Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy

The role of the thymus in HIV-1 pathogenesis remains unclear. We developed an assay to quantify the number of recent thymic emigrants in blood based on the detection of a major excisional DNA byproduct (termed alpha 1 circle) of T cell receptor rearrangement. By studying 532 normal individuals, we found that alpha 1 circle numbers in blood remain high for the first 10-15 yr of life, a sharp drop is seen in the late teen years, and a gradual decline occurs thereafter. Compared with age-matched uninfected control individuals, alpha 1 circle numbers in HIV-1-infected adults were significantly reduced; however, there were many individuals with normal alpha 1 circle numbers. In 74 individuals receiving highly active antiretroviral therapy, we found no appreciable effect on alpha 1 circle numbers in those whose baseline values were already within the normal range, but significant increases were observed in those with a preexisting impairment. The increases in alpha 1 circle numbers were, however, numerically insufficient to account for the rise in levels of naive T lymphocytes. Overall, it is difficult to invoke thymic regenerative failure as a generalized mechanism for CD4 lymphocyte depletion in HIV-1 infection, as alpha 1 circle numbers are normal in a substantial subset of HIV-1-infected individuals.