Although CD4 is required for efficient virus entry, it is not sufficient for entry of all primary HIV-1 strains. There may be additional virus-cell interactions, possibly involving the V3 region of the extracellular envelope protein, gp120, that occur following conformational changes induced by CD4 binding. This second interaction would precede fusion events and entry of the virus core. Primary HIV-1 strains appear to have a higher virion envelope density and retain gp120 better than HIV-1 strains adapted to growth in T cell lines in culture. These properties may confer a growth advantage in vivo to primary strains on the basis of less well exposed CD4 binding and neutralization domains. HIV-1 entry into both activated and quiescent T cells, as well as macrophages, is efficient for most primary strains, but there are different patterns of reverse transcription. Productive infection of activated T cells is associated with cell proliferation and accumulation of full-length reverse transcripts within 4 to 6 h. In resting, nondividing T cells, reverse transcription is aborted prior to full-length viral DNA formation. A third pattern of reverse transcription is seen in nondividing cultured macrophages with slow kinetics and accumulation of full-length viral DNA between 36 and 48 h. This rate can be increased by adding exogenous nucleotides, but still not to the rate seen in activated T cells. Future antiretroviral therapies may involve interference with cell-specific functions involved in reverse transcription.