Professor John Murray
School of Mathematics and Statistics
University of New South Wales
Modelling HIV and the immune system
Since the beginning of the HIV epidemic in the early 1980's approximately 40 million people have been infected and three-quarters have died. Antiretroviral therapy (ART) has significantly reduced mortality and morbidity in the developed world but access to these drugs is severely restricted in poorer countries in sub-Saharan Africa where the majority of HIV infections occur. Although prevention methods have reduced HIV incidence in many of these countries the burden of disease is growing. In 2007 there were 2.7 million new HIV infections and 2 million HIV-related deaths globally.
In Australia there are approximately 20,000 men and women living with HIV/AIDS. Although ART has been successful in reducing morbidity and mortality, ART has not been able to clear the infection. Much of the work here is associated with obtaining a better understanding of how the complex system of HIV and the immune system interact, and possibly determining the causes of HIV persistence.
HIV latent infection
Persistence of HIV infection despite ART is suspected to be due to viral reservoirs which include long-lived infected cells, latent infection in various forms and sanctuary sites. The role some of these play in viral production has been estimated previously from the dynamics of plasma HIV RNA levels (pVL) and HIV DNA after commencement of ART. Although pVL quickly decreases at a rate initially indicative of the loss of productively infected CD4+ T cells, second and third phases occur that reflect other sources, such as long-lived infected cells and reactivation of latently infected cells. Ultra sensitive assays have shown that pVL remains detectable despite prolonged ART.
HIV DNA exhibits significantly less change over time. This cellular component is established early in infection and decreases very slowly following ART. Moreover, viral DNA is expressed in a variety of forms including integrated and productive, integrated but latent, an unintegrated linear form, and circular episomal forms of 1-LTR and 2-LTR HIV DNA that represent aborted integration events. The timing of progression through these separate stages of the viral life cycle and their implications for levels of ongoing infection with ART are uncertain and of considerable interest. In the PINT study we have characterized the dynamics of pVL and HIV DNA during ART containing the integrase inhibitor raltegravir. Recent reports by our group have appeared in AIDS (Koelsch et al. AIDS 2011, and Murray et al., AIDS 2012.)
Viral dynamics and their implications
Most activity in terms of viral replication and the immune response occurs in tissue, such as lymphoid tissue for HIV infection, that is not easily accessible. Most analyses instead follow the dynamics of infection in blood, that can be easily accessed and reasonably represents changes in tissue. The dynamics of this complex system of infection and immune response are then analysed in the usual mathematical way through perturbations. How a system changes after these perturbations provides important information on the underlying dynamic parameters such as the half-life of an infected cell. Perturbations for HIV are achieved through the commencement (or cessation) of ART and the number of HIV RNA molecules (there are 2 per virion) per ml of blood are then tracked over time. Fitting dynamical models to these data provides estimates of the underlying parameters and an understanding of the biological processes that are hidden inside the body. Early work in this area was spearheaded by mathematicians Alan Perelson and Martin Nowak in collaboration with their medical colleagues.
After the commencement of ART, HIV RNA levels decrease in a multiphasic manner until they drop below the assay limits of detection. Each phase represents a different source of viral production. Our work with the first integrase inhibitor raltegravir showed that the previous hypotheses for the source of the second phase of virus was incorrect (Murray et al., AIDS 2007). Further investigations of HIV viral dynamics with raltegravir and drugs from other antiretroviral classes allowed us to estimate fine details of the HIV infection cycle within a cell (Murray et al. J Virology 2011).
HIV gene therapy
ART has significantly decreased the morbidity and mortality of HIV/AIDS. However it does not eradicate HIV infection and there can be complications associated with antiretroviral drugs. A new therapeutic approach involves delivering a protective gene to the cells of an infected person using gene therapy. A recent trial conducted by Johnson & Johnson Australia showed that anti-HIV gene therapy is safe and biologically active. We have continued investigation of gene therapy with researchers at Calimmune, through an ARC Linkage Grant: "Can an anti-HIV gene in blood stem cells protect from immune depletion by HIV?".
HIV neurocognitive impairment
HIV infects cells in the brain and central nervous system and can result in HIV-associated dementia (HAD), and lesser forms such as HIV-associated neurocognitive disorders (HAND) despite antiretroviral therapy that suppresses plasma viral levels. Proper assessment of these disorders requires extensive testing by qualified neurologists and is beyond the expertise of the treating HIV general practitioner. In collaboration with researchers from Applied Neurosciences at St Vincent's Hospital, we developed a simple first step method to identify HIV-infected individuals who may be suffering from HIV neurological disorders and who should be further assessed by the full neurological battery of tests. This research was published in a mathematical journal describing the methodology and the application (Dunbar et al., European Journal of Operational Research, 2010), as well as being published in the journal HIV Medicine where the method and its accuracy for correct prediction of HAD was described (Cysique et al., HIV Medicine, 2010). This latter article was the most viewed article by HIV clinicians on Medscape in 2011.