We respond to infections in two key ways. One is 'resistance', where the body attacks the invading pathogen and reduces its numbers. Another, which is much less well understood, is "tolerance," where the body tries to minimize the damage caused by the pathogen. A study using data from a large Swiss group of HIV-infected individuals gives us a glimpse into why some people deal with HIV better than others.
The authors note that tolerance varies considerably between individuals, which is determined at least in part, by what is inherited genes, and genes that influence the tolerance of HIV are different from those that influence resistance. The team, led by Roland Regoes at ETH Zurich, publishes his work on 16 September in the open access journal PLoS Biology.
HIV offers a unique opportunity to break the way the human body deals with the disease. After the initial event of the infection, the virus starts to reside in a population of white blood cells called CD4 + T lymphocytes. The number of viruses, a few months after the infection, called a "set-point viral load", can be used to measure resistance - how well a person is battling the virus. However, HIV infection also offers an immediate measure of tolerance - the slower you lose your CD4 + T cells, the better you are tolerating the infection. This situation of coexistence between the human being and the virus can last for many years, but when the number of CD4 + T cells drops below a critical level (less than 200 cells per microliter of blood), the immune system becomes compromised and the carrier of HIV becomes an AIDS patient with potentially fatal consequences if not treated properly.
Key to the study is the existence of the Swiss HIV cohort study, initiated in 1988, - which provided this opportunity to the authors, with more than 3000 HIV-infected persons who could measure both the viral load setpoint and the rate of CD4 + T and the loss of CD4 cells. These two values could be used to simultaneously assess resistance and tolerance, and by combining them with a wealth of demographic and genetic data on the same individuals, allowed the authors to begin exploring the functioning of tolerance.
The first question they asked was age and about sex. On average, they found, men and women tolerated HIV equally equally, but older people had a lower tolerance, with the disease progressing almost twice as fast in one with 60 years of age, relative to one of 20's age.
The authors then looked at hereditary factors that influence HIV tolerance. They observed the genetic differences that are known to be associated with HIV resistance and asked whether they were also associated with tolerance. The answer was an overwhelming "no", confirming the expectation that resistance and tolerance are biologically distinct phenomena.
However, a gene that is involved in resistance also appears to be involved in tolerance. HLA-B gene, which encodes a protein involved in recognition of pathogens by the immune system varies considerably between individuals. Although some of these variants are known to affect a person's resistance to HIV, the authors found other variants of the same gene correlated with tolerance.
So this game key in the immune system appears to influence both tolerance and resistance, but in different ways.
Surprisingly, there seemed to be nothing between tolerance and resistance - this was expected from other studies, but it seemed that this cohort of patients with HIV, tolerance and resistance could be independent or walk side by side.
"These results add to our understanding of how" hosts "tolerated infections and could open new avenues for treatment of infections." The most exciting thing about tolerance is that - unlike resistance - it is expected in a way to be "evolution-proof." One of the problems with getting resistance to a virus, either naturally or through the use of drugs, is that it is in the interest of the virus to develop evasive tactics that circumvent the resistance mechanism. However, the tolerance of the virus lies so that viral evolution of the human host should not be a problem.
The work described here represents a first step in exploring the mechanism of tolerance in humans, and once we understand how tolerance works, we might then be in a favorable position to manipulate it and help people living with HIV more comfortably and for longer.
Review: Cláudio Santos de Souza
The above story is based on materials provided by PLoS.
- Roland R. Regoes, Paul J. McLaren, Manuel Battegay, Enos Bernasconi, Alexandra Calmy, Huldrych F. Gunthard, Matthias Hoffmann, Andri Rauch, Amalio Telenti, Jacques Fellay. Dissociate human tolerance and resistance against HIV. PLoS Biology, 2014; 12 (9): e1001951 DOI: 10.1371 / journal.pbio.1001951