Yesterday, a group of Australian researchers published a study in the journal Cell that has now received extensive media coverage, much of it extremely misleading. The researchers themselves bear the blame, as their institution’s press release about the paper makes dubious claims that were inevitably destined to sow confusion. Most notably, the study involves mice infected with a strain of lymphocytic choriomeningitis virus (LCMV) that causes chronic infection. This is a widely used model of persistent viral infection, but it does not represent “a mouse model of HIV infection” as the press release states. There are potentially very important differences in the mechanisms by which this strain (called clone 13) of LCMV establishes chronic infection compared to HIV; LCMV clone 13 causes widespread infection of macrophages and fibroreticular cells, while CD4 T cells – particularly HIV-specific CD4 T cells – are the primary target of HIV. More broadly, LCMV and HIV are completely different types of virus (an arenavirus and a retrovirus, respectively). These differences mean that the applicability of the mouse LCMV results to human HIV infection is extremely uncertain, and studies in the more relevant animal model of macaque SIV infection are needed before any claims about curative potential can be made. LCMV is certainly not HIV or “mouse HIV” as a number of media articles have erroneously stated.
The researchers should also have noted that IL-7 has already been studied in people with HIV, and results of the two phase I trials are published (both are available in full text online, see here and here). The approach showed promise for enhancing immune restoration, but there was no evidence that it cured infection. One ongoing phase II clinical trial is now evaluating the role of long-term IL-7 treatment in promoting CD4 T cell recovery in people with a suboptimal immunological response to antiretroviral therapy (ART), while a second study is exploring its use in a more cure-related context; the trial will explore whether IL-7 can enhance the depletion of HIV reservoirs when combined with intensified ART.
In sum, the new study in Cell may offer important insights into the mechanisms by which immunity to chronic viral infections can be enhanced, but the results should not have been misrepresented and oversold by the researchers and the Walter and Eliza Hall Institute of Medical Research.
Cell, 03 February 2011
doi: 10.1016/j.cell.2011.01.011
IL-7 Engages Multiple Mechanisms to Overcome Chronic Viral Infection and Limit Organ Pathology
Marc Pellegrini, Thomas Calzascia, Jesse G. Toe, Simon P. Preston, Amy E. Lin, Alisha R. Elford, Arda Shahinian, Philipp A. Lang, Karl S. Lang, Michel Morre, Brigitte Assouline, Katharina Lahl, Tim Sparwasser, Thomas F. Tedder, Ji-hye Paik, Ronald A. DePinho, Sameh Basta, Pamela S. Ohashi, Tak W. Mak
Summary
Understanding the factors that impede immune responses to persistent viruses is essential in designing therapies for HIV infection. Mice infected with LCMV clone-13 have persistent high-level viremia and a dysfunctional immune response. Interleukin-7, a cytokine that is critical for immune development and homeostasis, was used here to promote immunity toward clone-13, enabling elucidation of the inhibitory pathways underlying impaired antiviral immune response. Mechanistically, IL-7 downregulated a critical repressor of cytokine signaling, Socs3, resulting in amplified cytokine production, increased T cell effector function and numbers, and viral clearance. IL-7 enhanced thymic output to expand the naive T cell pool, including T cells that were not LCMV specific. Additionally, IL-7 promoted production of cytoprotective IL-22 that abrogated liver pathology. The IL-7-mediated effects were dependent on endogenous IL-6. These attributes of IL-7 have profound implications for its use as a therapeutic in the treatment of chronic viral diseases.
Comments