Elevated levels of tumor necrosis factor alpha (TNF-alpha) in human immunodeficiency virus type 1-transgenic mice: prevention of death by antibody to TNF-alpha

Abstract

Homozygous human immunodeficiency virus type 1 (HIV-1)-transgenic mice (Tg26) appear normal at birth but die within 3 to 4 weeks. The skin of these animals shows diffuse scaling and high-level expression of both HIV-1 mRNA and gp120. Previous experiments showed that treatment with human chorionic gonadatropin (hCG) prevented death and the expression of HIV-1 mRNA and gp120. The present experiments were initiated to study the role of tumor necrosis factor alpha (TNF-alpha) in HIV-1-induced pathology. Examination of the sera of Tg26 mice revealed a 50-fold increase in TNF-alpha levels compared to those in nontransgenic mice. Treatment with antibody to TNF-alpha prevented death, resulted in near normal growth, and produced a marked decrease in skin lesions and a profound reduction in the expression of HIV-1 mRNA and gp120. Both TNF-alpha antibody and hCG reduced TNF-alpha levels in sera by approximately 75%. We conclude that TNF-alpha contributes in a major way to HIV-1-induced pathology in transgenic mice and that both hCG and antibody to TNF-alpha prevent the development of pathology by suppressing the level of TNF-alpha.

FIG. 1.

Cytokine levels in sera of nontransgenic, Tg26 heterozygous, and Tg26 homozygous mice. (A) IL-1α; (B) IL-1β; (C) IL-6; (D) TNF-α. Serum samples from eight animals were collected and analyzed in triplicate. Bars denote the standard error of the mean. *P < 0.05; **P < 0.005.

FIG. 2.

Body weight of Tg26 homozygous mice treated with PBS (8 animals), TNF-α (4 animals), or anti-TNF-α (10 animals) and body weight of Tg26 heterozygous mice treated with PBS (7 animals). Bars denote the standard error of the mean.

FIG. 3.

Effects of TNF-α and anti-TNF-α on gp120 expression in the skin of Tg26 homozygous mice. Sections of skin from Tg26 mice treated with PBS (A), anti-TNF-α (B), or TNF-α (C) and incubated with polyclonal sheep anti-gp120 immunoglobulin G (1:2,000 dilution); sections of skin from Tg26 mice incubated with normal sheep serum (D). Immunoperoxidase staining was performed by the streptavidin-biotin complex technique using a Histostain-SP kit (Zymed, Burlingame, Calif.). All sections were counterstained with hematoxylin.

FIG. 4.

Effect of TNF-α, anti-TNF-α, and hCG on HIV-1 mRNA expression in the skin of Tg26 homozygous mice as determined by Northern blot analysis. Hybridization was carried out with an HIV-1-specific Nef cDNA probe (1). RNA samples in each lane were equalized prior to loading on the gel and confirmed by ethidium bromide staining of the gel (not shown).

FIG. 5.

TNF-α concentration in sera of 20- to 30-day-old Tg26 homozygous mice that had been treated with PBS, anti-TNF-α, or hCG. Each sample was assayed in triplicate, and the bars denote the standard error of the mean. *P < 0.005.