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 t he human immunodeficiency virus type 1 (HIV-1), and it is now recognized as acting synergistically with select chemokine receptors (coreceptors) in th e infection process. The present study was undertaken to determine whether the extracellular region of CD4 is sufficient to induce fusion of HIV-1 vir ions with target cells in the absence of its anchoring function. Using pseu dotype reporter viruses to quantitate infection, soluble CD4 (sCD4) was tes ted for its ability to induce fusion by viruses utilizing CCR5 as their cor eceptor. We found that sCD4 was competent to replace membrane-bound CD4 to trigger infection mediated by several HIV-1 envelopes. Furthermore, in a co mparison 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 suscep tibility to induction by sCD4. In addition, using truncated and mutant deri vatives of sCD4, the amino-terminal D1 domain of CD4 was found to be necess ary and sufficient for induction of fusion and to require an intact gp120-b inding 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 t rans.