Mechanism of HIV-1 viral protein R-induced apoptosis q Karuppiah Muthumani, Andrew Y. Choo, Daniel S. Hwang, Michael A. Chattergoon, Nathanael N. Dayes, Donghui Zhang, Mark D. Lee, Umaheswar Duvvuri, and David B. Weiner * Department of Pathology and Laboratory Medicine, University of Pennsylvania, 505 Stellar Chance Laboratories 422 Curie Blvd., Philadelphia, PA 19104, USA Received 2 February 2003 Abstract The paradigm of HIV-1 infection includes the diminution of CD4 þ T cells, loss of immune function, and eventual progression to AIDS. However, the mechanisms that drive host T cell depletion remain elusive. One HIV protein thought to participate in this destructive cascade is the Vpr gene product. Accordingly, we review the biology of the HIV-1 viral protein R (Vpr) an apoptogenic HIV-1 accessory protein that is packaged into the virus particle. In this review we focus specifically on VprÕs ability to induce host cell apoptosis. Recent evidence suggests that Vpr implements a unique mechanism to drive host cell apoptosis, by directly depo- larizing the mitochondria membrane potential. VprÕs attack on the mitochondria results in release of cytochrome c resulting in activation of the caspase 9 pathway culminating in the activation of caspase 3 and the downstream events of apoptosis. Vpr may interact with the adenine nucleotide translocator (ANT) to prompt this cascade. The role of Vpr-induced apoptosis in HIV pathogenesis is considered. Ó 2003 Elsevier Science (USA). All rights reserved. Keywords: HIV-1 Vpr; Apoptosis; Caspase; Mitochondrial membrane potential; NF-jB; AIF; Cytochrome c Background Programmed cell death or apoptosis is a strictly regulated mechanism, which purges unnecessary, aged, or damaged cells. Not surprisingly then, an abnormal resistance to apoptotic cell death is the basis of devel- opmental malformations, autoimmune disease second- ary to a failure to remove auto-reactive lymphocytes, and many cancers where transformed cells are not cleared. In contrast, enhanced susceptibility of cells to apoptotic signals participates in tissue damage second- ary to acute diseases such as infection by toxin pro- ducing microorganisms, ischemia–reperfusion damage and infarction, as well as chronic pathologies including neurodegenerative and neuromuscular diseases and acquired immune deficiency syndrome (AIDS) [1]. Human immunodeficiency virus (HIV) principally infects T helper (Th) cells and cells of the monocyte/ macrophage lineage, which express the CD4 þ cell sur- face protein. The gradual and selective loss of the CD4 þ subset of T-lymphocytes is a central feature of the pathogenesis of HIV which can correlate with the pro- gression from asymptomatic HIV infection to AIDS [2]. HIV infection is characterized by a progressive dimi- nution of the circulating CD4 þ T-lymphocyte popula- tion, a process which inevitably compromises the hostÕs immune system. Yet, the exact mechanism underlying this CD4 þ depletion remains nebulous. Several mecha- nisms have been proposed to explain this decline, in- cluding the rapid turnover and death of infected host cellsaswellas‘‘bystander’’celldeathviaindirectmeans. Many reports support both of these possibilities as po- tential mechanisms by which HIV-induced CD4 þ T-cell depletion occurs. Specifically it has been reported that HIV replication leads to rapid death in infected cells, Biochemical and Biophysical Research Communications 304 (2003) 583–592 www.elsevier.com/locate/ybbrc BBRC q Abbreviations: AIDS, acquired immunodeficiency syndrome; HIV-1, human immunodeficiency virus-1; Vpr, viral protein R; AIF, apoptosis inducing factor; NF-jB, nuclear factor kappa B. * Corresponding author. Fax: 1-215-573-9436. E-mail address: dbweiner@mail.med.upenn.edu (D.B. Weiner). 0006-291X/03/$ - see front matter Ó 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0006-291X(03)00631-4