CXCR4 sequences involved in coreceptor determination of human immunodeficiency virus type-1 tropism. Unmasking of activity with M-tropic Env glycoproteins.
The interaction of human immunodeficiency virus type 1 (HIV-1) with CD4 and one of a cadre of chemokine receptors triggers conformational changes in the HIV-1 envelope (Env) glycoprotein that lead to membrane fusion. The coreceptor activity of the second extracellular loop of CXCR4, which is restricted to dual tropic and T-tropic strains, was insensitive to the removal of charged residues either singly or in combinations by alanine scanning mutagenesis or to the conversion of acidic residues to lysine. Conversion of Asp-187 to a neutral residue exclusively unmasked activity with M-tropic Env in fusion and infection experiments. Insertion of the D187V mutation into chimeras containing extracellular loop 2 of CXCR4 in a CXCR2 framework also resulted in the acquisition of M-tropic coreceptor activity. The independence of CXCR4 coreceptor activity from charged residues and the extension of its repertoire by removing Asp-187 suggest that this interaction is not electrostatic and that coreceptors have the potential to be utilized by a spectrum of Env, which may be masked by charged amino acids in extracellular domains. These findings indicate that the primary structural determinants of coreceptors that program reactivity with M-, dual, and T-tropic Env are surprisingly subtle and that relatively insignificant changes in CXCR4 can dramatically alter utilization by Env of varying tropism.
Wang
Z X
ZX
Henry Vogt Cancer Research Institute, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky.
Berson
J F
JF
Zhang
T Y
TY
Cen
Y H
YH
Sun
Y
Y
Sharron
M
M
Lu
Z H
ZH
Peiper
S C
SC
D005434:Flow Cytometry; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D008561:Membrane Fusion / Q000235:genetics; D008565:Membrane Proteins / Q000737:chemistry; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D019718:Receptors, CXCR4 / Q000737:chemistry* / Q000235:genetics; D011956:Receptors, Cell Surface / Q000502:physiology; D019707:Receptors, Chemokine / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics; D023063:Receptors, Interleukin-8B; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D013601:T-Lymphocytes / Q000821:virology; D018523:Tropism / Q000502:physiology*
D015699:HIV Envelope Protein gp120; D008565:Membrane Proteins; D019718:Receptors, CXCR4; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D018123:Receptors, Interleukin; D023063:Receptors, Interleukin-8B; D011993:Recombinant Fusion Proteins