New study uncovers human genes controlling HIV infection

A map of HIV infection that highlights genetic weaknesses during the infection process has been published by an international research team involving researchers at University College Dublin.
Dr Ariane Watson, a postdoctoral researcher in Systems Biology Ireland, is co-lead author of the work, published in the current issue of the journal Molecular Cell. Ariane carried out the research as part of her PhD project under the supervision of Dr Gerard Cagney, UCD Conway Institute and School of Biomolecular and Biomedical Science.

Viruses are parasites that grow by living off their hosts. When viruses infect a human host, they use human proteins to complete their life cycle and often change the human cells to sustain their growth. The human host tries to defend itself by activating mechanisms to withstand infection.

Most current drugs against viral infections target the virus itself. However, scientists are trying to develop therapies that aim for host proteins instead, or the genes that produce them. This may provide clinicians with therapies that are less likely to cause drug resistance.

To do this, scientists need to know all the host proteins and genes that support or stall a viral infection. They also want to understand the dynamics of the relationships between these host genes and proteins (for example whether they work together or independently).

This research used a large-scale genetic approach pioneered by Nevan Krogan, Professor of Cellular and Molecular Pharmacology at University of California San Francisco (UCSF), and Director of the UCSF Quantitative Bioscience Institute who led the collaborative project. 

Professor Krogan developed the approach based on the idea that richer information about the relationship between genes can be revealed when they are tested in pairs rather than one by one.

Co-lead authors, Ariane Watson (UCD) and David Gordon (UCSF) developed a map (vE-MAP) by testing 63,000 combinations of human genes. This map allows them to visualise the many genes and cellular processes that control HIV growth in human cells. They uncovered a previously unsuspected set of genes required for the growth of the virus in human cells.

Commenting on the findings, Dr Watson said, "The vE-MAP allows us to investigate the relationship between pathogens and their hosts in an exciting new way, by focusing on the host systems, which viruses and bacteria depend upon for replication and survival.

Resistance is a critical issue when targeting pathogens directly. Using our approach, we can identify new vulnerabilities by finding host genes, which pathogens depend on to target.

Furthermore, the vE-MAP platform also allows us to study how mutations in a pathogen impact on its interaction with the host. Not least of all, the vE-MAP can be used to characterise the mechanism of action of poorly characterised antiviral drugs and antibiotics, allowing us to identify the host pathways through which such therapeutics function."
The team uncovered a previously unknown link between genetic machinery (RNA processing enzyme complex) and the innate immunity pathway. This shows how the virus can manipulate the host's protein network. 

Viruses such as HIV/AIDS have evolved multiple ways of tapping their hosts’ resources. This knowledge is important as it would greatly increase the options for effective therapies.

Professor Neven Krogan, UCSF said, “vE-MAP provides an unprecedented view of how HIV hijacks and rewires the cellular machinery in human cells during infection. It will generate many new ideas and avenues to identify and test novel therapies.”

Commenting on the research collaboration, Dr Gerard Cagney said, "Nevan and I have worked together for 20 years now on different projects, and this work shows how international study visits can add great value to research programmes. We were delighted to formally recognise this recently with an affiliation agreement signed by UCD Research and the Quantitative Biosciences Institute at UCSF to underline these links."

IV is a major public health concern, with an estimated 36.7 million people living with chronic infection and over 20.9 million people receiving continuous treatment. Funders for the work included Science Foundation Ireland.