Abstract
DNA damage can activate the oncosuppressor protein ataxia telangiectasia mutated (ATM), which phosphorylates the histone H2AX within characteristic DNA damage foci. Here, we show that ATM undergoes an activating phosphorylation in syncytia elicited by the envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) in vitro. This was accompanied by aggregation of ATM in discrete nuclear foci that also contained phospho-histone H2AX. DNA damage foci containing phosphorylated ATM and H2AX were detectable in syncytia present in the brain or lymph nodes from patients with HIV-1 infection, as well as in a fraction of blood leukocytes, correlating with viral status. Knockdown of ATM or of its obligate activating factor NBS1 (Nijmegen breakage syndrome 1 protein), as well as pharmacological inhibition of ATM with KU-55933, inhibited H2AX phosphorylation and prevented Env-elicited syncytia from undergoing apoptosis. ATM was found indispensable for the activation of MAP kinase p38, which catalyzes the activating phosphorylation of p53 on serine 46, thereby causing p53 dependent apoptosis. Both wild type HIV-1 and an HIV-1 mutant lacking integrase activity induced syncytial apoptosis, which could be suppressed by inhibiting ATM. HIV-1-infected T lymphoblasts from patients with inactivating ATM or NBS1 mutations also exhibited reduced syncytial apoptosis. Altogether these results indicate that apoptosis induced by a fusogenic HIV-1 Env follows a pro-apoptotic pathway involving the sequential activation of ATM, p38MAPK and p53.
Highlights
In spite of the spectacular success of highly active anti-retroviral therapy (HAART), human immunodeficiency virus-1 (HIV-1) infection continues to pose a public health problem because an ever increasing percentage of viral strains have acquired resistance against the major anti-retroviral drugs [1]
The activation of DNA damage foci containing ATMS1981P and c-H2AX is likewise due to cytogamy among non-synchronized cells leading to the fusion of nuclei that are in distinct phases of the cell cycle
Syncytium formation induced by envelope glycoprotein complex (Env), wild type HIV-1 (Fig. 5–6), or integrase-defective HIV-1 (Fig. 5–6) triggers an apoptotic pathway that involves the activation and action of ataxia telangiectasia mutated (ATM)
Summary
In spite of the spectacular success of highly active anti-retroviral therapy (HAART), HIV-1 infection continues to pose a public health problem because an ever increasing percentage of viral strains have acquired resistance against the major anti-retroviral drugs [1]. HIV-1 encodes for several apoptogenic proteins including Env, Vpr and Tat [4,5,6,7]. The membraneanchored Env gp120/gp complex expressed on the surface of HIV-1-infected cells can induce apoptosis through an interaction with uninfected cells expressing the receptor (CD4) and the chemokine co-receptor (CXCR4 or CCR5). This type of bystander killing often involves the formation of syncytia by fusion of the interacting cells. Syncytia or ‘‘multinuclear giant cells’’ accumulating in the cerebral cortex are pathognonomic for HAE [16,17], meaning that their presence allows for the histopathological diagnosis of neuro-AIDS
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
