Friday, November 21, 2008

HIV, TRIM5 and the Red Queen

Dated: 18th November 2008

Venue: Darwin Lecture Theatre, Darwin Building, UCL

Time: 1:15 - 2:00 pm


I was running a bit late and made a dash as soon as I got off the bus. By the time I reached the hall, it was almost full. I quickly settled myself on a seat and tuned my senses to the lecture by Dr. Greg Towers (UCL, Immunology & Molecular Pathology). Its been a long time since I attended a strictly medical science lecture I thought to myself.


Anyway, the lecture was about retroviruses such as HIV that have been infecting mammals for millions of years. Host species have therefore evolved ways to protect themselves but then the virus counter-evolution is leading to an evolutionary arms race, described by the Red Queen hypothesis. Focusing on HIV /AIDS, the speaker discussed about the innate antiviral restriction factors (RFs) and pointed how viruses escape them to cause disease. In immunology, we are taught of three immune system responses - the antibodies, the cytotoxic T cells (together forming Adaptive Immune system) and the Innate Immune system, comprising of natural killer cells, antiviral protiens and RFs.


Currently there are about 33.2 million people living with HIV, and 22.5 million are in sub-Saharan Africa alone!!! So why do humans contract HIV? Well, lets see what is this Red Queen hypothesis. Simply put, it states, If the host changes through evolution, so must the virus in order to catch up with that change. And what are these restriction factors...Well, they are proteins that inactivate viral infection and provide symptom free immunity. The RF, TRIM5 (tripartite motif) works by labelling viral cells for destruction by other RFs. But this HIV destruction occur in certain primate species (Rhesus monkeys, Owl monkey, etc.) and not in humans. The human version of this RF inhibits other kinds of viruses (murine leukemia virus-MLV and equine infectious anemia virus -EIAV). Another RF, Tetherin that is present in humans on the cell membrane surfaces, act by adhereing and causing aggregation of viral duaghter cells, thus making them more easy for killer cells to identify and destroy them. But then as the RFs kill HIV viral particles, the viruses too have started developing new ways to escape detection by the RFs, and they do that by changing the structure of their capsid (HIV core). Hence the Red Queen hypothesis!!!


Currently, human gene therapy for HIV/AIDS is the only treatment that can make a patient symptom free. Dr Greg also cited the news item about an HIV-positive man has been left free of the infection, almost two years after undergoing a bone marrow transplant. He was suffering from leukemia as well, and doctors in Germany replaced his cancer cells with healthy stem cells from a donor who had a natural genetic resistance to HIV (see http://uk.news.yahoo.com/5/20081113/tuk-bone-transplant-offers-aids-hope-45dbed5.html).


Dr. Greg pointed that only a small amount of change was needed to be applied to RF's structure to enable it to outsmart the viral counter-measure and kill it. So his reasearch is how to make the race (according to the Red Queen hypothesis) be in favour of the RF. Some of the other points I took home were:


> RF mediate potent species specific blocks to viral infection (eg. like in Rhesus monkeys).


> Expression of RF are stimulated by Interferons.


> Both RF and their viral counter-measure are under strong selection pressure to change as proposed by the Red

Queen hypothesis.


Well, it was an exciting lecture.

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