Mechanistic and pharmacological analyses of HIV-1 integration

Significant advances have transpired in the human immunodeficiency virus type 1 (HIV-1) integration field 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 gammaretroviruses 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, as well as other techniques topical to the study of HIV-1 integration, are described in this issue of Methods.