Now comes a report from researchers associated with the Swiss HIV Cohort Study identifying a link between the gene for a protein responsible for pumping toxic interlopers out of cells and the magnitude of CD4 cell count rise within six months of starting ART. The gene is called MDR1 (for "multi-drug resistance") and it codes for a transporter protein called P-glycoprotein (P-gp). In the Swiss study, people with very low amounts of P-gp had a significantly better immunological response to ART containing nelfinavir or efavirenz than those who had moderate or high levels of the protein. Specifically, the best CD4 response was linked to having a double lack (TT) of the MDR1 gene for functional P-gp in one's inherited DNA; poor response was linked to having a double dose (CC) of the gene, and moderate response was associated with having a single dose (CT).
Significant amounts of P-gp have also been detected in stem cells that eventually give rise to blood cells, including lymphocytes such as CD4 and macrophages. P-gp is also found on mature T-cells that have exited the thymus, and are especially common on the so-called naive subset of CD4 cells that are often quickly depleted by HIV infection and difficult to replenish. In this study, naive CD4 cells also recovered at a faster pace in people with stunted P-gp expression. The authors speculate that "the immunological benefit noted in individuals with the MDR1 TT genotype and low expression of P-glycoprotein could suggest enhanced penetration of antiretroviral drugs in cell populations susceptible to HIV-1 infection, in infected lymphocytes and in pharmacological sanctuaries." In other words, P-gp may be responsible for trying to keep drugs out of the very cells and reservoirs that need them the most. If so, people with the least amount of P-gp may have a genetic advantage for fighting HIV because their cells put up fewer barriers to letting drugs in to do their job.
In the case of P-gp, there is evidence that if there is a "C" nucleotide code at position number 3,435 in the MDR1 gene sequence, then normal copies of functional P-gp can be produced at a normal pace. But if the normal "C" at that position accidentally turns into a "T" nucleotide, then the production of P-gp is greatly slowed. Some people have one normal "C" MDR1 allele in one chromosome and a mutant "T" allele in the other chromosome. These mixed alleles are represented as CT and together they produce a moderate amount of P-gp. If the person has two normal copies (CC) of MDR1, then they produce a large amount of P-gp. Not surprisingly, if they have a TT genotype, they produce very little P-gp. In the Swiss study, the people with the TT genes had the best response to HIV treatment, possibly because they have very little P-gp at work keeping nelfinavir out of their cells.
The MDR1 gene is not the first allele identified that has significance for HIV disease. There are several genetic factors that may affect the likelihood of becoming infected with HIV or of how virulent the course of one's disease can be. Another cell surface protein, CCR5, is used as a coreceptor along with CD4 when HIV attempts to bind to and enter a new cell. A few individuals carry alleles for a double lack of CCR5 and it has been proposed that these lucky people may be highly impervious to HIV infection.
In their study design, the Swiss researchers were careful to examine whether other genes coding for other proteins involved in drug metabolism could be producing the observed responses to treatment. Yet with the available data, only MDR1 seemed to show the CD4 linkage. In a seeming paradox, individuals with the TT allele had lower blood concentrations of the drugs than those with the genes for greater P-gp production. Furthermore, while MDR1 expression was significantly associated with T-cell response after six months treatment, the magnitude of viral suppression achieved during the same time was roughly equivalent no matter which pairing of genes an individual had. The authors note, however, that the study lacked the resolution to track viral decay rates during the first weeks and months of therapy. Indeed, it remains to be seen if the differences in immune response will continue to be seen over longer periods of time. Another nagging question is why immune benefit was also observed for patients who received efavirenz, a drug not thought to be directly expelled by P-gp.
Although the impact of P-gp on intracellular drug concentrations provides an attractive explanation for this study's results, there may be other explanations for the immunological effect seen. The authors speculate that P-gp could actually be exerting its influence by regulating the accumulation of certain chemokine proteins involved in the process of CD4 cell destruction downstream from direct HIV activity. It's also been noted that P-glycoprotein tends to localize in lipid rafts on a cell's surface in close proximity to other proteins. These rafts also harbor the CD4 and CCR5 proteins that HIV uses to attach and enter new target cells. Again, more research is needed to understand if there are interactions among these cell surface proteins that could possibly inhibit or facilitate HIV infection.
Back to the GMHC Treatment Issues January 2002 contents page.