TAG HIV Basic Science, Vaccines, and Cure Project Blog

Can Protease Inhibitors Boost Thymic Output?

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)

Increased thymic output in HIV-negative patients after antiretroviral therapy.
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

Abstract:
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.

Merck HIV Vaccine Trial Expands

Merck has announced that the Phase IIb efficacy trial of their HIV vaccine candidate will be doubled in size, recruiting 3,000 volunteers at high risk for HIV infection instead of the originally slated 1,500. A rather uninformative article appears in today's Wall Street Journal: http://www.aegis.com/news/wsj/2005/WJ050907.html Background about the trial can be found on the TAG website at: http://www.aidsinfonyc.org/tag/tagline/0407.html#2 and in TAG's recent pipeline report: http://www.aidsinfonyc.org/tag/tx/pipelineReportJuly05.pdf

The expansion of the trial is due to an alteration in the entry criteria. The Merck vaccine uses a virus called adenovirus serotype 5 (Ad5 for short) as a "vector" for carrying dummy HIV components into the body and thereby triggering immune responses against HIV. Unfortunately Ad5 is common in the environment (it causes severe colds) and many people have been exposed to it during their lives. As a result, many people have antibodies against Ad5, and high levels of anti-Ad5 antibodies have been shown to reduce the ability of Merck's vaccine to trigger HIV-specific immune responses. For the efficacy trial, Merck originally decided to include only individuals with very low levels of anti-Ad5 antibodies (a titer of less than 200). The company wanted to study their vaccine under ideal conditions to see if the type of immune responses it triggers (CD4 "helper" T cells and CD8 "killer" T cells) could offer any protection against HIV infection and/or disease progression.

According to the Wall Street Journal article, in a recent study it was found that "volunteers got a strong immune response even if they previously had developed antibodies to the adenovirus because of prior cold infections." Exactly what study is being talked about is unclear. But the upshot is that individuals with titers of anti-Ad5 antibodies higher than 200 are now being allowed to enroll in the phase IIb efficacy trial. TAG is querying Merck about the details and will post more information as we get it.

UPDATE 9/28: Janet Skidmore, Merck's vaccine PR person, tells us that the trial is now stratified: 1,500 enrollees will have anti-Ad5 antibody titers <200 while another 1,500 will be allowed to have a titer >200  with no upper ceiling. Apparently new studies using the latest "trivalent" version of the vaccine (that encodes the Gag, Pol and Nef proteins of HIV) found that the presence of anti-Ad5 antibodies affected the immunogenicity less than was seen in earlier studies which used a monovalent construct that encoded only the HIV Gag protein. We also have to digress and congratulate Janet on her recent marriage to Emilio Emini, former Director of Vaccine Research at Merck and one of the giants of the HIV research field.

Aplaviroc on the Rocks?

GlaxoSmithKline released a statement yesterday announcing that studies of their CCR5 inhibitor, aplaviroc, have been halted for treatment naive individuals. The statement says that "GSK has received reports of severe hepatotoxicity with elevated liver enzymes (AST, ALT) and total bilirubin in clinical trials involving treatment-naïve patients." Studies are continuing in people with treatment experience. It remains uncertain whether this problem is specific to GSK's drug or affects CCR5 inhibitors as a class. Results from studies of two other compounds currently in trials, Pfizer's maraviroc and Schering Plough's equally unpronouncable vicriviroc, should help clarify this question. Keith Alcorn has written about the GSK statement for AIDSmap:

http://www.aidsmap.com/en/news/E5B361A5-CD4C-47B0-995F-869D174F1007.asp