The DNA Damage Response and HIV-Associated Pulmonary Arterial Hypertension

Abstract

The HIV-infected population is at a dramatically increased risk of developing pulmonary arterial hypertension (PAH), a devastating and fatal cardiopulmonary disease that is rare amongst the general population. It is increasingly apparent that PAH is a disease with complex and heterogeneous cellular and molecular pathologies, and options for therapeutic intervention are limited, resulting in poor clinical outcomes for affected patients. A number of soluble HIV factors have been implicated in driving the cellular pathologies associated with PAH through perturbations of various signaling and regulatory networks of uninfected bystander cells in the pulmonary vasculature. While these mechanisms are likely numerous and multifaceted, the overlapping features of PAH cellular pathologies and the effects of viral factors on related cell types provide clues as to the potential mechanisms driving HIV-PAH etiology and progression. In this review, we discuss the link between the DNA damage response (DDR) signaling network, chronic HIV infection, and potential contributions to the development of pulmonary arterial hypertension in chronically HIV-infected individuals.

Keywords: DNA damage; HIV; Nef; Tat; endothelial; pulmonary arterial hypertension.

Figure 1

Simplified diagram of the dynamic and interconnected DNA damage response network orchestrated by the signal transducing kinases ATM, ATR, and DNA-PKcs: (A) Tip60 acetylates ATM at lysine residue 3016, resulting in auto phosphorylation and activation of ATM kinase monomers. ATM phosphorylation of Chk2 and P53 leads to induction of cell cycle arrest, while ATM phosphorylation of Brca1 initiates double stranded DNA repair through homologous recombination (HR). Chk2 phosphorylation of P53 independent of ATM leads to apoptosis. (B) ATR and TopBP1 localize to sites of DNA Damage and replicative stress, where ATR phosphorylates effectors substrates. ATR mediated activation of Chk1 and P53 induce cell cycle arrest, while phosphorylation of Brca1 augments DNA end resection and single stranded DNA break repair by HR. Phosphorylation of P53 by activated Chk1 further augments cell cycle arrest. (C) DNA-PK stabilizes P53 in response to excessive genotoxic stress, inducing apoptosis. The ku70 and Ku80 subunits of the DNA-PK complex act as scaffolding adaptors for DNA-PKcs and recruitment to dsDNA lesions, where DNA-PKcs facilitates DNA repair through the error prone non-homologous end joining pathway.

Figure 2

HIV factors Tat and Nef modulate the DNA Damage Response. (A) Tat is known to impair Tip60 activity, which in turn may attenuate ATM activation, resulting in impaired signaling to downstream effector substrates. Tat results in depression od DNA-PKcs and results in impaired dsDNA repair capacity and impaired checkpoint entrance ability. (B) Nef induces a pro-survival phenotype through PI3K and AKT activation, resulting in excessive phosphorylation of Bad and depression of apoptosis signaling.