Should we treat immune activation in HIV-infected patients? If so, when and how?
As mentioned above, a large set of data suggest that targeting the HIV-associated immune activation may represent a promising therapeutic strategy to be considered, in addition to ART, in the clinical management of HIV infection. However, the fact that the pathophysiologic mechanisms underlying this chronic activation are still poorly understood is a major obstacle to the implementation of a safe and effective immunosuppressive approach, especially when considering that, ultimately, HIV infection results in a state of immunodeficiency and that the wrong kind of immunosuppression might exacerbate this condition. The interventions should be carefully targeted, mechanism based and hypothesis driven, as preliminary studies have demonstrated that broad-spectrum immunosuppressive agents (such as cyclosporine and mycophenolate) are unlikely to provide the specificity that will enable the immune system to downregulate its hyperactivation and recover.[97,98,99,100,101] Novel and better 'targeted' immune interventions should be tested in short-term, proof-of-concept clinical trials conducted in small groups of well characterized patients treated during chronic infection (perhaps those defined, immunologically, as non-responders to ART or showing discordant response). As noted earlier, the line between 'immune modulation' and 'immune reconstitution' is not as clear-cut as was previously thought, and it is possible that the beneficial immunological effect of cytokines such as IL-2 and IL-7 may not only, or not primarily, lie in the improvement of CD4 T-cell homeostasis but also in reducing the prevailing level of T-cell activation and apoptosis. Finally, it is interesting to observe that ongoing clinical trials of CCR5 blockade in patients with dual-tropic viruses may allow us to assess whether blocking CCR5 signaling can reduce immune activation and improve the overall immune function, beyond the intended purpose of blocking virus entry and replication. In any immuno-modulatory intervention to be used in HIV-infected individuals, an important issue is how to best monitor changes in the existing level and pattern of immune activation. Unfortunately, none of the available cellular markers of T-cell activation or proliferation (HLA-DR, CD38, Ki67, loss of CD127, and others) seems to be able to consistently and robustly assess the level of the HIV-associated immune activation across all subsets of HIV-infected patients. It will be important to design studies in which multiple potential markers of immune activation are measured longitudinally in a sufficiently large cohort of HIV-infected individuals and the relative value of each of these markers, or of particular combinations, in predicting disease progression is assessed.
The Authors also wish to thank B. Autran, S. Deeks, D. Douek, M. Feinberg, Z. Grossman, M. Lederman, F. Miedema, and L. Picker for the helpful discussion, and J. Milush, M. Paiardini, and A. Chahroudi for critical reading of this manuscript.Reprint Address
G. Silvestri, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 705 Stellar-Chance Laboratories, 422 Curie Blvd, Philadelphia, PA 19104, USA. Tel: +215 573 5363; fax: +215 573 5369; e-mail: firstname.lastname@example.org
AIDS. 2008;22(4):439-446. © 2008 Lippincott Williams & Wilkins
Lippincott Williams & Wilkins
Cite this: Immune Activation and AIDS Pathogenesis - Medscape - Feb 19, 2008.