Integration of viral DNA into host genomic DNA

Stable Identifier
R-HSA-175567
Type
Pathway
Species
Homo sapiens
Related Species
Human immunodeficiency virus 1
Compartment
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Following nuclear entry, the viral preintegration complex (PIC) must select a site for integration in a host cell chromosome, and then carry out the chemical steps of the reaction.

At the chromosomal level, HIV has been found to favor active transcription units for integration. Subsequent studies established that the cellular PSIP1/LEDGF/p75 protein is important in this reaction. PSIP1/LEDGF/p75 binds tightly to HIV integrase, and also to chromatin. Knocking down PSIP1/LEDGF/p75 in cells resulted in several perturbations of integration targeting in vivo, including reduced integration in transcription units. Thus PSIP1/LEDGF/p75 has been hypothesized to act as a tethering factor that dictates at least in part the placement of HIV integration sites.

The integration target DNA is also expected to be coated with nucleosomes. Tests of integration into mononucleosomes in vitro have shown that wrapping integration target DNA actually boosts integration activity. Kinked positions on the DNA gyre are particularly favored for integration.

Integration does not take place at a unique sequence in the integration target DNA (i.e. it is not like a restriction enzyme). However, favored and disfavored primary sequences can be detected when many integration sites are aligned. Synthesis and testing of favored HIV integration sites showed that they were favored for integration by PICs in vitro.

After a target DNA is bound, the integration reactions take place via a single-step transesterification.

Integration of both ends of the viral DNA, followed by melting of the target DNA segments between the points of joining, yields single stranded gaps at each host-virus DNA junction, and a two base overhang derived from the viral DNA. The manner by which this intermediate is subsequently repaired to yield the fully integrated provirus is unclear. For many parasitic DNA replication reactions, the parasite carries out reaction steps only up to a point that the host cannot easily reverse, forcing the host to complete the job (Bushman 2001; Craig et al. 2002). For retroviral integration, it is reasonable to infer that host DNA repair enzymes complete provirus formation. DNA gap repair enzymes are known to be involved in a variety of DNA repair pathways, so their recruitment to gaps at host-virus DNA junctions is readily envisioned. Consistent with this, known gap repair enzymes have been shown to act on model host-virus DNA junctions in vitro (Yoder and Bushman, 2000).

Literature References
PubMed ID Title Journal Year
16175173 Genome-wide analysis of retroviral DNA integration

Lewinski, M, Ciuffi, A, Barr, S, Leipzig, J, Hannenhalli, S, Hoffmann, C, Bushman, FD

Nat Rev Microbiol 2005
16291214 Retroviral DNA integration--mechanism and consequences

Lewinski, MK, Bushman, FD

Adv Genet 2005
  Retroviruses

Coffin, JM, Hughes, SH, Varmus, HE

  1997
Participants
Participant Of
Event Information
Disease
Name Identifier Synonyms
Human immunodeficiency virus infectious disease 526 HIV infection
Authored
Reviewed
Created