Abstract
Multifactorial mechanisms comprising countless cellular factors and virus-encoded transactivators regulate the transcription of HIV-1 (HIV). Since poly(ADP-ribose) polymerase 1 (PARP-1) regulates numerous genes through its interaction with various transcription factors, inhibition of PARP-1 has surfaced recently as a powerful anti-inflammatory tool. We suggest a novel tactic to diminish HIV replication via PARP-1 inhibition in an in vitro model system, exploiting human primary monocyte-derived macrophages (MDM). PARP-1 inhibition was capable to lessen HIV replication in MDM by 60–80% after 7 days infection. Tat, tumor necrosis factor α (TNFα), and phorbol 12-myristate 13-acetate (PMA) are known triggers of the Long Terminal Repeat (LTR), which can switch virus replication. Tat overexpression in MDM transfected with an LTR reporter plasmid resulted in a 4.2-fold increase in LTR activation; PARP inhibition caused 70% reduction of LTR activity. LTR activity, which increased 3-fold after PMA or TNFα treatment, was reduced by PARP inhibition (by 85–95%). PARP inhibition in MDM exhibited 90% diminution in NFκB activity (known to mediate TNFα- and PMA-induced HIV LTR activation). Cytoskeleton rearrangements are important in effective HIV-1 infection. PARP inactivation reduced actin cytoskeleton rearrangements by affecting Rho GTPase machinery. These discoveries suggest that inactivation of PARP suppresses HIV replication in MDM by via attenuation of LTR activation, NFκB suppression and its effects on the cytoskeleton. PARP appears to be essential for HIV replication and its inhibition may provide an effective approach to management of HIV infection.
Highlights
Human immunodeficiency virus (HIV)-1 crosses the blood brain barrier and infects glial cells of the central nervous system (CNS)
poly(ADP-ribose) polymerase (PARP) Inhibition Diminishes HIV-1 Infection of monocyte-derived macrophages (MDM) Given the gene regulatory role that PARP suppression plays in immune cells, we examined whether specific PARP inhibitors may affect HIV-1 replication
When PARPi were added after HIV-1ADA infection, AIQ and PJ34 diminished HIV-1 reverse transcriptase (RT) activity by almost 80%, while AZD and EB47 treatment resulted in 60 ± 2% and 25 ± 4% reduction in HIV-1 RT activity, respectively (Figure 1B)
Summary
Human immunodeficiency virus (HIV)-1 crosses the blood brain barrier and infects glial cells of the central nervous system (CNS). Human immunodeficiency virus (HIV)-1-associated neurological disorder (HAND) is defined as cognitive, motor and/or behavioral impairments caused by HIV replication, immune activation and release of neurotoxins in the brain that results in neuronal injury (Ellis et al, 2011). Post-translational modification of proteins by poly(ADP-ribosyl)ation has wellknown effects on various cellular functions involving cell death, differentiation and gene expression (Krishnakumar and Kraus, 2010). PARP, being an enzyme and a scaffold protein, is a crucial factor of the transcriptional machinery that regulates spatial organization of transcription-regulating supramolecular complexes, architecture of chromatin and histone shuttling (Krishnakumar and Kraus, 2010), thereby regulating inflammation-associated genes. PARP inactivation was shown to play a role in the HIV-1 virus cycle, where PARP participated in HIV-1 LTR functions in U1 cells (Kameoka et al, 1999b, 2005), competed for binding to TAR RNA with positive transcription elongation factor b (p-TEFb) in vitro (Parent et al, 2005), and was required for efficient HIV-1 integration in (PARP-1−/−) mouse embryonic fibroblasts (Ha et al, 2001)
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