New evidence that CD4 cells in the gut may be a reservoir of HIV could impact future treatment strategies, say researchers in an article published in the online version of The Journal of Infectious Diseases. Their cross-sectional study found relatively high levels of HIV among the depleted CD4 cell population of the gut lymph tissue, even in the presence of effective antiretroviral therapy. New drug regimens targetting these cells might one day lead to more effective control of the virus, they propose.
Effective antiretroviral therapy is able to reduce of HIV in the blood to undetectable levels. However, current therapies do not completely eradicate HIV from the body. Simply put, there is no cure for HIV. One possible reason for this is that virus persists in areas of the body that are unaffected by current drugs. These reservoirs could form a long-standing source of HIV-infected cells.
The gut-associated lymphoid tissue (GALT) is a potential reservoir. It is the largest lymphoid tissue in the body and contains the most HIV-susceptible CD4 cells. It is associated with HIV replication early in infection, but there are few investigations into its role in later infection. In the current article, Chun and colleagues from the US National Institutes of Health provide evidence that HIV persists in the GALT, even in the presence of successful antiretroviral therapy.
The study recruited 8 HIV-positive individuals who had been on long-term antiretroviral therapy (average 8.4 years). The group’s mean blood CD4 cell count was 622 cells/mm3 and they had had an undetectable viral load (< 50 copies/ml) for an average of 5.6 consecutive years at the study's start.
The researchers first isolated CD4 cells from blood samples and from biopsies of the terminal portion of the small intestine of study participants. They found that the levels of CD4 cells were significantly lower in the GALT than in the blood (p = 0.005), and much lower than what would be expected in a healthy individual. While the percentage of CD4 cells in GALT is generally lower than than in the blood of healthy individuals (about 40% versus about 65%, respectively), the mean CD4% in GALT of the study participants was 11.3%.
During the natural course of HIV infection, CD4 cell counts slowly drop as the virus replicates. When a person starts antiretroviral therapy, viral replication is suppressed and CD4 cell counts normally rebound, often reaching values within the range found in HIV-negative individuals. Thus, the low CD4 percentage found in GALT of infected individuals, the authors state, suggests that the CD4 cells in the GALT never completely rebounded and that the virus persists in GALT CD4 cells.
The researchers then determined the level of HIV genetic material in CD4 cells from blood and from GALT. Levels of HIV genetic material can give a measure of frequency of infection. Researchers found that viral genetic material was present in all cell types and was highest among CD4 cells of the GALT at 4887 cells infected per million CD4 cells. Blood CD4 cells reported significantly lower infection rates, 1083 cells per million cells (p < 0.001) for resting CD4 cells and 1796 cells per million cells (p = 0.001) for activated CD4 cells.
Combining the findings of reduced presence of CD4 cells with high level of infection, the researchers conclude that “CD4+ T cells in the GALT, even when present in low numbers, may support low but readily detectable HIV replication in infected individuals, despite their having received years of effective antiretroviral therapy that resulted in sustained, undetectable levels of plasma viremia.”
Finally, the researchers tested whether CD4 cells were migrating between the blood and the GALT. They did this by comparing the DNA sequences of HIV taken from infected CD4 cells harvested from the two compartments. In this type of analysis, a lack of cross-infection would lead to all the DNA sequences from HIV in the blood being similar to each other and distinct from HIV DNA from the GALT. Instead, the researchers found that sequences were sometimes shared between blood and tissue compartments, suggesting that virus or infected cells had migrated. This finding, they write, “may explain, in part, the persistence of HIV in peripheral blood CD4+ T cells, possibly as a consequence of new rounds of infection in the tissue compartment.”
In an accompanying editorial commentary, Yuki and Wong support the researchers’ interpretation of the data and add, “The effect of treatment intensification or novel treatment strategies on the reservoir of HIV cells in GALT should be explored.” Intensification of regimens by adding more drugs is known to further decrease blood viral load among individuals with already suppressed virus. They propose that a similar strategy, especially including new agents such as integrase and entry inhibitors, might yield similar results in GALT cells.