HIV integration and T cell death: additional commentary
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COMMENTARY
Open Access
HIV integration and T cell death: additional commentary Arik Cooper1, Mayra García1, Constantinos Petrovas2, Takuya Yamamoto2, Richard A Koup2 and Gary J Nabel1,3* Abstract Estaquier et al. provide commentary on our paper that elucidated the mechanism by which HIV-1 causes cell death in activated CD4 T lymphocytes. We showed that proviral DNA integration triggers DNA-PK dependent death signaling, leading to p53 phosphorylation and cell demise (Cooper A et al. Nature 498:376-379, 2013). They have raised several hypothetical points that we further clarify here.
1. In their commentary, the authors note that cell death in our study was observed only in cells lacking p24 antigen expression (p24-) and argue that a mechanism in which integration triggers death would lead to cell killing before the virus had a chance to replicate in its target cell. Response: Estaquier et al. provide no data to support their claim that cell death is immediate, and none was suggested in the paper. In our study, we showed that viral gene expression can be detected prior to the onset of cell death using a GFP reporter gene. Thus, we noted that dying p24- cells originate from productively infected cells that express viral genes before they lose expression, which is concomitant with cell death (Figure two c in ref. [1]). The explanation for the loss of viral proteins upon cell death is unknown but may result from activation of cellular proteases that degrade them or from epigenetic downregulation. This finding explains why death is observed only in p24- cells and indicates that the virus productively infects its host cell prior to inducing death, a notion reinforced by the observed viral spread in primary cultures infected with a replication-competent HIV-1 (Figure one c in ref. [1]). We found that productively infected cells die within 2 to 4 days after infection * Correspondence: [email protected] 1 Virology Laboratory, Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bldg. 40, Room 4502, MSC-3005, 40 Convent Drive, Bethesda, MD 20892-3005, USA 3 Current address: Sanofi, 640 Memorial Drive, Cambridge, MA 02139, USA Full list of author information is available at the end of the article
in vitro and within 3 days ex vivo, consistent with the in vivo half-life of CD4 lymphocytes in humans infected with HIV-1 and in macaques infected with SIV [2,3]. Given that HIV-1 integrates its cDNA within 24 hours following infection [4,5], the onset of cell death is relatively delayed, possibly as a result of anti-apoptotic activities of host and viral machineries [6-8], allowing HIV-1 sufficient time to complete its replication cycle. The DNAPK-p53 death pathway is therefore induced in productively infected cells and can be regarded as an innate defense mechanism that eliminates them. HIV-1 replication is reduced but not abolished by this death response [1,9]. 2. Estaquier et al. cite previous reports concerning the role of DNA-PK in lentiviral replication and sugg
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