The Changeable Fitness of HIV: Implications for Early Treatment
By Jeffrey Laurence, M.D., and Rowena Johnston, Ph.D.
L to R: Researchers Darren Jardine, Kim Wilson,
Dale McPhee, Alicia Arnott, and Elizabeth Dax.
October 18, 2010—In general, only a single HIV virus is responsible for infecting an individual during penile-vaginal transmission. But that virus doesn’t stay single for long. It reproduces with enormous efficiency and mutates to form swarms of virus isolates known as quasispecies. Even before these changes take place, however, the single virus exhibits a high level of “fitness,” or ability to cause disease, according to recently published research from amfAR grantee Dale McPhee, Ph.D., who studied the fitness of HIV at various points after infection. This surprising finding may affect recommendations on when to initiate antiretroviral therapy (ART).
Dr. McPhee and colleagues from five research institutions in Australia report in the September issue of the online journal PLoS One on the rate of DNA formation by HIV viruses obtained from individuals shortly after initial infection and at several later points. This is an accepted way to measure in the test tube how fit the virus is in terms of its growth and ability to induce disease. The more fit a virus is, the better able it is to make copies of itself within the body of an infected person.
Viruses obtained shortly after initial infection from individuals who were not taking ART were found to have a high fitness—an unexpected finding. Most scientists had assumed that because there appears to be a bottleneck at initial infection—a barrier through which only one or two viruses pass to establish infection—the lack of virus diversity and quantity must mean poor adaptability. Not so. The test-tube fitness of the viruses that cause initial infection—and their subsequent ability to cause disease—may be much greater than previously assumed.
Seven of nine individuals not taking ART showed an increase in virus fitness over time. Dr. McPhee and his colleagues thought that this was related to the fact that the immune system limits but does not prevent diversification of the virus as it grows. Because the immune system does not completely prevent HIV from replicating, in the absence of treatment the virus constantly evolves into a fitter version of itself with each generation.
If patients were taking ART, however, McPhee and associates found, just as they anticipated, that the fitness of the virus decreased over time. Because ART destroys HIV as it reproduces, it eliminates the fittest virus, which is the most capable of reproducing. The only way HIV can evade the drugs is by accumulating mutations that make it less vulnerable to ART, but these viruses are also less fit.
The researchers explained their observations using two classic genetic principles. The first, known as the “Red Queen hypothesis,” comes from Lewis Carroll’s Through the Looking-Glass, in which the Red Queen tells Alice that it takes “all the running you can do to stay in the same place.” In other words, to maintain its initially high level of fitness, HIV must constantly change, or mutate. This is consistent with the high or increasing fitness of HIV isolates shortly after infection in the absence of ART.
The decrease in HIV’s fitness in patients taking ART is explained by “Muller’s ratchet.” For HIV, this theory states that deleterious mutations go in only one direction, just as ratchets do, and they build on the mutations of prior generations. As the fittest viruses are destroyed by ART or by the immune system, the overall fitness of the remaining HIV also decreases.
McPhee’s research—colorfully explained through Lewis Carroll and Muller’s tool—suggests that treating HIV very early after infection is a strategy worth pursuing.
Dr. Laurence is amfAR’s senior scientific consultant and Dr. Johnston is vice president and director of research.