Determinants of Retroviral Integration and Implications for Gene Therapeutic MLV—Based Vectors and for a Cure for HIV-1 Infection

Abstract

To complete their replication cycle, retroviruses need to integrate a DNA copy of their RNA genome into a host chromosome. Integration site selection is not random and is driven by multiple viral and cellular host factors specific to different classes of retroviruses. Today, overwhelming evidence from cell culture, animal experiments and clinical data suggests that integration sites are important for retroviral replication, oncogenesis and/or latency. In this review, we will summarize the increasing knowledge of the mechanisms underlying the integration site selection of the gammaretrovirus MLV and the lentivirus HIV-1. We will discuss how host factors of the integration site selection of retroviruses may steer the development of safer viral vectors for gene therapy. Next, we will discuss how altering the integration site preference of HIV-1 using small molecules could lead to a cure for HIV-1 infection.

Chronic HIV Transcription, Translation, and Persistent Inflammation

“…Another error-prone process that potentially contributes to generating defective proviruses is integration. Briefly, the process of integration begins with HIV-1 cDNA complexed with viral integrases, capsid proteins, and several host nuclear proteins, to form a pre-integration complex (PIC) [43][44][45][46][47][48]. Within the PIC, viral integrases multimerize at the ends of the linear cDNA, forming an intasome, which facilitates two critical catalytic activities, 3 ′ processing, and strand transfer.…”