One of the less well-publicized consequences of the persistent immune activation caused by HIV infection is a type of scarring damage to lymph tissues described as fibrosis. Some early studies of lymph nodes from HIV-infected individuals reported evidence of this problem, but it wasn't until the publication of a study by the research group of Ashley Haase in 2002 that a connection was made between the extent of fibrosis (as measured by deposition of collagen) and maintenance of CD4 T-cell numbers. Haase and colleagues showed that there was an inverse correlation between lymph node fibrosis and the number of CD4 T cells measurable in the same node. Importantly, they also found that the degree of fibrosis was significantly associated with the magnitude of CD4 T-cell increases after initiation of antiretroviral therapy, with greater fibrosis linked to poorer CD4 T-cell recovery.
In the subsequent years, Haase's group has delved further into the mechanisms underlying these findings. In 2011, they reported that fibrosis disrupts the fibroblastic reticular cell (FRC) network, which forms pathways along which T cells travel on their journey through lymph tissue. The FRC network provides fuel for maintaining T-cell health in the form of the cytokine IL-7, and fibrotic damage to FRCs was found to inhibit the ability of T cells to access IL-7, leading to cell death. The study also identified the cytokine lymphotoxin-β as critical for maintaining FRCs, and suggested that loss of CD4 T cells was linked to a decline in lymphotoxin-β production, further exacerbating the problem created by the fibrosis.
In an important paper published last summer that I neglected to write about at the time, the researchers confirm that CD4 T cells are the major source of lymphotoxin-β, thus demonstrating that fibrosis creates a vicious cycle by depleting factors needed for CD4 T-cell survival, leading to CD4 T-cell loss, which in turn removes a critical source of factors needed to maintain the FRC network that provides sustenance to CD4 T cells. The study offers evidence that this problem is relevant to not just HIV infection but also CD4 depletion after chemotherapy and irradiation in individuals with cancer.
In an accompanying editorial, Steve Deeks from UCSF notes that the research suggests possible interventions that could be evaluated in the context of HIV-induced persistent immune activation and CD4 T-cell depletion: "These experimental interventions include drugs that remove pro-inflammatory pathogens and microbial products (eg, valganciclovir for CMV, rifaximin for gut microbes, sevelamer for lipopolysaccharide), drugs that directly prevent fibrosis (eg, angiotensin II receptor antagonists* and ACE inhibitors), and drugs that have more broad effects in reducing inflammation (eg, statins, nonsteroidal antinflammatory drugs, methotrexate, and mesalamine)." Deeks also points out that the best way of avoiding fibrotic damage to the lymph nodes is to suppress HIV replication as soon as possible after infection.
A more recent study, published in the Journal of Infectious Diseases this past October, offers further support for the conclusions of Haase et al. Researchers led by Brian Tabb from the laboratory of Jacob Estes at NCI–Frederick report that blocking the inflammatory cytokine TNF alpha in early SIV infection reduced lymphoid-tissue fibrosis and was associated with better preservation of CD4 T-cell numbers in macaques (without affecting SIV viral load). The authors conclude: "This initial study highlights the importance of early inflammatory responses to lentiviral infections and underscores the need for additional studies to ascertain the potential clinical benefits of adjunctive therapies to attenuate these responses and to improve patient outcomes." [Read an editorial related to this topic.]
* TAG's new HIV project director, Tim Horn, has recently led an effort to support AIDS Clinical Trial Group investigators seeking to obtain the angiotensin II receptor antagonist telmisartan (trade name: Micardis) from the manufacturer, Boehringer Ingelheim, for a study in people with HIV. Unfortunately, the company remains unwilling to provide drug for the planned trial, citing regulatory concerns. This situation highlights issues that will likely arise again in the future as investigators attempt to conduct exploratory studies of these types of potential adjunctive treatments in HIV infection: many of the candidate interventions are already indicated for other uses and are off-patent or toward the end of their patent life; additionally, the research is at such an early stage that it is probing questions of disease pathogenesis rather than carving a clear path toward an FDA-approved HIV indication. Activists are continuing to discuss possible approaches to addressing these issues in order to ensure that needed research can proceed.
Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.