The lab will lead a DARPA funded ($5M+) project to understand the functional organization of influenza virus and develop novel resistance-proof gene therapeutics based on evolutionary and population dynamic principles. Read the news release here.
Patients infected by hepatitis C virus (HCV) can be cured within 3 weeks of therapy using an NS3 protease inhibitor and dual NS5A inhibitor–NS5B nucleotide analogue – the so called ‘direct acting antivirals (DAA)’! See the work published very recently:
- Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study [Link]
We’ve been involved to use a nonlinear mixed effect modeling approach to analyze the viral kinetic data to show that the DAA combinations used in this study are highly effective at blocking viral RNA synthesis, replication and assembly.
One caveat of the study is the sample size – although 100% of patients who are treated with 3-week DAA therapies are cured of HCV, the total sample size is 18, and all participants are Asian. It is not clear how these results scale to a larger population or populations of other ethnicities.
HCV infects approximately 150-180 million people (3% of total population). The development of direct acting antivirals against HCV has enjoyed remarkable successes recently – it changed the HCV treatment from interferon therapy which lasts 48-week long with severe side effects and low cure rates to 8-week, 6-week and now possibly 3-week DAA therapies with little side effects and extremely high cure rates (>90%). Sounds great, doesn’t it?
Participated the Biology and Medicine Through Mathematics (BAMM!) Conference held at Richmond, VA. Learnt a range of topics in mathematical biology. Really enjoy the discussions with other math biologists!
Participated in the 23rd HIV Dynamics & Evolution meeting held at Woods Hole. Gave two talks on determinants of latency reversing agent efficacy to reduce HIV reservoir size and death rate of abortive infection in SHIV infection, respectively. Learnt a lot about state-of-art HIV research ranging from epidemiology, clinical and experimental studies! One of my favorite meetings!
Participated in the HIV persistence workshop held at Miami, FL. Learnt a lot about virology, immunology, drug discovery and clinical trials surrounding the issue of finding a ‘cure’ for HIV infection. A very exciting workshop!
Participated in the two day symposium and breakout groups at the Triangle Center for Evolutionary Medicine (TriCEM). The theme of the meeting is ‘The Use of Pathogen Genetic Data for Informing the Spread of Infectious Diseases Within and Between Individuals’.Thanks to Katia Koelle’s invitation that I gave a talk on a previous work which combines phylogenetic analysis and dynamic modeling to understand the emergence and spread of defective dengue viruses (see the work here).
I particularly enjoy fruitful discussions with researchers from a range of research areas, which are very inspirational. One of the outcomes is that a group of us start to think about linking within-host and between-host population dynamics and genetic diversity to understand how viral substitution and/or adaptation rates are influenced by viral life-cycle parameters.
Our work on one of the first HIV latency reversing agents, vorinostat, is published by PLoS Pathogens. As stated in the title of this paper, by fitting mathematical models to clinical data, we show that vorinostat induces both transient and delayed HIV transcriptional activation in vivo, but minimal killing of latently infected cells (read here for more details).
If you are not working on this area and would like to know a little background why we care about latency reversing agents and/or current challenges to cure HIV infection, here below is a short writing. Hopefully it is useful in terms of putting our work into a broader picture.
Efforts to cure HIV infection are hindered by the existence of latently infected cells, i.e. cells infected by HIV but that do not actively produce virus. These cells form the HIV latent reservoir. A majority of these cells are resting memory CD4+ T cells. What do these ‘resting’ ‘memory’ CD4+ T cells do? The short answer is that they provide immunity to us: they are generated during prior exposure to pathogens to fight an infection. Once the infection is resolved, they switch to a ‘resting’ state, and hardly do anything apart from moving around within our body. However, once they encounter a pathogen they have ‘seen’ before, they respond immediately and signal to other immune cells to fight the pathogen right away.
Resting memory CD4+ T cells live for a long period of time (up to many years). This is a great property in terms of immunity: the longer they live, the longer we are protected. However, when they are infected with HIV, this property becomes problematic. HIV can ‘hide’ in these cells without doing anything for an extremely long time. In this way, HIV is invisible to the immune surveillance: neither infected cells themselves nor other immune cells see anything wrong. From time to time, HIV can start to express gene products and viral particles when the condition is right (the exact conditions have not been figured out, although this is a very active research area). These newly produced HIV particles may reseed the infection in the absence of an effective anti-retroviral therapy (the so called ‘cocktail’ therapy). Because this population of infected cells is extremely stable, patients have to be treated with the ‘cocktail’ therapy life-long.
Thus, recent research has focused on developing/testing latency reserving agents, such as vorinostat we study here, to activate HIV production in latently infected cells, such that they could be recognized and purged by cellular protective mechanisms (i.e apoptosis/suicide) or extracellular immune mediated killing (antibodies or cytotoxic T cell response). The aim is to reduce the population size of the latently infected cells, eradicate this reservoir and ultimately cure HIV infection. To us, this is such an exciting research area to work on!