Roles of DNA Damage and its Cellular Response in the Transduction of Human Immunodeficiency Virus-1

Infection by Human Immunodeficiency Virus-1 (HIV-1) is modulated by the interaction of host cell, viral proteins, and environmental stimuli. Critically involved cellular factors are apolipoprotein B mRNA-editing enzyme-catalytic, polypeptide-like 3 protein family (APOBEC3), tetherin, and SAM and HD domain-containing protein 1 (SAMHD1). The functions of these restriction factors are overcome by viral mediators that include Viral Infectivity Factor (VIF) for APOBEC3, viral protein U (vpU) for tetherin, and Vpx (in HIV-2) for SAMHD1. In addition, DNA damage, the most common environmental stimulus, influences the multiple steps of the viral infection. Notably, DNA repair proteins play critical roles in the integration steps of viral DNA. The activated DNA damage response by viral infection leads to apoptotic cell death and prevents the viral propagation, suggesting that it is an intrinsic viral restriction mechanism. In contrast, the DNA damage responses can increases the frequency of viral infection when the integrase activity is defective or inhibited by integrase inhibitors, implying that DNA damage and its cellular response function like dual sides of the same coin. In this review, we first summarize our current understanding of the restriction factors, and then focus on the roles of HIV-1-associated DNA damage response on the transduction of viral DNA. In particular, the functional association of viral integration with the DNA repair pathways will be discussed.