expression of a replication deficient HIV-1plasmid that contains all the structural viral proteins except Gag and Pol reproduces characteristic lesions of HIVAN in the FVB/NJ genetic background (TgFVB strain) [4,5,6] This finding indicates that perturbations in alternative biological pathways, in the absence of APOL1, can produce HIVAN in the mammalian kidney, and analysis of mouse models of HIVAN may inform the pathogenesis of human disease. While wild-type FVB-HIVAN1CAST mice were phenotypically normal, HIV-1 transgenic counterparts developed early onset and more severe kidney disease by 6–8 weeks of age compared to TgFVB This initial congenic interval contained over 300 protein coding genes, leaving open the possibility that multiple genes contribute to increased susceptibility to nephropathy. These new HIVAN1 sub-congenic strains allowed us to refine the HIVAN1 locus to a maximum 7.4Mb interval, enabling detailed annotation of positional candidates and analysis of molecular pathways producing susceptibility to nephropathy
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