Maybe More Than a Gut Feeling

Why do studies now show that starting combination therapy earlier than previously recommended (that is, at above 500 CD4 cells) can reduce mortality by 60%? Why do some folks with undetectable viral loads still lose T cells?

Perhaps the answer will be found in the lining of the gut, which is home to more than 50% of our T cells.

Researchers have learned that within the first three weeks of HIV infection the majority of our CD4 cells are depleted, especially those in the gut. There is also a decrease in the cell barrier function of the intestinal lining. This allows for leakage into the body of both outside infectious agents and the normal bacterial flora.

This bacterial migration, called translocation, sets off a persistent immune-activation reaction in the body that stimulates an overproduction of pro-inflammatory cytokines and chemokines. High levels of these subtle but vital regulators of organ function and hormonal balance can have serious negative effects on one's overall health. For example, studies show that the greater the level of immune activation, the faster HIV progresses.

This may correlate with the fact that higher levels of lipopolysaccharide, which is found in bacterial cell walls and is a measure of bacterial translocation, is also associated with faster HIV progression.

Meanwhile, this great devastation of T cells creates a heavy demand for T-cell replacement. This shortens the T-cell half-life, increases T-cell turnover, drains memory T-cell pools, and causes fibrosis of lymph nodes. We have also learned that not all of this stops once a patient is put on highly active antiretroviral therapy. In particular, the return of T cells in the gut is poor and never reaches pre-HIV levels. Nor is there complete repair of the mucosal barrier, which permits persistent bacterial translocation and more immune activation. Still, the sooner HAART is started, the better the return of T cells and gut function.

In other words, HIV quickly catapults the immune system into chronic overdrive and the whole body suffers. This scenario may help explain the benefit of really early HAART-the sooner you can take your body out of high gear the less wear and tear there is.

Chronic immune activation may also account for the mysterious continual loss of T cells in some individuals who have undetectable viral loads. In these folks the level of immune activation remains very high, and the higher the level of immune activation markers, the greater the T-cell decline.

From a practical standpoint learning more about the role of the gut in HIV can suggest new avenues for HIV research, such as vaccines that protect at the mucosal level, gut microbicides, immune deactivators, and different regimens for pre- and postexposure prophylaxis.

Let's hope this is more than a gut feeling.