The repertoire of functional CD4⁺ T lymphocytes in human immunodeficiency virus type 1-infected individuals remains poorly understood. To explore this issue, we have examined the clonality of CD4⁺ T cells in simian immunodeficiency virus (SIV)-infected macaques by assessing T-cell receptor complementarity-determining region 3 (CDR3) profiles and sequences. A dominance of CD4⁺ T cells expressing particular CDR3 sequences was identified within certain V-expressing peripheral blood lymphocyte subpopulations in the infected monkeys. Studies were then done to explore whether these dominant CD4⁺ T cells represented expanded antigen-specific cell subpopulations or residual cells remaining in the course of virus-induced CD4⁺ T-cell depletion. Sequence analysis revealed that these selected CDR3-bearing CD4⁺ T-cell clones emerged soon after infection and dominated the CD4⁺ T-cell repertoire for up to 14 months. Moreover, inoculation of chronically infected macaques with autologous SIV-infected cell lines to transiently increase plasma viral loads in the monkeys resulted in the dominance of these selected CDR3-bearing CD4⁺ T cells. Both the temporal association of the detection of these clonal cell populations with infection and the dominance of these cell populations following superinfection with SIV suggest that these cells may be SIV specific. Finally, the inoculation of staphylococcal enterotoxin B superantigen into SIV-infected macaques uncovered a polyclonal background underlying the few dominant CDR3-bearing CD4⁺ T cells, demonstrating that expandable polyclonal CD4⁺ T-cell subpopulations persist in these animals. These results support the notions that a chronic AIDS virus infection can induce clonal expansion, in addition to depletion of CD4⁺ T cells, and that some of these clones may be SIV specific.