HIV can leave permanent scars on the lymph nodes and destroy an area called the T cell zone that is vital to the production of new CD4 cells after starting Highly Active Antiretroviral Therapy, according to new research from the University of Minnesota, published online in the Journal of Clinical Investigation.
The researchers say that the process is similar to the disease process in hepatitis, where viral replication and inflammation can eventually lead to scarring of the liver tissue and a permanent reduction in liver capacity.
Researchers at the University of Minnesota demonstrated that the portion of lymph nodes called the T cell zone is significantly damaged by chronic inflammation, which causes fibrosis, or scarring. This is important because the T cell zone is where a significant portion of the human immune response occurs. The findings may explain why some people do not experience substantial CD4 cell increases despite long periods of viral suppression on HAART.
T cell home is destroyed
The group carried out lymph node biopsies on 11 patients. Seven started HAART after the first biopsy and underwent up to three subsequent biopsies during the first six months of treatment. Four patients deferred HAART and underwent three biopsies over the course of a month. The individuals who participated in the study had a median baseline CD4 cell count of 400 cells/mm3 (range 112-905) and mean viral load of 20,014 copies/ml (range 10, 684 – 484,694 copies/ml).
Although all individuals who started HAART had viral load below 500 copies/ml within two weeks of starting treatment, three out of seven experienced CD4 cell increases of less than 62 cells/mm3 over the next six months. The individual with the lowest baseline viral load had the smallest CD4 cell increase during the study (+60 cells).
Analysis of the lymph node tissue found that whilst individuals who started therapy soon after infection had relatively intact T-cell zones, and showed signs of repair after six months on treatment, a patient with more advanced HIV infection showed no increase in the size of the T-cell zone after six months.
The T cell zone plays host to 98% of the body’s CD4 cells, and 99% of HIV production occurs in this zone too.
"HIV infection ultimately depletes the body of CD4 T cells, making it impossible to mount an immune response," said Dr Timothy W. Schacker, associate professor of medicine and author of the study. "For the first time, we show that one mechanism of this depletion is damage to the structure that these cells need to maintain a normal-sized population and to mount an immune response to other infections. In essence, the T cell home is destroyed."
The researchers also noted that the size of the CD4 T cell population measured in peripheral blood (the CD4 count used to monitor disease progression) does not accurately reflect the size of the population in lymph tissues. "You could have a reasonable peripheral count and a very poor count in lymph tissues," said Schacker.
Second, the amount of fibrosis and scar tissue in the T cell zone was significantly related to the size of the CD4 population in that space (i.e. the more scar tissue, the fewer cells) and the recovery of the CD4 population with therapy.
"We knew that T cells are destroyed by direct viral replication," said Schacker, "but we now know that the population is unable to recover to a normal size because the environmental niche used to support the cells is destroyed. New CD4 T cells are unable to get into the space they need to be in to function, and there is no space for the cells to divide."
One implication of this discovery is that through testing of the lymph nodes (similar to what is done to stage cancer), physicians might accurately stage the disease and predict the response to standard therapies.
"This is essentially a new concept in how HIV infection causes damage to the human immune system," said Schacker. "Our observation may explain why up to 25 percent of people placed on HIV therapy may have good viral suppression but still have no significant increase in T cell count.
"Currently, most treatment strategies for HIV/AIDS focus on stopping the virus from replicating itself in the body, which is essential to begin the process of immune reconstitution, but it does not happen for everyone. These findings suggest that therapies targeting the damage from inflammation and accumulation of scar tissue might enhance current antiviral therapy."
Schacker TW et al. Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis. Journal of Clinical Investigation, Online publication, Sept 30 2002.