This week’s BEACON Researchers at Work post is by MSU postdoc Aditi Gupta.
It all started in 1981. A few patients suffering from unusual opportunistic infections, that immune system normally easily takes care of, walked into doctors’ offices and nobody could understand why their immune systems were not working. Something was wiping out their T-lymphocytes, the cells that regulate the immune response to infection. With the number of cases rapidly increasing, no treatment or cure in sight, and biggest of all, no knowledge about what is causing this deadly disease and how it is spreading, HIV became synonymous with fear and death. Scientists at The Pasteur Institute in Paris finally isolated the Human Immunodeficiency Virus (HIV) in 1983, and a blood test was soon developed. Almost three decades later, more than 34 million people worldwide are currently living with HIV and more than 2 million new infections were reported in 2012. This rapid spread of HIV is in part due to its long incubation period, where an HIV-positive person does not show any symptoms for years, and thus may pass on the virus to someone else without even knowing it. However, HIV infection is not a death sentence anymore. There are treatments available that can keep the viral load (the amount of virus in blood) in a person at such a low level that the immune system can fight off opportunistic infections as it normally does.
HIV first caught my attention when I saw entire families dying from AIDS in my hometown in India circa early 2000. Even today, more than a million people die from AIDS every year, mostly in resource-poor countries where patients cannot afford treatment. For those who can afford treatment, strict adherence to treatment for the rest of their lives is essential. Timely and regular HIV-testing is encouraged in at-risk individuals, as early detection positively impacts treatment outcome. Thus, years of research have found ways to make HIV infection quite manageable, but we still don’t have a permanent cure or vaccines for HIV. To better understand why, let’s review what we know about HIV.
HIV is a retrovirus, meaning that once it gets inside a cell that it can infect, it takes over the host-cell system to make more copies of itself. The following video gives a nice overview of the HIV life-cycle:
The current drugs target the reverse transcriptase and the protease proteins of the HIV. Reverse transcriptase makes a DNA copy of the viral RNA genome that then gets integrated into the host-cell genome for making multiple new copies of the HIV. Protease plays an important role in maturation of new viruses, rendering them infectious. HIV-infected individuals take medicines every day that target both reverse transcriptase and protease proteins of the virus, to minimize the production of new viruses and thus protect the immune system. However, the reverse transcriptase of HIV frequently makes errors (mutations) when it makes the DNA copy of the HIV genome, which allows the virus to rapidly evolve. Thus, any lapses in taking the drugs give the virus enough room to make drug-resistant copies of itself, which leads to treatment failure. Tests to find the drug-resistance causing mutations are available and routinely used in clinical practice to design new drug-regimens for patients. However, there are limited alternatives to these drugs, requiring a better understanding of how drug resistance develops in HIV, and how it can be prevented.
My research focuses on just that: How does the HIV population in a patient becomes drug-resistant? While error-prone reverse transcription of HIV genome is one contributing factor, it is the large population size of the virus that allows HIV to try multiple mutations simultaneously, and select the ones that can escape the effect of the drugs. That’s why keeping the viral load low is so important in treatment. Computational simulations show that large populations of rapidly evolving “computer organisms” are very robust as they can adapt faster to adverse changes in their environment. When I joined Dr. Chris Adami’s lab at Michigan State University as a postdoc, we decided to study the evolutionary dynamics of HIV populations in vitro. This started a collaboration with Dr. Yong-hui Zheng’s lab, also at Michigan State University, to do experiments where T-lymphocytes are infected with HIV in lab, and after a few days the HIV RNA is extracted from the T-cells for sequencing. We also collaborate with Dr. C. Titus Brown’s lab at MSU for analysis of next-generation sequencing data.
Once the HIV RNAs in the infected T-cells are extracted and sequenced, we can identify the mutations that appear in the HIV populations. By repeating this experiment at several time-points, we can basically observe HIV evolution in action. Drugs can be added to the infected T-cells as well, to see what mutations arise specifically in response to treatment.
This research will further uncover the mysteries that surround HIV, and hopefully will take us one step closer towards finding a cure. In my opinion, rapid evolution is the biggest weapon in HIV’s arsenal, and therein might lay its biggest weakness. Decades of research has unearthed valuable knowledge, not only about HIV, but also about how our immune system works, and the pieces of the puzzle are slowly but surely being assembled together.
For more information about Aditi’s work, contact her at agupta at msu dot edu.