Host Factors in Retroviral Integration and the Selection of Integration Target Sites

Abstract

In order to replicate, a retrovirus must integrate a DNA copy of the viral RNA genome into a chromosome of the host cell. The study of retroviral integration has advanced considerably in the past few years. Here we focus on host factor interactions and the linked area of integration targeting. Genome-wide screens for cellular factors affecting HIV replication have identified a series of host cell proteins that may mediate subcellular trafficking for preintegration complexes, nuclear import, and integration target site selection. The cell transcriptional co-activator protein LEDGF/p75 has been identified as a tethering factor important for HIV integration, and recently, BET proteins (Brd2, 4, and 4) have been identified as tethering factors for the gammaretroviruses. A new class of HIV inhibitors has been developed targeting the HIV-1 IN-LEDGF binding site, though surprisingly these inhibitors appear to block assembly late during replication and do not act at the integration step. Going forward, genome-wide studies of HIV-host interactions offer many new starting points to investigate HIV replication and identify potential new inhibitor targets.

Figure 1

Sites of HIV DNA integration in chromosomes. The human chromosomes are shown in the outermost ring. The green histograms indicated relative G/C content; red indicates gene density, orange indicates density of HIV integration sites in T cells (78), and purple indicates MLV integration site density in T cells(115).

Figure 2

The inhibitor GSK1264 bound to the LEDGF-binding site on the HIV IN catalytic domain dimer. The alpha carbon backbone of the IN catalytic domain dimer is shown in gold. The GSK1264 compound is show in cyan (carbons) and red (oxygens). Active site residues are shown in orange. Details on the structure and function of GSK1264 are reported in (137).