Implication of p38 mitogen-activated protein kinase isoforms (α, β, γ and δ) in CD4+ T-cell infection with human immunodeficiency virus type I

The CD4 + T-cell reduction characteristic of human immunodeficiency virus type 1 (HIV-1) infection is thought to result, in addition to infected T-cell death, mainly from uninfected bystander T-cell apoptosis. Nevertheless, the immunological and virological mechanisms leading to T-cell death during HIV-1 infection are not yet fully understood. In the present study, we analysed the individual implication of the p38 mitogen-activated protein kinase (MAPK) isoforms (p38 α , p38 β , p38 γ and p38 δ ) during apoptosis induced by HIV-1, taking into account that HIV-1 replication is known to be blocked by p38 inhibitors. For this purpose, we used the SupT1 cell line, where death induced by HIV-1 mainly occurs by uninfected bystander cell apoptosis. A variety of SupT1-based cell lines were constructed constitutively expressing, under the control of cytomegalovirus promoter (PCMV), each dominant-negative (dn) p38 isoform and each wild-type p38 isoform as a control. An enhanced green fluorescent protein marker gene, under the control of the HIV-1 promoter, was inserted in all of them. These cell lines were infected with HIV-1 and analysed by flow cytometry. We found that survival in SupT1-based cell lines infected by HIV-1 was increased by the p38 α dn, p38 γ dn and p38 δ dn isoforms, but not by the p38 β dn isoform. HIV-1 replication was delayed most by p38 δ dn and to a lesser extent by p38 α dn and p38 γ dn. Moreover, these three isoforms, p38 α dn, p38 γ dn and p38 δ dn, reduced apoptosis induced by HIV-1. These results suggest that, in SupT1-based cell lines, p38 α , p38 γ and p38 δ , but not p38 β , are implicated in both HIV-1 induced replication and apoptosis in infected and uninfected bystander cells.