Qh. Liu et al., HIV-1 gp120 and chemokines activate ion channels in primary macrophages through CCR5 and CXCR4 stimulation, P NAS US, 97(9), 2000, pp. 4832-4837
Citations number
50
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
HIV type 1 (HIV-1) uses the chemokine receptors CCR5 and CXCR4 as corecepto
rs for entry into target cells. Here we show that the HIV-1 envelope gp120
(Env) activates multiple ionic signaling responses in primary human macroph
ages. which are important targets for HIV-1 in vivo. Env from both CCR5-dep
endent JRFL (R5) and CXCR4-dependent IIIB (X4) HIV-1 opened calcium-activat
ed potassium (K-Ca), chloride, and calcium-permeant nonselective cation cha
nnels in macrophages. These signals were mediated by CCR5 and CXCR4 because
macrophages lacking CCR5 failed to respond to JRFL and an inhibitor of CXC
R4 blocked ion current activation by IIIB, MIP-1 beta and SDF-1 alpha, chem
okine ligands for CCR5 and CXCR4, respectively, also activated K-Ca and Cl-
currents in macrophages, but nonselective cation channel activation was un
ique to gp120. Intracellular Ca2+ levels were also elevated by gp120. The p
atterns of activation mediated by CCR5 and CXCR4 were qualitatively similar
but quantitatively distinct, as R5 Env activated the K-Ca current more fre
quently, elicited Cl- currents that were approximate to 2-fold greater in a
mplitude, and elevated intracellular Ca+2 to higher peak and steady-state l
evels. Env from R5 and X4 primary isolates evoked similar current responses
as the corresponding prototype strains. Thus, the interaction of HIV-1 gp1
20 with CCR5 or CXCR4 evokes complex and distinct signaling responses in pr
imary macrophages. and gp120-evoked signals differ from those activated by
the coreceptors' chemokine ligands, Intracellular signaling responses of ma
crophages to HIV-1 may modulate postentry steps of infection and cell funct
ions apart from infection.