amfAR, The Foundation for AIDS Research

Studies Shed Light on Changes in HIV Virulence Over Time

amfAR fellow Dr. Ryan Troyer has collaborated on two recent studies that highlight the changeability of HIV over time. In one study, he and his colleagues detail increases in the ability of HIV to reproduce within an infected individual during the course of infection. Another study presents evidence suggesting that strains of HIV responsible for recent infections might be “weaker” than viral strains that were infecting people in the 1980s.

October 18, 2005One of the greatest research successes in HIV/AIDS has been the development of an impressive arsenal of antiretroviral drugs that can significantly prolong the lives of people infected with HIV. So with more than 20 antiretrovirals on the market, why do scientists continue to look for more?

The reason is that HIV’s astonishing ability to mutate enables the virus to generate versions of itself that do not respond to drug therapy. This constant process of diversification was recently described by Dr. Ryan Troyer, of Case Western Reserve University in Cleveland, in the July 2005 issue of the Journal of Virology.

“We already know that HIV has the capacity to mutate very rapidly, but what surprised us was how consistently and relentlessly the mutation process generates that viral variability throughout the course of infection,” Dr. Troyer said.

Under the guidance of Dr. Eric Arts, Dr. Troyer set out to discover how the virus changes over time during the course of an individual’s HIV infection. What emerged was a chilling portrait of a virus that continues to increase not only in diversity, but also in its ability to reproduce itself and ultimately cause disease.

Dr. Troyer looked at blood samples from patients with HIV and compared the diversity of the virus at different dates during several years of infection. In each case there was an increase in the number of quasispecies, or different variants of the virus, over time. In other words, the HIV inside a patient’s body becomes more diverse because an increasing number of different strains of HIV is present.

This increase in viral diversity is bad news because it can make selecting the most effective drug treatment combination more complicated. Dr. Troyer also uncovered another downside of diversity – as diversity increases, so does the ability of the virus to make copies of itself and thus to spawn additional distinct viruses. It is this spiral of diversity and replication that ultimately leads to disease.

While we do not yet know for certain the order in which the events occur, Dr. Troyer suspects that the virus uses its ability to generate diversity as a means of increasing its ability to reproduce.

“We think the virus is continuously generating new quasispecies as a way of exploring its options, so to speak. Some of those new quasispecies will be fitter, better able to reproduce, and will come to dominate the weaker ones.” When that happens, the fitness of the virus population overall rises to a new level, and the process of generating new variants to improve fitness even further starts again.

While this first study outlined the increasing ability of HIV to reproduce during the course of an individual’s infection, Dr. Troyer also took part in another amfAR-supported research project that aimed to describe changes in the fitness of HIV in large populations over time. This time, rather than looking at changes within individual patients, the researchers studied trends in the strength of HIV across a population of patients in the Netherlands. When they compared blood samples taken from one set of patients in the 1980s with those taken from a different set of patients in the past few years, what they found and published in the October 14 issue of the journal AIDS was a hint that HIV might be weakening.

This phenomenon is not unusual among infectious diseases – viruses and bacteria that kill their hosts routinely make themselves weaker and less deadly in order to ensure their own survival. What is remarkable in this case is that these researchers observed a weakening in only twenty years. Most experts are cautioning that regardless of the extent of weakening in the virus, HIV and AIDS are still causing disease and death around the world at an unprecedented rate.

Although these findings present a grim picture of the challenges we face in treating HIV-positive patients, there is also good news in Dr. Troyer’s research. Initiating antiretroviral therapy short-circuits the spiral of increasing HIV virulence within patients since one of the immediate effects of anti-HIV drugs is to slow the rate at which HIV replicates. As a result, viral diversity is decreased and, for the patient, progress to AIDS is slowed considerably. However, it is still unclear when patients are best advised to start taking highly active antiretroviral therapy.

Currently available antiretroviral drugs clearly prolong lives, but at a high cost. That is why we continue to need new, improved, and affordable drugs that can keep the virus at bay for a lifetime.