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HIV virulence depends on where virus inserts itself in human host DNA.

The human immunodeficiency virus (HIV) can insert itself at different locations in the DNA of its human host, and this specific integration site determines how quickly the disease progresses, report researchers at KU Leuven’s Laboratory. The opensource study is published in the journal Cell Host & Microbe.

When HIV enters the bloodstream, virus particles bind to and invade human immune cells. HIV then reprogrammes the hijacked cell to make new HIV particles.

The HIV protein integrase plays a key role in this process: it recognises a short segment in the DNA of its host and catalyzes the process by which viral DNA is inserted in host DNA.

Integrase can insert viral DNA at various places in human DNA. But how the virus selects its insertion points has puzzled virologists for over 20 years.

Now a team of KU Leuven researchers has discovered that the answer lies in two amino acids. HIV integrase is made up of a chain of more than 200 amino acids folded into a structure. By modelling this structure, the team found two positions in the protein that make direct contact with the DNA of the host. These two amino acids determine the integration site. This is not only the case for HIV but also for related animal-borne viruses.

In a second phase of the study, the researchers were able to manipulate the integration site choice of HIV. The team changed the specific HIV integrase amino acids for those of animal-borne viruses and found that the viral DNA integrated in the host DNA at locations where the animal-borne virus normally would have done so.

The team also showed that HIV integrases can vary.  Sometimes different amino acids appeared in the two positions the researchers identified. These variant viruses also integrate into the host DNA at a different site than the normal virus does.

Together with thenUniversity of KwaZulu-Natal, the team studied the impact of these viral variants on the progression towards AIDS in a cohort of African HIV patients.

To their surprise, the group found that the disease progressed more quickly when the integration site was changed. In other words, the variant viruses broke down the immune system more rapidly.

This insight both increases the medical community’s knowledge of the disease and opens new perspectives. By retargeting the integration site to a ‘safer’ part of the host DNA, the researchers hope to eventually develop new therapies.

Source:  KU Leuven

 

Distinct integration patterns of different retroviruses, including HIV-1, have puzzled virologists for over 20 years. A tetramer of the viral integrase (IN) assembles on the two viral cDNA ends, docks onto the target DNA (tDNA), and catalyzes viral genome insertion into the host chromatin. We identified the amino acids in HIV-1 IN that directly contact tDNA bases and affect local integration site sequence selection. These residues also determine the propensity of the virus to integrate into flexible tDNA sequences. Remarkably, natural polymorphisms INS119G and INR231G retarget viral integration away from gene-dense regions. Precisely these variants were associated with rapid disease progression in a chronic HIV-1 subtype C infection cohort. These findings link integration site selection to virulence and viral evolution, but also to the host immune response and antiretroviral therapy, since HIV-1 IN119 is under selection by HLA alleles and integrase inhibitors.  HIV-1 Integrase Variants Retarget Viral Integration and Are Associated with Disease Progression in a Chronic Infection Cohort.  Gijsbers et al 2014.
Distinct integration patterns of different retroviruses, including HIV-1, have puzzled virologists for over 20 years. A tetramer of the viral integrase (IN) assembles on the two viral cDNA ends, docks onto the target DNA (tDNA), and catalyzes viral genome insertion into the host chromatin. We identified the amino acids in HIV-1 IN that directly contact tDNA bases and affect local integration site sequence selection. These residues also determine the propensity of the virus to integrate into flexible tDNA sequences. Remarkably, natural polymorphisms INS119G and INR231G retarget viral integration away from gene-dense regions. Precisely these variants were associated with rapid disease progression in a chronic HIV-1 subtype C infection cohort. These findings link integration site selection to virulence and viral evolution, but also to the host immune response and antiretroviral therapy, since HIV-1 IN119 is under selection by HLA alleles and integrase inhibitors. HIV-1 Integrase Variants Retarget Viral Integration and Are Associated with Disease Progression in a Chronic Infection Cohort. Gijsbers et al 2014.

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