Abstract
HIV-1 blocks apoptosis, programmed cell death, an innate defense of cells against viral invasion. However, apoptosis can be selectively reactivated in HIV-infected cells by chemical agents that interfere with HIV-1 gene expression. We studied two globally used medicines, the topical antifungal ciclopirox and the iron chelator deferiprone, for their effect on apoptosis in HIV-infected H9 cells and in peripheral blood mononuclear cells infected with clinical HIV-1 isolates. Both medicines activated apoptosis preferentially in HIV-infected cells, suggesting that the drugs mediate escape from the viral suppression of defensive apoptosis. In infected H9 cells, ciclopirox and deferiprone enhanced mitochondrial membrane depolarization, initiating the intrinsic pathway of apoptosis to execution, as evidenced by caspase-3 activation, poly(ADP-ribose) polymerase proteolysis, DNA degradation, and apoptotic cell morphology. In isolate-infected peripheral blood mononuclear cells, ciclopirox collapsed HIV-1 production to the limit of viral protein and RNA detection. Despite prolonged monotherapy, ciclopirox did not elicit breakthrough. No viral re-emergence was observed even 12 weeks after drug cessation, suggesting elimination of the proviral reservoir. Tests in mice predictive for cytotoxicity to human epithelia did not detect tissue damage or activation of apoptosis at a ciclopirox concentration that exceeded by orders of magnitude the concentration causing death of infected cells. We infer that ciclopirox and deferiprone act via therapeutic reclamation of apoptotic proficiency (TRAP) in HIV-infected cells and trigger their preferential elimination. Perturbations in viral protein expression suggest that the antiretroviral activity of both drugs stems from their ability to inhibit hydroxylation of cellular proteins essential for apoptosis and for viral infection, exemplified by eIF5A. Our findings identify ciclopirox and deferiprone as prototypes of selectively cytocidal antivirals that eliminate viral infection by destroying infected cells. A drug-based drug discovery program, based on these compounds, is warranted to determine the potential of such agents in clinical trials of HIV-infected patients.
Highlights
Human immunodeficiency virus type 1 (HIV-1) evades the innate and adaptive responses of the immune system, and exploits both to its advantage
These observations, together with accumulating data on the inhibitory action of both CPX and DEF on eukaryotic translation initiation factor 5A (eIF5A) hydroxylation [35,38], HIV-1 infection in PBMCs and viral gene expression in model systems [23], suggested that the two drugs might have a common mode of action via the induction of apoptosis in HIVinfected cells
The viral load reduction persisted throughout seven weeks of monitoring after cessation of DEF (Saxena et al, unpublished data). These data suggest that medicinal activation of apoptosis in pathogenic infected cells is a viable antiviral strategy, for which we propose the term ’therapeutic reclamation of apoptotic proficiency’ (TRAP)
Summary
Human immunodeficiency virus type 1 (HIV-1) evades the innate and adaptive responses of the immune system, and exploits both to its advantage. HIV-1 establishes infection that resists clearance by all current antiretrovirals. A major feature of this resistance is HIV1 interference with the primal cellular defense against viral invasion and takeover, programmed cell death (apoptosis) [2,3,4,5]. In brain and blood, infected monomyelocytic cells are protected against apoptosis [11]. Their stable antiapoptotic gene expression secures viability as mobile infective units and long-term reservoirs [12]. T cell depletion, due to virally promoted apoptotic death of uninfected and eventually of infected cells, is the major cause of immune deficiency [12,13,14,15]
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