By Elliot Eton
Early on my first morning in Gaborone, I arrived at the Botswana-Harvard AIDS Institute Partnership (BHP) Research Lab and met Dr. Simani Gaseitsiwe, the Deputy Research Director. The night before, I had again reviewed several recently published articles he had sent to me, all analyzing immune system-driven HIV adaptation. He helped me synthesize this material, and we began to consider hypotheses to test.
I then heard from all the members of the research lab – University of Botswana students, visiting fellows, and expert scientists – in the weekly Research Updates meeting. After only a few minutes, I felt like a part of the team. I connected with the scientists’ passion for unraveling the complexities of HIV and AIDS – all with the goal of relieving suffering and improving the lives of those afflicted.
Indeed, the reason I was enthralled by the works of Charles Darwin and Herman Melville in high school, as I mentioned in my first post, was that these luminaries sought to understand and find common patterns in what they were seeing and observing in nature while exploring the “watery part of the world.” Darwin and Melville each reflected on the anatomy, physiology, metabolism, ethology, ecology, and phylogeny of species they encountered. As objects of curiosity and awe, Darwin’s finches were really not too different from Melville’s sperm whales.
This past year, viruses have been my finches or whales. HIV has then been like the “Moby Dick” – the virus that seems to continually escape control. HIV’s strongest asset is its ability to copy itself extraordinarily quickly. In the replication process, the virus mutates regularly, thereby allowing it to evade natural immune and synthetic drug attacks.
What strikes me is how complex HIV behavior may be rooted in profound simplicity. At its core, HIV behavior is relatively predictable when considering Darwin’s theories of evolution. Evolution acts on genetic variation—one source of which is mutation—and this variation results in different phenotypes (traits). The members of a species that have favorable phenotypes survive and reproduce more successfully than those that do not, and these members are termed the “fittest.” Advantageous traits can thereby accumulate within a species over time. Importantly, this may not result in organisms perfectly suited to their environments – the traits just need to be “good enough” to permit successful reproduction. Furthermore, the definition of “goodness” can vary, as pressures driving selection can change over time.
While the evolution of mammals occurs over millennia, the evolution of viruses, because they reproduce so quickly, can occur in days. This characteristic complicates the immune system’s already very difficult job: discriminating between “self” and “non-self,” or recognizing a tremendous diversity of “altered” (non-healthy) cells and pathogens from healthy cells and peptides. Disorders in this ability can result in extremes of tolerance (infection, cancer) or virulence (autoimmunity, chronic or acute inflammation).
In the battle between host and pathogen, the immune system relies on a specific set of tools to protect the host, but, in doing so, these tools can also drive viral evolution. The tool I am evaluating in my research is the human leukocyte antigen (HLA) molecule. Located within the cell, HLA molecules grab specific peptides (short amino acid chains) of pathogen-derived proteins, which are harmful to the cell and host. Once an HLA is stabilized by a peptide, it migrates to the surface of a cell where it acts as a beacon for a cytotoxic T lymphocyte (CTL) to come and dock in the first signal of immune recognition. If subsequent signaling between the infected cell and the CTL occur properly, the CTL will then kill the infected cell.
HLA molecules essentially act as defenders: their job is to recognize and bind foreign intruders, which are, in HIV infection, the HIV-derived peptides. HLA molecules, tremendously diverse, are continuously circulated in the cell and will only successfully present a peptide and trigger an immune response if that peptide fits snugly into the HLA molecule’s binding region. If an HLA molecule were a lock, its suitable peptides would be the keys. If one of these keys mutates and changes shape, it could evade recognition. Hence, when considering the theory of natural selection, one would hypothesize that immune system pressure over time could result in the accumulation of viruses with specific mutations that confer the advantage of escape from HLA recognition.
Mutations are not always advantageous – many could be disadvantageous or neutral. Yet, remember how mutations can accumulate in a population if they express traits that are “good enough” to allow successful replication. For example, even though harmful mutations in genes expressing cones in the eye – which normally help us perceive color – can cause colorblindness, these mutations could accumulate because they do not directly affect humans’ ability to reproduce. In HIV, some mutations that confer escape can also harm the structure of the virus.
HIV adaptation to HLA selection pressure is almost like a seesaw: on the one side, mutated viruses have the advantage of escaping immune system recognition; on the other, they have the disadvantage of deleterious structure, which can harm the viral life cycle – especially fitness or replicative ability. Replication unbounded by the immune system could mean faster progression to AIDS; controlled replication, slower progression. To level the seesaw, there may be an accumulation of dangerous “compensatory” mutations that reduce the fitness cost while maintaining the escape ability.
One of the challenges in HIV research is to identify mutations that confer survival advantages under the selective pressure of host immunosurveillance. I am thus exploring the intra-population evolution of a specific region of HIV in the context of HLA phenotype in order to discern new genomic locations that could be under significant immune system pressure.
After my meeting with Dr. Gaseitsiwe, I jumped into the scientific method. I began reviewing more relevant literature and then met with Dorcas Maruapula, an expert in genetic sequencing and analysis, whom I would be shadowing the next several weeks to develop my own skills. She gave me an in-depth tour of the lab and then forwarded me several protocols to study. I knew I was in good hands.
Title image: CC- BY NC 2008 Wolf G.
Elliot Eton is an incoming freshman at Harvard College. This is the first in a series of posts about his gap year conducting research at the Botswana Harvard Partnership.