Scientists have identified two locations where slight differences in genetic code can change the way human immunodeficiency virus infects cells – a change associated with worsening symptoms and resistance to antiretroviral drugs.
The study, published in PLOS ONE, is the first to link genetic changes in these two locations with alterations in the progression of the human immunodeficiency virus (HIV).
“In this study, we have uncovered new ways this wily virus can escape the control of anti-HIV treatments,” says principal investigator Dr. Grace Aldrovandi, chief of the Division of Infectious Diseases at Children’s Hospital Los Angeles.
According to the Centers for Disease Control and Prevention (CDC), more than 1.2 million people in the US are currently living with HIV infection. Of these people, it is estimated that almost 1 in 7 (14%) are unaware of their infection.
HIV infects the immune system by entering specific white blood cells called CD4+ T cells. These cells are responsible for sending signals to activate the body’s immune response when viruses and bacteria are detected.
The virus enters these cells using two different receptors – CCR5 (R5) or CXCR4 (X4). The majority of HIV infections use the R5 receptor, but in around 50% of cases the virus changes receptor and begins using the X4 receptor.
At present, there is no cure for HIV infection, although people living with HIV can take a combination of different drugs to control the virus. One particular class of anti-HIV drugs is entry or fusion inhibitors, used to block HIV’s entry into T cells by targeting specific receptors on the surface of the cells.
Changing to the X4 receptor often occurs alongside an increase in the severity of the virus. What is more, any antiretroviral drugs being taken that target the R5 receptor such as CCR5 receptor antagonists become ineffective.
Discovery could allow scientists to counter HIV’s ability to evade control
Entry into the CD4+ T cells is controlled by a viral envelope, consisting of part of the T cell’s membrane and molecules generated by HIV’s genetic code called glycoproteins. The two glycoproteins specifically involved are gp120 and gp41, and three units of gp120 can be found on the surface of the cell.
Every gp120 molecule is divided into five constant regions (C1-C5), five variable regions (V1-V5) and a bridging sheet that works as a connecting structure. Previous studies have revealed that signaling from the V3 region is crucial in determining which receptor the virus uses to infect the white blood cell.
The researchers wanted to find out precisely what was behind the switch from using the R5 receptor to using the X4 receptor. To do so, they examined closely-related viral envelopes with identical V3 sequences that were signaling different receptors.
By doing this, the team discovered that it is was not just the V3 region that controlled use of the X4 receptor. For the first time ever, the researchers identified that genetic changes to the C2 region and the bridging sheet also influenced use of this receptor.
“It is our hope that discovery of additional mechanisms for HIV’s switch from the R5 to the X4 receptor may allow scientists and clinicians to better predict, and potentially counter, the ability of HIV to escape antiretroviral control via this mechanism,” says co-author Dr. Nicole Tobin, research scientist at Children’s Hospital Los Angeles.
Recently, Medical News Today reported on a study that found shutting the sugar pipeline in activated immune cells can help prevent the spread of HIV by stopping the virus from replicating.
Written by James McIntosh