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 FVB͞N 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, DBA͞2, CAST͞Ei, C3H͞He, BALB͞c) 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 TgFVB͞CAST F1 ؋ 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.

HIV-1 Upregulates VEGF in Podocytes

“…One possible explanation is that these transgenic mice are on the C57/b6 background, which is known to be resistant to GS. 23 In contrast, recent studies have shown that podocyte-specific expression of Nef in transgenic mice on the FVB/N genetic background develop significant GS. 24 In these mice, podocytes exhibit a loss of differentiation markers in the absence of proliferation.…”

Genetic Susceptibility, HIV Infection, and the Kidney

“…For assessment of the influence of genetic background on the development of HIVAN, Tg26 mice were outcrossed with five other inbred strains to generate F1 hybrids. Transgenic F1 hybrids, which share 50% of their genome from each parental strain, demonstrated striking variations in renal disease, which were independent of transgene expression levels (79). Two strains, CAST/EiJ and Balb/cJ, were completely protected from renal disease.…”

“…These genetic modifiers may be identified by intercrossing that is susceptible to resistant strains. Therefore, in an informative mapping cohort between the susceptible Tg26 (FVBN/J) and resistant CAST/EiJ strains, a genome-wide analysis of linkage has identified a locus on mouse chromosome 3A1-3 that influences the HIVAN phenotype (named HIVAN1 locus) (79). It is interesting that this locus is syntenic to human chromosome 3q25-27, an interval that shows suggestive evidence of linkage to human diabetic and hypertensive nephropathies (81)(82)(83)(84).…”

In-Depth Review of Human Immunodeficiency Virus-Associated Nephropathy

“…Among all animal models, the HIV-transgenic mouse model, which expresses HIV genes on their murine genetic background ("transgenic 26" or "Tg26"), is the most studied one. Based on the existence of different renal phenotypes depending on the mice's genetic background, "HIVAN1" and "HIVAN2", the two susceptibility loci associated with HIVAN in Tg26 mice were identified (Gharavi et al, 2004;Chan et al, 2009).…”