Researchers at the University of Minnesota (UM) in the United States conducted a study of genetic variation in HIV-1 (Human Immunodeficiency Virus type 1) and in the cells it infects, explaining in part why the virus rapidly sickens some people, while in others it has difficulties to develop. This is a finding that potentially opens the door to new treatments.
T-cells (or T-lymphocytes) are white blood cells that play important roles in the immune system. After HIV-1 enters the body, it works its way inside of T-cells, hijacking their molecular machinery to replicate itself, and then destroying the host cells. When the virus has destroyed a great part of the T-cells weakening the immune system, the infected person becomes more susceptible to other deadly diseases.
T-cells have their own defense mechanisms, among those there is the release of an mRNA editing enzyme known as APOBEC3s (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G) that have the ability to block the HIV-1’s ability to replicate. However, HIV-1 has evolved a counter-defense mechanism, a protein called Vif (Viral infectivity factor) that interacts with APOBEC3G and triggers its degradation
While some individuals develop the HIV infection quicker, others are less susceptible or even immune to the disease. The researchers of the University of Minnesota’s College of Biological Sciences and Medical School suspected that the differential susceptibility to HIV-1 might be related to genetic variations the APOBEC3 – Vif system.
Conducting the study, published in PLOS Genetics, the researchers found that HIV-1 infection boosts the production of one kind of APOBEC3, called APOBEC3H. Therefore, the researchers thought it is a key player in fighting back. Then, using an experimental technique known as separation of function mutagenesis, they discovered that different people have different strengths/potencies of APOBEC3H, with some proteins expressed stably and others inherently unstable. The stable variations, the researchers found, were able to successfully limit HIV-1’s ability to replicate, but only if the infecting virus had a weak version of Vif , and not for HIV-1 viruses that had strong Vif.
“This work shows that the competition between the virus and the host is still ongoing. […] The virus hasn’t completely perfected its ability to replicate in humans,” said doctoral student Eric Refsland, coauthor of the study.
Team leader Professor Reuben Harris said that armed with this clearer picture of the multifaceted interactions between Vif and APOBEC3, the next step is to figure out how to stop Vif from disabling the APOBEC3 enzymes. “One could imagine drugs that stop Vif from binding with APOBEC,” he said. “This is a bonafide HIV killing pathway, and we just have to devise clever ways to activate it in infected persons. Such an approach could indefinitely suppress virus replication, and even result in curing it.”
Through: University of Minnesota