Tuesday, November 18, 2014

HIV Integration Site Affects Disease Progression

The human retrovirus HIV is well-known for both the ongoing burden it places on many countries, developed and developing, and for its particularly unique replication strategies.  HIV makes a DNA copy of its genome and sticks it right inside host cell DNA in a process called "integration."  This enables the virus to stay within a cell over a long period of time and is a particularly resource-efficient way to use host machinery for replication and viral protein production.  Exactly how the virus achieves this integration and where in the genome it integrates are imperfectly characterized and under investigation by viral researchers.

In a paper published November 12th of this year, a team of researchers explored the locations and selectivity of HIV integration into host genomes.  They identified two key amino acid residues in the protein that comprises the HIV integrase enzyme that interact directly with the host genome.  These two amino acids therefore determine the integration site specificity of the virus.  By manipulating these residues to match those of related animal viruses, the researchers were able to creates viruses that integrated at the same spots those animal viruses do, confirming that these two residues are responsible for integration specificity.

The researchers also found that changes in those two specificity-determining residues can be caused by selective pressures in an HIV patient who is undergoing treatment.  These changes in specificity could have important implications for disease progression because different enzyme integration sites are associated with different speeds of infection progression and disease severity.  For example, regions of DNA that have a high density of encoded genes will be transcribed more frequently by the host so more host replication machinery is generally present around such segments.  If the virus integrates in a gene-dense region, it will benefit from that concentration of translation machinery to make more virus particles quickly.  Perhaps this could cause a more rapid or severe disease presentation in the patient.  However, selective pressures could also drive the virus to integrate in less gene-dense regions if this would enable it to achieve latency and persist in a host undergoing antiretroviral treatment.

Read more at: http://www.sciencedirect.com/science/article/pii/S1931312814003497


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