Thymic output of CD4+ cells contributes to CD4+ cell and viral load dissociation

Successful HIV treatment with HAART generally results in a significant reduction in viral load, in many cases to below levels of detection, and a rise in CD4+ cell counts.

In some patients, however, a discordant response occurs in which the viral load fails to fall or rapidly rebounds despite continued treatment but the CD4+ cell count substantially and persistently improves. The mechanism for this discordance, which is not currently well understood, may have significant importance in treatment decisions for some patients.

A number of mechanisms for CD4+ cell depletion during HIV infection have been proposed. These include direct cytopathic effects of HIV, infected cell elimination by the immune system, virus-induced apoptosis, abnormalities in cell trafficking, and impairment of CD4+ cell production in the thymus. In the April 1, 2001 issue of The Journal of Infectious Diseases, French Researchers report that the improvement in CD4+ cell counts in HAART-treated patients with virologic failure is likely to be the result of thymic output, not decreased spontaneous or activation-induced cell death.

In this study, spontaneous and activation-induced cell death and thymic output were evaluated in 42 adult patients, 30 of who were HIV-positive and 12 that were not. Of the 30 HIV-positive patients, 18 patients experienced treatment failure of their initial protease inhibitor-based HAART regimen but continued on that therapy for at least one year after virologic treatment failure had occurred and 12 patients were antiretroviral-naive.

The 18 patients on HAART had a mean CD4+ cell count of 60 cells/mm3 at baseline and, despite a mean change in viral load of +0.03 log10 copies/mL during treatment, their mean CD4+ cell count had risen by 179 cells cells/mm3. At the time of evaluation, 15 of the 18 HAART-treated patients were above pretreatment levels, but there was significant interpatient variability in CD4+ cell changes.

The researchers found that average spontaneous losses of CD4+ and CD8+ cells during 48 hour cell culture were not significantly different between the HIV-positive and HIV-negative patients.

While higher viral loads did correlate with increased spontaneous loss of CD4+ and CD8+ cells during culture, there was no correlation between this finding and the improvement in CD4+ cell counts in patients with virologic failure. Further, Fas ligand-induced (which assesses T cell death caused by cross-linking receptors of the tumour necrosis factor family) and activation-induced cell death also failed to correlate with the improvement in CD4+ T cell counts in these patients.

On the other hand, thymic output, as reflected by T cell receptor excision circle (TREC) levels, directly correlated with improvement in CD4+ cell counts in the HAART-treated patients experiencing virologic failure. Further, TREC levels were unrelated to plasma viral load or with viral load changes following HAART initiation. Finally, as would be expected if thymic output is responsible for CD4+ cell increases in patients failing HAART, the researchers found that increases in CD4+ cell counts in these patients correlated with age.

Based upon these findings, the authors state “that decreased viral replicative capacity due to accumulated drug resistance mutations, together with adequate residual thymic function (e.g., younger patients without irreversible thymic damage), both contribute to improved CD4+ T cell counts through the restoration of thymic output [and] we found no evidence that a reduction in the death of T cells contributes to discordant immunovirologic responses.” They conclude that their results “support the potential usefulness of therapeutic strategies designed to restore thymic function in HIV-positive individuals.”

D Lecossier and others. Discordant Increase in CD4+ T Cells in Human Immunodeficiency Virus-Infected Patients Experiencing Virologic Treatment Failure: Role of Changes in Thymic Output and T Cell Death. The Journal of Infectious Diseases. 2001; 183:1099-16.