Intrahypothalamic injection of the HIV-1 envelope glycoprotein induces fever via interaction with the chemokine system

Abstract

Wasting syndrome is a common complication of HIV infection and is marked by progressive weight loss and weakness, often associated with fever. The mechanisms involved in the pathogenesis of these syndromes are not well defined, and neither are the brain areas involved. The present study tests a new hypothesis: that the preoptic anterior hypothalamus (POAH), the main brain area for thermoregulation and fever, has a role in the pathogenesis of fever induced by glycoprotein 120 (gp120), the surface envelope protein used by the HIV to gain access into immune cells, and that the CXC chemokine receptors (CXCR4) that serve as a coreceptor for HIV entry mediate the effect. A sterilized stainless steel C313G cannula guide was implanted into the POAH, and a biotelemetry system was used to monitor the body temperature (Tb) changes. The administration of gp120 into the POAH induced fever in a dose-dependent manner. To demonstrate possible links between the gp120 and CXCR4 in generating the fever, we pretreated the rats with 1,1'-[1,4-phenylenebis(methylene)]bis[1,4,8,11-tetraazacyclotetradecane] octohydrobromide dihydrate (AMD 3100), an antagonist of stromal cell-derived growth factor (SDF)-1alpha/CXCL12, acting at its receptor, CXCR4, 30 min before administration of gp120. AMD 3100 significantly reduced the gp120-induced fever. The present studies show that the presence of HIV-1 envelope glycoprotein gp120 in the POAH provokes fever via interaction CXCR4 pathway.

Fig. 1.

Effect of intra-POAH injection of gp120 (33–133 ng) on Tb. gp120 was injected at time 0. Data are expressed as the mean ± S.E.M. from baseline. Basal body temperatures before treatment of each group was as follows: ▴, 37.45 ± 0.12°C; ■, 37.51 ± 0.14°C; ▾, 37.37 ± 0.10°C; ●, 37.47 ± 0.16°C. ***, p < 0.001. N, number of rats.

Fig. 2.

Effect of intra-POAH injection AMD 3100 (1.5–5 μg) on Tb. AMD 3100 was injected at time 0. Data are expressed as the mean ± S.E.M. from baseline. Basal body temperatures before treatment of each group was as follows: ▴, 37.37 ± 0.15°C; ■, 37.51 ± 0.18°C; ▾, 37.43 ± 0.12°C; ●, 37.39 ± 0.18°C. N, number of rats.

Fig. 3.

Effect of intra-POAH with AMD 3100 (5 μg, −30 min) on gp120-induced fever. gp120 was injected at time 0. Data are expressed as the mean ± S.E.M. from baseline. Basal body temperatures before treatment of each group was as follows: ■, 37.29 ± 0.18°C; ●, 37.47 ± 0.17°C.*, p < 0.05. N, number of rats.

Fig. 4.

A, anatomical mapping in successive frontal section illustrating the distribution of some individual sites of microinjection in the POAH. B, photomicrograph showing an injection site. oc, optic chiasma; LV, lateral ventricle; ca, anterior commissure; cp, caudate putamen.