How HIV Interferes With Infected Cell Division
Montréal researchers identify cellular proteins recruited by HIV to compromise CD4+T cell function and enhance viral replication. Dr. Éric A. Cohen, a researcher at the IRCM (Institut de recherches cliniques de Montréal), and his team published in PLoS Pathogens July 13 a discovery that could lead to the development of a new class of drugs to combat HIV.
Human immunodeficiency virus type 1 (HIV-1) causes AIDS by depleting essential immune cells called CD4+T lymphocytes in infected individuals, resulting in a compromised immune system.
At the center of this process is the HIV protein, viral protein R (Vpr), which stops infected CD4+T cells from dividing and as a consequence compromises their immune function. In addition, by arresting cell division, Vpr helps HIV to harness the infected cell’s resources to enhance viral replication. The way Vpr exerts this effect is by interacting with cellular proteins that control cell division.
Dr. Cohen and his team have identified a novel cellular protein complex targeted by HIV-1 Vpr to stop infected cell division. This protein complex, designated DDB1-CUL4-VprBP, is involved in a process called ubiquitination. Ubiquitination is a mechanism by which a small protein called ubiquitin is conjugated to cellular proteins in order to modulate their biological activity or induce their degradation.
The researchers demonstrated that association of Vpr with this ubiquitinating complex, also called an E3 ubiquitin ligase complex, is essential for the defect in cell division induced by Vpr. Further characterization of this protein complex as well as the elucidation of the mechanism by which it affects cell division may open new avenues for therapeutic intervention against HIV.
Andersen JL, DeHart JL, Zimmerman ES, Ardon O, Kim B, et al. PLoS Pathogens Vol. 2, No. 12, e127 doi:10.1371/journal.ppat.0020127
The HIV-1 accessory protein viral protein R (Vpr) causes G2 arrest and apoptosis in infected cells. We previously identified the DNA damage–signaling protein ATR as the cellular factor that mediates Vpr-induced G2 arrest and apoptosis. Here, we examine the mechanism of induction of apoptosis by Vpr and how it relates to induction of G2 arrest. We find that entry into G2 is a requirement for Vpr to induce apoptosis. We investigated the role of the mitochondrial permeability transition pore by knockdown of its essential component, the adenine nucleotide translocator. We found that Vpr-induced apoptosis was unaffected by knockdown of ANT. Instead, apoptosis is triggered through a different mitochondrial pore protein, Bax. In support of the idea that checkpoint activation and apoptosis induction are functionally linked, we show that Bax activation by Vpr was ablated when ATR or GADD45α was knocked down. Certain mutants of Vpr, such as R77Q and I74A, identified in long-term nonprogressors, have been proposed to inefficiently induce apoptosis while activating the G2 checkpoint in a normal manner. We tested the in vitro phenotypes of these mutants and found that their abilities to induce apoptosis and G2 arrest are indistinguishable from those of HIV-1NL4–3 vpr, providing additional support to the idea that G2 arrest and apoptosis induction are mechanistically linked.