Molecular function of the CD4 D1 domain in coreceptor-mediated entry by HIV type 1.
The surface molecule CD4 plays a key role in initiating cellular entry by the human immunodeficiency virus type 1 (HIV-1), and it is now recognized as acting synergistically with select chemokine receptors (coreceptors) in the infection process. The present study was undertaken to determine whether the extracellular region of CD4 is sufficient to induce fusion of HIV-1 virions with target cells in the absence of its anchoring function. Using pseudotype reporter viruses to quantitate infection, soluble CD4 (sCD4) was tested for its ability to induce fusion by viruses utilizing CCR5 as their coreceptor. We found that sCD4 was competent to replace membrane-bound CD4 to trigger infection mediated by several HIV-1 envelopes. Furthermore, in a comparison of the envelopes of HIV-1 NL4-3 and a chimera containing the gp120 V3 loop of Ba-L, the V3 region was found to be one factor affecting susceptibility to induction by sCD4. In addition, using truncated and mutant derivatives of sCD4, the amino-terminal D1 domain of CD4 was found to be necessary and sufficient for induction of fusion and to require an intact gp120-binding site for this activity. These results delineate determinants on CD4 and gp120 required for fusion induction in collaboration with a coreceptor, and suggest a mechanism whereby CD4 may contribute to viral infection in trans.
Esser
U
U
Gladstone Institute of Virology and Immunology, San Francisco, California 94141, USA.
Speck
R F
RF
Deen
K C
KC
Atchison
R E
RE
Sweet
R
R
Goldsmith
M A
MA
D015704:CD4 Antigens / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008561:Membrane Fusion; D010446:Peptide Fragments / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019713:Receptors, CCR5 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014779:Virus Replication
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D019713:Receptors, CCR5; D011994:Recombinant Proteins; C076613:recombinant soluble CD4