Loss of G(1)/S checkpoint in human immunodeficiency virus type 1-infected cells is associated with a lack of cyclin-dependent kinase inhibitor p21/Waf1

productive high-titer infection by human immunodeficiency virus type I (HIV -1) requires the activation of target cells. Infection of quiescent periphe ral CD4 lymphocytes by HIV-1 results in incomplete, labile reverse transcri pts and lack of viral progeny formation. An interplay between Tat and p53 h as previously been reported, where Tat inhibited the transcription of the p 53 gene, which may aid in the development of AIDS-related malignancies, and p53 expression inhibited HIV-1 long terminal repeat transcription. Here, b y using a n ell-defined and -characterized stress signal, gamma irradiation ,we find that upon gamma irradiation, HIV-1-infected cells lose their G(1)/ S checkpoints, enter the S phase inappropriately, and eventually apoptose. The loss of the G(1)/S checkpoint is associated,with a toss of p21/Waf1 pro tein and increased activity of a major G(1)/S kinase, namely, cyclin E/cdk2 . The p21/Waf1 protein, a known cyclin-dependent kinase inhibitor, interact s with the cdk2/cyclin E complex and inhibits progression of cells into S p hase. We find that loss of the G(1)/S checkpoint in HIV-1-infected cells ma y in part be due to Tat's ability to bind p53 (a known activator of the p21 /Waf1 promoter) and sequester its transactivation activity, as seen in both in vivo and in vitro transcription assays. The loss of p21/Waf1 in HIV-1-i nfected cells mas specific to p21/Waf1 and did not occur with other KIP fam ily members, such as p27 (KIP1) and p57 (KIP2). Finally, the advantage of a loss of the G(1)/S checkpoint for HIV-1 per se may be that it pushes the h ost cell into the S phase, which mag then allo,v subsequent virus-associate d processes, such as RNA splicing, transport, translation, and packaging of virion-specific genes, to occur.