Dissecting the mechanism of action of CHD1L, a novel regulator of HIV-1 infection

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HIV, the virus that causes AIDS, remains an important cause of ill health and mortality, with 37 million people living with the virus worldwide and annually being responsible for around 1 million deaths. This is despite significant progress in antiviral treatments. The virus interacts with infected human cells, and some of these interactions involve host defence molecules that critically affect the ability of the virus to complete its life cycle. This knowledge has informed the targeting of crucial viral processes in current treatment regimes. Most screening studies on how human genetics affect HIV replication have been conducted on European populations, despite more than 70 % of infected individuals and nearly half of new infections each year being in Africa. A recent study conducted by our collaboration has revealed a novel gene which has an enormous impact on HIV replication in patients of African ancestry. Upon infection, the level of the HIV in the body of the infected patient reaches a steady state and this level is a key factor in determining how quickly the immune system is compromised by the virus. This, in turn, is an important determinant of how long an HIV-infected individual takes to progress to AIDS. Our genomic study shows that a higher level of expression of a gene, chd1l, is associated with a lower steady state level of virus. The strength of the association between the level of protein produced by this gene CHD1L and the HIV level is equivalent to that of well described mutations in CCR5, one of the molecules necessary for most commonly transmitted viruses to gain entry into a cell, and these mutations are known to confer significant protection from HIV in patients harbouring them. Thus CHD1L has the potential to have an enormous impact on HIV replication.It remains unclear, however, how CHD1L is able to inhibit HIV infection. Here we propose research to understand the interaction between CHD1L and HIV. We aim to pinpoint the step(s) in the virus life cycle at which CHD1L may be exerting an effect, through quantifying the markers of the different stages in cells with and without CHD1L. CHD1L unwinds the packaging of DNA in response to specific signals in the cell. There are two candidate parts of the life cycle where this could be important. 1. In order to express its proteins, HIV inserts its genome into the host DNA in a process called integration. CHD1L could affect the efficiency and/or specificity of this process. 2. DNA also needs to be unwound for the encoded proteins to be expressed; again CHD1L could affect this process. We will also determine whether CHD1L binds to any specific HIV proteins by using highly sensitive techniques to see what CHD1L is bound to in infected and uninfected cells. In this way, we will identify the proteins and pathways in the cell through which CHD1L affects HIV replication. We will also identify features of the CHD1L protein that are essential for its ability to limit HIV infection by making changes to key parts of the protein and monitoring the ability of modified versions of the protein to inhibit HIV infection. Interactions with specific viral or cellular proteins could be exploited therapeutically to generate new treatments for HIV. The knowledge generated by our proposed experiments is necessary to translate our initial observation into clinically useful treatment for this devastating virus. The group of experts assembled to carry out this work are uniquely well-placed position to do this due to their expertise in the technology required for this work and their links to clinical and commercial partners.