Just as a spacecraft may settle onto a more or less propitious spot, a scrap of viral DNA may insert itself at different locations in its host’s DNA—and some locations may better serve a retrovirus’ disease-propagating purpose than others. Unlike a spacecraft, however, retroviruses such as HIV lack guidance systems. So, just how does HIV home in on its target? The question has puzzled virologists for over 20 years.
Dispelling at least some of the mystery, researchers at KU Leuven’s Laboratory for Virology and Gene therapy report that they have uncovered new details about the workings of the HIV protein integrase. This protein recognizes a short segment in the DNA of its host and catalyzes the process by which vial DNA is inserted into host DNA. In the researchers’ words, “A tetramer of the viral integrase assembles on the two viral cDNA ends, docks onto the target DNA, and catalyzes viral genome insertion into the host chromatin.”
According to the KU Leuven researchers, HIV integrase selects one landing site or another depending on the identity of the amino acids that occupy two strategic locations in the protein. The researchers presented this finding November 12 in the journal Cell Host & Microbe, in an article entitled, “HIV-1 Integrase Variants Retarget Viral Integration and Are Associated with Disease Progression in a Chronic Infection Cohort.”
“We identified the amino acids in HIV-1 IN that directly contact target DNA bases and affect local integration site sequence selection,” wrote the authors. “These residues also determine the propensity of the virus to integrate into flexible target DNA sequences.”
“These two amino acids determine the integration site,” emphasized doctoral researcher Jonas Demeulemeester, first author of the study. “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, explained professor Rik Gijsbers: “We 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.”
“We also showed that HIV integrases can vary,” continued Gijsbers. “Sometimes different amino acids appeared in the two positions we identified. These variant viruses also integrate into the host DNA at a different site than the normal virus does.”
Together with Thumbi Ndung’u, Ph.D., an HIV/AIDS researcher at the University of KwaZulu-Natal, Durban, South Africa, the KU Leuven team studied the impact of these viral variants on the progression toward AIDS in a cohort of African HIV patients. “Remarkably, natural polymorphisms INS119G and INR231G retarget viral integration away from gene-dense regions,” the authors of the Cell Host & Microbe observed. “Precisely these variants were associated with rapid disease progression in a chronic HIV-1 subtype C infection cohort.”
The researchers stated that their findings link integration site selection not only to virulence and viral evolution, but also to the host immune response and antiretroviral therapy. “By retargeting the integration site to a ‘safer’ part of the host DNA, we hope to eventually develop new therapies,” said study co-author professor Zeger Debyser.