Discovery of HIV Feature Provides New Drug Target

An essential component of HIV that can explain how the virus can remain undetected by the immune system as it continues to infect other cells has been discovered by researchers at the MRC Laboratory of Molecular Biology in Cambridge and the University of London. The results yielded by the study, published in Nature, can be used to improve the efficacy of antiretroviral drugs currently used to treat HIV in addition to providing researchers with a new drug target.

HIV remains a threat in the United States as well as in other countries around the world. According to the Centers for Disease Control and Prevention (CDC), by the end of 2012, 1.2 million people were living with HIV in the United States. Furthermore, in 2014, about 44,073 people were newly diagnosed with the virus in the United States alone. The CDC notes that there has been a 19% decline in new diagnoses over the last decade (possibly due to increased testing and targeted prevention efforts) but progress towards decline remains uneven.

According to a press release, since HIV is a retrovirus, "it has to copy its RNA genome into DNA in order to infect cells." Prior to this discovery it was unknown how HIV acquired nucleotides, what the press release describes as “the building blocks of genetic material [the virus] needs” as well as how the virus coud perform these functions while remaining undetected by a cells' 'alarm systems,' which are supposed to detect foreign DNA.

Researchers of the study have found that HIV builds this foreign DNA while inside the capsid, a protein shell that surrounds the virus. Through the use of a hybrid approach, they were able to separate and study the capsid’s atomic structure in various states and through the creation of mutant versions of HIV, and analyze how this altered infection.

The results of these experimental approaches showed that there were “iris-like pores in the capsid that open and close like those in the eye,” according to the press release. Nucleotides, needed to replicate the virus, are quickly sucked into these pores, and at the same time, do not allow any other unwanted molecules inside. Through this process, HIV is able to effectively evade the immune system without detection.

Senior author, Leo James, PhD, from the MRC Laboratory of Molecular Biology, said, “We used to think that the capsid came apart as soon as the virus entered a cell but now realise that the capsid protects the virus from our innate immune system. The channels we’ve discovered explain how the fuel for replication gets into the capsid to allow the viral genome to be made.”

The researchers then designed a channel inhibitor, hexacarboxybenzene, as a means to block the capsid pores. They found that after the pores were effectively blocked with this molecule, the virus could no longer replicate, and thus, became non-infectious.

Study authors feel that with these results, drugs similar to hexacarboxybenzene can be developed to effectively enter the cell membrane of human cells, where this molecule cannot. In addition, researchers can examine as well as work on improving the transit of antiretroviral drugs currently used to treat HIV through these pores, according to the press release.

When speaking on the implications of these findings, lead author David Jacques, PhD, from the MRC Laboratory of Molecular Biology, said, “We have already designed a prototype inhibitor that directly targets the channel. We predict that this feature may be common to other viruses and will be an attractive target for new antiviral drugs, including new treatments for HIV and related viruses.”