The loss of naïveté that comes with getting older is familiar to just about everyone. Somewhat less familiar is the fact that this is also true immunologically; our repertoire of naïve T cells and B cells – vital to responding to pathogens that have not previously been encountered, and keeping up with evolving chronic infections – steadily diminishes. For T cells, the loss is associated with declining output from the thymus, which also shrinks in size over time. It has been appreciated for many years that chronic infections can accelerate the pace of naïve T cell decline, but the effects of HIV far exceed those of any other chronic virus; progression to AIDS is typically associated with an almost complete loss of naïve CD4 and CD8 T cells.
Recent studies of long-term immune reconstitution on antiretroviral therapy (ART) have identified the ratio of naïve T cells to memory T cells as an important factor predicting the extent of CD4 T cell repopulation after 7+ years of treatment. A study from Timothy Schacker at the University of Minnesota now addresses the question of whether baseline measures of naïve CD4 T cell numbers can predict the potential for immune reconstitution on ART. The results of an analysis of 348 participants in AIDS Clinical Trials Group (ACTG) trials show that, indeed, baseline naive but not total CD4 T cell counts strongly predicted the magnitude of CD4 T cell increases after ART initiation. Lower naïve CD4 T cell levels at baseline were also associated with greater time spent with low CD4 T cell counts on ART, which is known to be associated with a greater risk of clinical events. The study findings suggest that measurements of naïve CD4 T cells could help optimize timing of ART initiation and lessen the incidence of poor immune reconstitution despite HIV suppression.
J Acquir Immune Defic Syndr. 2010 Feb 24. [Epub ahead of print]
Measurement of Naive CD4 Cells Reliably Predicts Potential for Immune Reconstitution in HIV.
Schacker TW, Bosch RJ, Bennett K, Pollard R, Robbins GK, Collier AC, Gulick RM, Spritzler J, Mildvan D; for the AIDS Clinical Trials Group (ACTG).
From the *Department of Medicine, University of Minnesota, Minneapolis, MN; daggerDepartment of Biostatistics, Harvard School of Public Health, Boston, MA; double daggerDivision of Infectious Diseases, University of California, Sacramento, CA; section signDivision of Infectious Diseases, Massachusetts General Hospital, Boston, MA; parallelDepartment of Medicine, University of Washington, Seattle, WA; paragraph signDivision of Infectious Diseases, Weill-Cornell Medical College, New York, NY; and #Division of Infectious Diseases, Beth Israel Medical Center, New York, NY.
BACKGROUND:: Pathogenesis studies show that naive CD4 cells are preferentially depleted in lymphoid tissues during HIV infection, and studies of advanced patients suggest levels of naive CD4 cells in blood correlate to total CD4 cells after starting antiretroviral therapy (ARV). We hypothesized that measuring naive CD4 cells in blood in people at earlier stages of disease would identify those at highest risk for poor CD4 reconstitution who may benefit from earlier initiation of ARV. METHODS AND FINDINGS:: We identified 348 patients from multiple AIDS Clinical Trials Group studies who were ARV naive, had a CD4 count between 200 and 500 cells per microliter, a measure of pretreatment-naive CD4 percent, and serial follow-up measures of CD4 count and plasma HIV RNA after starting ARV. We used logistic regression to model the ability of naive CD4 percent to predict 100 and 200 CD4 cell increases after 24 months of therapy. After controlling for baseline viral load and demographic variables, baseline naive but not total CD4 cell count strongly predicted CD4 cell increases. Lower baseline naive CD4 percent was associated with greater time spent at lower CD4 T-cell counts after initiating ARV. CONCLUSIONS:: Measurement of naive CD4 percent in patients can identify those least likely to reconstitute immunity, who may benefit from earlier ARV treatment.
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