HIV gp120 inhibits the somatotropic axis: a possible GH-releasing hormone receptor mechanism for the pathogenesis of AIDS wasting

Abstract

AIDS is often associated with growth retardation in children and wasting in adults. The dissociated envelope protein of the HIV (HIV-1), gp120, can be found in significant concentrations in the parenchyma and cerebrospinal fluid of brains in infected individuals, even in the earliest stages of HIV-1 disease. On the basis of this and the fact that we observed pentapeptide sequence homology between GH-releasing hormone (GHRH) and the V2 receptor-binding region of gp120, we initiated experiments to determine whether gp120 could affect GH secretion and growth in vivo and/or interact with anterior pituitary GHRH receptors in vitro. Although acute IV administration of gp120 in conscious rats had no effect on plasma GH levels, acute administration of gp120 (400 ng) into the brain significantly suppressed pulsatile GH release over a 6-h period compared with saline-injected controls. Furthermore, the putative gp120 antagonist, Peptide T (DAPTA), prevented the suppression of GH by gp120. In support of these in vivo findings, gp120 also significantly (P < 0.05) suppressed GHRH-stimulated GH release in static cultures of dispersed pituitary cells and from cells undergoing perifusion with the peptides. DAPTA prevented the GH suppression by gp120 in both of the pituitary cell paradigms. Furthermore, chronic administration of gp120 into the third ventricle significantly reduced body weight in juvenile rats, compared with saline-injected controls. Thus, gp120 appears to act both at the hypothalamus and pituitary to suppress GH release, and its action at these two locations is associated with a significant loss in body weight in chronically treated young animals. These findings may suggest a specific mechanism for the pathogenesis of wasting in HIV-1 patients that involves blockade of endogenous GHRH receptors by gp120.

Figure 1

(A) Effects of administration of gp120 (400 ng ICV) on circulating GH levels in conscious adult rats. (B) Effects of ICV administration of DAPTA (Peptide T) in the presence of gp120 on circulating GH levels in conscious adult rats. (C) Area beneath the curve of GH in control (saline), gp120, and gp120 + DAPTA-treated adult rats. ∗, P < 0.05 vs. saline controls.

Figure 2

Effects of gp120 (0.01 and 0.1 nM) on GHRH-mediated GH secretion from static, dispersed pituitary cell cultures. The inhibitory effects of both doses of gp120 are significant at 0.1 nM GHRH (P < 0.05) and 1.0 nM GHRH (P < 0.0001).

Figure 3

(Upper) Effects of gp120 on GHRH-mediated GH secretion from dynamic perifusion of pituitary cell cultures. Fractions were taken every 5 min under basal perifusion conditions and in the presence of GHRH, gp120, or GHRH + gp120. (Lower) Combined effects of gp120 and DAPTA (Peptide T) on GHRH-stimulated GH release from dynamic perifusion of pituitary cell cultures. Fractions were taken every 5 min under basal perifusion conditions and in the presence of GHRH, gp120, DAPTA, or GHRH + gp120 + DAPTA.

Figure 4

Effects of chronic central injections of saline vehicle or gp120 (4 ng in 1 μl, twice daily) on cumulative whole body weight gain in conscious juvenile rats. The dotted horizontal line is the zero identity line. ∗, P < 0.05 vs. saline controls.