Cutaneous Disorders and Viral Gene Expression in HIV-1 Transgenic Mice

Abstract

Patients infected with HIV-1 experience several hyperproliferative skin disorders, including seborrheic dermatitis, ichthyosis, and psoriasis. Transgenic mice carrying a subgenomic HIV-1 proviral construct lacking the gag and pol genes were found to develop proliferative epidermal lesions, manifested as diffuse epidermal hyperplasia in homozygous transgenic mice and benign papillomas in heterozygous transgenic mice. Nonpapillomatous skin from both homozygotes and heterozygotes expressed viral RNA, and the viral envelope protein gp120 was localized to the suprabasal keratinocyte. Papillomas contained increased amounts of both viral mRNA and envelope glycoprotein. Exposure of transgenic mice to doses of ultraviolet B (UV-B) irradiation that induced cutaneous injury increased viral gene expression and resulted in the development of papillomas within 14-21 days. Cutaneous injury induced by phenol and liquid nitrogen had similar effects. These data support a role for HIV-1 gene products in the pathogenesis of proliferative epidermal disorders associated with HIV-1 infection. Further, they suggest that the process of wound repair increases HIV-1 gene expression in this transgenic mouse model.

Maternal-Fetal Interactions Affect Growth of Human Immunodeficiency Virus Type 1 Transgenic Mice

“…Nor can we exclude differences in renal metabolism of salt and water, particularly in view of the 10% reduction in weight in the first 24 h. Another possibility is that growth failure in mice homozygous for the transgene relates to abundant expression of viral gene products in skin. In this regard, homozygous neonatal mice uniformly develop a progressive, and potentially debilitating, skin disease characterized clinically by dry, thickened, scaling lesions and histologically by epidermal hyperproliferation and hyperkeratosis (34). Growth-retarded mice transgenic for the infectious HIV-1 provirus were also reported to manifest this phenotype (49).…”

“…Descriptions of the nephropathy that develops in heterozygous transgenics have been published previously (31,33). Transgenic mice also develop hyperproliferative skin disorders manifested as benign papillomas in heterozygous mice and diffuse epidermal hyperplasia in homozygotes (34). In addition to the skin lesions, homozygous mice develop a syndrome of growth failure and cachexia with lymphoproliferation, preservation of CD4+ and CD8+ T-lymphocyte number, thymic atrophy, and early death (32).…”

Expression of HIV-1 matrix protein p17 and association with B-cell lymphoma in HIV-1 transgenic mice

“…Under control of the LTR, viral RNA is expressed in various mouse tissues, including skin, kidney, spleen, and lymph nodes. A proportion of the heterozygous mice develop cataracts, cutaneous papillomas, and renal disease (24,26,27). We recently reported that Tg26 mice without cutaneous papillomas did not develop lymphomas, but that 15% of Tg26 mice with cutaneous papillomas spontaneously developed leukemia/lymphoma by 1 y of age, characterized by widespread lymphadenopathy, splenomegaly, and extranodal involvement of the liver, gastrointestinal tract, and central nervous system (25).…”

Congenital nuclear cataracts and uveitis in HIV-transgenic mice

“…Transgene RNA, assessed by Northern analysis, is expressed abundantly in muscle and skin and to a lesser extent in kidney, lymphoid tissue, intestine and eye. Other phenotypes included focal glomerulosclerosis, 19 cutaneous papillomas 20 and, in the homozygote, wasting and early death. 21 Transgene status was determined by Southern blotting, as described previously.…”

“…After paraffin embedding, 4 m sections were cut. Histochemical detection of HIV-1 envelope protein was performed exactly as previously described, 20 using a polyclonal sheep anti-gp120 antiserum (developed by M Phelan and obtained from ARRRP). This antiserum or its control, normal sheep serum, were diluted 1:2000 and applied to the sections for 1 h at 37°C.…”