These observations suggest that: 1) some CD4-independent viruses may have acquired changes that increase the stability of the envelope glycoproteins when assuming conformations that are near the CD4-bound state; and 2) the instability of the sCD4-activated envelope glycoproteins results from a process that is distinct from the formation/exposure of the HR1 coiled coil and is unnecessary for infection of CD4−CCR5+ cells. Here, ERVW-1 is linked to infection.