Human immunodeficiency virus type 1 (HIV-1) variants passaged in T-cell lines, often called laboratory isolates, are potently neutralized by soluble CD4 (sCD4), whereas primary HIV-1 variants are highly resistant to sCD4 neutralization. Previously, it was demonstrated that the domain from V1 to V3 of the HIV-1 gp120 molecule contains one of the major determinants of sCD4 neutralization sensitivity, and the same region has also been implicated as influencing syncytium-inducing (SI) capacity and T-cell-line tropism. To determine possible differences in sCD4 neutralization sensitivity between phenotypically distinct primary HIV-1 variants, a panel of non-syncytium-inducing (NSI) and SI HIV-1 variants was studied. Primary NSI and SI HIV-1 variants appeared to be equally resistant to sCD4 neutralization. Consistent with this observation, sCD4 did not induce gp120 shedding from either primary NSI or SI HIV-1 variants at 37 degrees C. Thus, it is not the potential of certain primary HIV-1 variants to infect T-cell lines but rather their adaptation to T-cell lines that is reflected in specific properties of the viral envelope which influence sCD4 neutralization sensitivity.