Apoptosis-induced activation of HIV-1 in latently infected cell lines

Abstract

BackgroundDespite 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.ResultsPro-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.ConclusionsThe 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.

Dual targeting of the thioredoxin and glutathione systems in cancer and HIV

“…By the same token, both NO donors and endogenously generated NO may stimulate HIV reactivation (113). Relatedly, Kahn et al (114) showed that anticancer conditioning agents (doxorubicin, etoposide, fludarabine phosphate, or vincristine) were able to induce HIV escape from latency and that this was associated with increased apoptosis rates (114). It is interesting to note that these drugs have been reported to induce oxidative stress (115)(116)(117), corroborating previous findings suggesting that the viral reservoir may be redox responsive and could potentially be eliminated by pro-oxidant drugs (118).…”

p53 Expression Activation of HIV-1 Latency in U1 Cells

“…These results indicate that proapoptotic proteins can increase HIV-1 replication and antiapoptotic molecules are able to inhibit HIV-1 replication, suggesting that HIV-1 has evolved ways to inhibit host cell apoptosis [12], an important way for the virus to enhance its replication when host cells initiate the apoptotic program as a way of limiting replication within the host. We and other investigators show that, in addition to HIV, infection with influenza virus (H1N1) [14], HSV-1 [12], KSHV [34], HHV6A, HHV6B, HHV7 and EBV [35] causes the host cell to undergo apoptosis and they adopt an emergency escape mechanism that leads to the rapid production of large amounts of virus. It has been shown that p53 expression is sufficient to initiate the emergency escape process [13].…”

“…This phenomenon is called an Alternative Replication Program (ARP), a process when the host cell is undergoing apoptosis during viral infection. Viruses adopt an emergency escape mechanism to produce a large amount of virus rapidly [12]. Expression/activation of some pre-apoptotic molecules from apoptotic pathways, such as p53, Bax, Fas ligand, FADD, caspase-3, and caspase-8 are sufficient to initiate the ARP in HIV-1 infection [13] and influenza A virus infection [14].…”

“…Expression/activation of some pre-apoptotic molecules from apoptotic pathways, such as p53, Bax, Fas ligand, FADD, caspase-3, and caspase-8 are sufficient to initiate the ARP in HIV-1 infection [13] and influenza A virus infection [14]. Treatment with cytotoxic drugs has been reported to produce and activate HIV-1 replication in pro-monocytic (U1) and lymphoid (ACH-2) cell lines persistently infected with HIV-1 with an increased expression of p53 [12]. Here using U1 cells, we found that p53 expression was able to activate HIV-1 replication from latent infection via upregulation of several host transcription factors in U1 cells.…”

Potential of Radiation-Induced Cellular Stress for Reactivation of Latent HIV-1 and Killing of Infected Cells

“…A recent publication from Zeichner laboratory indicated that cancer chemotherapeutic agents that induce apoptosis dramatically activated HIV-1 replication in latently infected cells. 33 The authors based their study on the observation that cytotoxic chemotherapy and bone marrow transplantation applied to HIV patients who developed lymphoma and appeared to be relatively more effective at depletion of the HIV-1 latent reservoir than LRAs. 34,35 In fact, treatment of both persistently HIV-1-infected T cells and monocytes with cytotoxic drugs, doxorubicin, etoposide, fludarabine phosphate, or vincristine, was associated with caspase-3 and -8 activation and therefore apoptosis response that followed dramatic increase of HIV-1 RNA and p24 count.…”