title: Apoptosis-induced activation of HIV-1 in latently infected cell lines.
abstract: BACKGROUND
  Despite much work, safe and effective approaches to attack and deplete the long-lived reservoir of cells latently infected with HIV-1 remain an elusive goal. Patients infected with HIV-1 treated with cytotoxic agents or bone marrow transplantation can experience decreases in the reservoir of HIV-1 latently infected cells. Other viruses capable of long-term latency, such as herpesviruses, can sense host cell apoptosis and respond by initiating replication. These observations suggest that other viruses capable of long-term latency, like HIV-1, might also sense when its host cell is about to undergo apoptosis and respond by initiating replication.
  
  
  RESULTS
  Pro-monocytic (U1) and lymphoid (ACH-2) HIV-1 persistently infected cell lines were treated with cytotoxic drugs - doxorubicin, etoposide, fludarabine phosphate, or vincristine - and activation of latent HIV-1 was evaluated using assays for HIV-1 RNA and p24 production. Both cell lines showed dose-dependent increases in apoptosis and associated HIV-1 activation following exposure to the cytotoxic agents. Pretreatment of the cells with the pan-caspase inhibitor Z-VAD-FMK prior to exposure to the cytotoxic agents inhibited apoptosis and viral activation. Direct exposure of the latently infected cell lines to activated caspases also induced viral replication. HIV-1 virions produced in association with host cell apoptosis were infectious.
  
  
  CONCLUSIONS
  The results indicate that latent HIV-1 can sense when its host cell is undergoing apoptosis and responds by completing its replication cycle. The results may help explain why patients treated with cytotoxic regimens for bone marrow transplantation showed reductions in the reservoir of latently infected cells. The results also suggest that the mechanisms that HIV-1 uses to sense and respond to host cell apoptosis signals may represent helpful new targets for approaches to attack and deplete the long-lived reservoir of cells latently infected with HIV-1.
authors.affiliation: Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC, USA. sokhan@childrensnational.org.
authors.forename: Sohrab Z
authors.initials: SZ
authors.lastname: Khan
authors.affiliation: Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University School of Medicine, Washington, DC, USA. nwhand@gwmail.gwu.edu.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hand
authors.affiliation: Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC, USA. Zeichner@gwu.edu.|Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University School of Medicine, Washington, DC, USA. Zeichner@gwu.edu.|Department of Pediatrics, The George Washington University, School of Medicine, Washington, DC, USA. Zeichner@gwu.edu.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Zeichner
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016655:HIV Core Protein p24 / Q000032:analysis; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D012367:RNA, Viral / Q000032:analysis; D014775:Virus Activation; D017735:Virus Latency
chemical_list: D016655:HIV Core Protein p24; D012367:RNA, Viral