Micronuclei formation and aneuploidy induced by Vpr, an accessory gene of human immunodeficiency virus type 1

Vpr, an accessory gene of HIV-1, induces cell cycle abnormality with accumu lation at G2/M phase and increased ploidy, Since abnormality of mitotic che ckpoint control provides a molecular basis of genomic instability, we studi ed the effects of Vpr on genetic integrity using a stable clone, named MIT- 23, in which Vpr expression is controlled by the tetracycline-responsive pr omoter. Treatment of MIT-23 cells with doxycycline (DOX) induced Vpr expres sion with a giant multinuclear cell formation. Increased micronuclei (MIN) formation was also detected in these cells. Abolishment of Vpr expression b y DOX removal induced numerous asynchronous cytokinesis in the multinuclear cells with leaving MIN in cytoplasm, suggesting that the transient Vpr exp ression could cause genetic unbalance. Consistent with this expectation, MI T-23 cells, originally pseudodiploid cells, became aneuploid after repeated expression of Vpr, Experiments using deletion mutants of Vpr revealed that the domain inducing MIN formation as well as multinucleation was located i n the carboxy-terminal region of Vpr protein. These results suggest that Vp r induces genomic instability, implicating the possible role in the develop ment of AIDS-related malignancies.