Mechanistic and pharmacological analyses of HIV-1 integration

Abstract

Significant advances have taken place in the field of human immunodeficiency virus type 1 (HIV-1) integration in recent years. Considering its essential nature, integrase has long been a target of interest for antiviral drug development. The most significant advance was the approval of the Merck compound raltegravir, the first licensed integrase inhibitor, in October 2007. Another milestone was the identification and characterization of specific nucleoprotein complexes that mediate integrase 3′ processing and DNA strand transfer activities in vitro. Genome-wide distribution analyses have furthermore revealed that different retroviruses differentially target distinctive regions of chromatin during integration. For examples, lentiviruses favor actively transcribed genes whereas γ-retroviruses such as Moloney murine leukemia virus prefer transcriptional start sites. Though the underlying mechanisms are unknown for most retroviruses, the lentiviral preference is in large part guided through the interaction with the integrase binding protein lens epithelium-derived growth factor (LEDGF)/p75. Experimental methods that formed the foundations for each of these advances are described in this issue of Methods.

Establishment of a high-throughput screening system for universal anti-HIV targets

“…HIV-1 fusion inhibitors [9,10]; HIV-1 entry inhibitors [11,12]; and HIV-1 integrase strand transfer inhibitors [13][14][15]. These drugs target different steps of HIV-1 life cycle.…”