Estimating the role of thymic output in HIV infection

The mechanisms by which infection with CCR5 tropic HIV causes the depletion of naive CD4+ and CD8+ T cells are poorly understood. As HIV infection affects the thymus, one hypothesis is 'reduced thymic output'. As HIV infection is associated with hyperactivation, another hypothesis is 'depletion by activation'. The best technique that is currently available for measuring thymic output in humans is to quantify TCR excision circles (TRECs) in peripheral T cells. Unfortunately, TREC data are very difficult to interpret.

The depletion of memory CD4+ T cells can be accounted for by the massive infection of these cells in the gut and mucosal tissues. The major controversy therefore remains to explain the depletion of naive T cells. SIV infection of thymectomized and euthymic Rhesus macaques revealed important new insights into the effects of thymectomy and SIV infection on naive T cell depletion.

Changes in the TREC content, i.e. the average number of TRECs per cell, are confounded by changes in division rates. By also expressing TREC measurements in terms of total TREC numbers, one obtains a much more reliable indication of thymic production. The relatively rapid changes in TREC contents observed in subsets of HIV patients are best explained by changes in T cell division rates. Infection of the thymus is expected to play a role in the long-term depletion of naive T cells, but direct evidence remains scarce. Routinely measuring TREC totals, in addition to the TREC content and naive T cell counts, would help to finally sort this out.