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Thirty-one different mutant forms of simian immunodeficiency virus (SIVmac) were created with changes in the region of env corresponding to the V3 domain of HIV-1. Sixteen of these mutants had one amino acid change, 12 had two changes, two had three changes, and one had four changes in the SIVmac "V3" loop. The ability of the mutant viruses to replicate in CEMx174 cells, rhesus monkey peripheral blood mononuclear cells, and rhesus monkey alveolar macrophages was investigated. Ten of the mutant viruses replicated with approximately wild-type kinetics in all three cell types. Of the 31 mutants, 22 were able to replicate in one or more of the cell types. Thus, this region of SIVmac gp120 is quite tolerant to change. Nine of the mutants replicated poorly or not at all in any of the cells tested. The lack of replication competence of some of the mutants was associated with inefficient proteolytic processing of the gp160 precursor. Some mutations had dramatic differential effects in different cell types. For example, changing P to S at position 321 and M to I at position 325 drastically reduced replication in macrophages and CEMx174 cells but had no effect on replication in peripheral blood mononuclear cells. Mutants with altered tropism were blocked at an early stage that includes virus entry into cells. Thus, sequences in SIVmac that correspond to V3 in HIV-1 can affect virus entry and cell tropism in a manner analogous to that of HIV-1 V3.