Potent stimuli for CD 4+ T cell differentiation are cytokines. Among them, IL-12 or IL-4 induce naive CD 4+ T cells to Th 1 or Th 2 cells, respectively. In this study we found that macrophage-tropic (M-tropic) HIV-1 strains more efficiently replicated in interleukin 12 (IL-12) induced T helper 1 (Th 1)-type culture derived from normal CD 4+ T cells than T-cell-line-tropic (T-tropic) strains did. In contrast, T-tropic strains preferentially infected IL-4 induced Th 2-type culture derived from same donor CD 4+ T cells. Additional studies using chimeric viruses demonstrated that the V 3 region of gp 120 was the principle determinant for this efficient replication. It was also isolated T-tropic viruses from an acutely infected patient who had been evidenced as severe CD 4 depletion during short time course. These results indicate that HIV-1 isolates exhibit differences in the ability to infect CD 4+ T cell subset such as Th 1 or Th 2 cells, and that this difference may partly correlate with the viral pathogensesis. The findings suggest that immunological condition is one of the factors responsible for inducing selection of HIV-1 strains. © 2000, The Japan Society for Clinical Immunology. All rights reserved.