A new study published in the Sept. 23 issue of the journal AIDS reports that treatment of HIV-negative people with a protease inhibitor (in this case nelfinavir aka Viracept) may boost the production of new T cells by the thymus (the body's T cell training camp, a small organ located just behind the breastbone). While treatment of HIV-infected individuals with protease inhibitor-containing regimens is typically associated with increases in T cell production, it has been assumed that this is the result of suppression of HIV replication by the drugs, not a direct effect on the thymus. The new report by David McKean and colleagues argues otherwise. However, the results should be interpereted with caution until confirmed.
The study took blood samples from eight HIV-negative people receiving 28 days of treatment with a nelfinavir-containing antiretroviral combination because of a potential exposure to HIV (this is known as post-exposure prophylaxis or PEP). Samples were taken before, during and after treatment. Thymic output was assessed by measuring the proportion of T cells in the blood containing a marker thought to indicate recent exit from the thymus (a circle of DNA in the T cell called a T cell receptor excision circle or TREC for short). One participant mysteriously disappears from the paper between the methods and results section, but of the remaining seven the authors report that five experienced significant increases in the proportion of TREC-containing T cells in the blood after treatment. In contrast, two HIV-negative unexposed control subjects experienced essentially no change in TREC levels over the same time period.
So far, so good. But if you look at the graph depicting the TREC levels in all participants, it's notable that the PEP recipients have uniformly lower TREC levels than controls prior to initiating treatment. One alternative interpretation of the data is that some of the PEP recipients may have been exposed to HIV and lost TREC-containing T cells from the blood due to redistribution of the cells to the lymph nodes to participate in the initiation of an immune response to the virus; initiation of treatment would then shut down HIV replication and abort the nascent immune response, allowing TREC-containing cells to return to the blood. The study authors do not clearly say whether they looked for the presence of HIV or immune responses to it in the PEP recipients, they simply say: "None of the patients examined in this study developed any signs of infectious disease after exposure to HIV."
Regardless of how the data are interpreted, the only way of rigorously evaluating whether protease inhibitors increase thymic output directly is to conduct a randomized controlled study in HIV-negative people that are at a low risk for exposure to HIV infection. Unfortunately some news stories have already treated these findings as definitive (see "HIV Drug Boosts Immune System Sharply" http://www.medpagetoday.com/InfectiousDisease/PublicHealth/tb/1798)
AIDS. 19(14):1467-1472, September 23, 2005.
Graham, Daniel B a; Bell, Michael P a; Huntoon, Catherine J a; Weaver, Joel GR b; Hawley, Nanci b; Badley, Andrew D b; McKean, David J a
Objective: To determine the effects of antiretroviral therapy on thymic output independent of HIV infection.
Methods: Thymic output was evaluated by quantifying signal joint T-cell receptor (TCR) recombination excision circles in peripheral blood lymphocytes from HIV-negative patients undergoing prophylactic antiretroviral therapy. Additionally, effects of the HIV protease inhibitor nelfinavir were assessed in vivo on TCR-induced death of murine double-positive thymocytes.
Results: Five out of seven HIV-negative patients undergoing prophylactic antiretroviral therapy exhibited a dramatic increase (1-3 log10) in recent thymic emigrants containing signal joint TCR recombination excision circles while their peripheral T cell compartments remained relatively unaffected. None of the patients developed subsequent HIV infections. Interestingly, nelfinavir did not have significant effects on TCR-induced apoptosis of murine thymocytes in vivo.
Conclusion: Antiretroviral therapy augments thymic output independent of HIV. Furthermore, nelfinavir does not dramatically affect TCR-induced thymocyte death in mice, thus central tolerance remains intact.