Chapter 45 : Host Factors in Retroviral Integration and the Selection of Integration Target Sites

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Retroviruses integrate a DNA copy of the viral genome into cellular DNA as an obligatory step in the viral replication cycle. Once integrated, the viral DNA is stably replicated with cellular DNA through cycles of DNA replication and cell division. The first clues regarding the mechanism of integration came from genetic experiments ( ). Mutations at two locations within the viral genome resulted in a phenotype in which reverse transcription occurred normally but the viral DNA failed to integrate. These mutations mapped to regions which we now know encode the viral integrase (IN) protein and the ends of the viral DNA sequence recognized by IN. The finding that viral DNA within extracts of infected cells efficiently integrated into exogenously added target DNA ( ) facilitated biochemical studies of integration. This integration system enabled the DNA breaking and joining events to be unambiguously determined ( ). It also established that the viral DNA forms part of a large nucleoprotein complex termed the preintegration complex (PIC) ( ). Later biochemical experiments showed that viral IN protein is necessary and sufficient to carry out the DNA cutting and joining steps of integration in the presence of divalent metal ions ( ). Subsequent studies established reaction conditions that facilitated efficient concerted integration of both viral DNA ends into the target DNA molecule ( ). This chapter focuses on mechanisms of targeting integration and the contributions of viral and cellular proteins. For structural information on nucleoprotein complexes involved in retroviral DNA integration see the chapter by Engelman and Cherepanov. For detailed discussions of the mechanisms of DNA transposition of related elements see other chapters in .

Citation: Craigie R, Bushman F. 2015. Host Factors in Retroviral Integration and the Selection of Integration Target Sites, p 1035-1050. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0026-2014
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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 ( ), and purple indicates MLV integration site density in T-cells ( ).

Citation: Craigie R, Bushman F. 2015. Host Factors in Retroviral Integration and the Selection of Integration Target Sites, p 1035-1050. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0026-2014
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Image of Figure 2
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 ( ).

Citation: Craigie R, Bushman F. 2015. Host Factors in Retroviral Integration and the Selection of Integration Target Sites, p 1035-1050. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0026-2014
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Table 1

Some resources for working with genome-wide data on HIV research

Citation: Craigie R, Bushman F. 2015. Host Factors in Retroviral Integration and the Selection of Integration Target Sites, p 1035-1050. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0026-2014