Evidence for Increased T Cell Turnover and Decreased Thymic Output in HIV Infection

Abstract

The effects of HIV infection upon the thymus and peripheral T cell turnover have been implicated in the pathogenesis of AIDS. In this study, we investigated whether decreased thymic output, increased T cell proliferation, or both can occur in HIV infection. We measured peripheral blood levels of TCR rearrangement excision circles (TREC) and parameters of cell proliferation, including Ki67 expression and ex vivo bromodeoxyuridine incorporation in 22 individuals with early untreated HIV disease and in 15 HIV-infected individuals undergoing temporary interruption of therapy. We found an inverse association between increased T cell proliferation with rapid viral recrudescence and a decrease in TREC levels. However, during early HIV infection, we found that CD45RO−CD27high (naive) CD4+ T cell proliferation did not increase, despite a loss of TREC within naive CD4+ T cells. A possible explanation for this is that decreased thymic output occurs in HIV-infected humans. This suggests that the loss of TREC during HIV infection can arise from a combination of increased T cell proliferation and decreased thymic output, and that both mechanisms can contribute to the perturbations in T cell homeostasis that underlie the pathogenesis of AIDS.

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

“…Moreover, the numbers of HIV-specific T-cells can rise following an interruption of anti-retroviral therapy 28,29 . Along with the evidence that HIV infections impair the thymic output, this furthermore reveals the retention of T-cells in established chronic infections that can expand substantially 30,31 . The demonstration that virus titers strongly rise following depletion of CD8 + T-cells in SIV infected macaques [32][33][34] and that protective immune responses can be elicited upon vaccinating SIV infected Rhesus macaques 35 further underscore the strong effector capacity of CD8 + T-cells in established chronic infections.…”

Dendritic cells from HIV-1 infected individuals are less responsive to toll-like receptor (TLR) ligands

“…Early in HIV-1 disease, innate immune cells such as pDC, mDC, NK, and iNKT are either diminished due to the direct cytopathic effects of HIV-1 or are dysfunctional due to a dysregulation of the cytokine network (38)(39)(40)(41)(42)(43). TLR agonists are promising molecules for initiating and/or maintaining immune cell function.…”

To kill or be killed: how HIV exhausts the immune system

“…26 A number of factors besides thymic production may determine TREC content of the T-cell population, including cell division (TRECs do not replicate during mitosis) and cell death, intracellular degradation of TRECs and reversion of memory cells to a naive phenotype, complicating the interpretation of TREC data. 27 However, an essential role for the thymus for T-cell renewal is suggested in early HIV-infected individuals, 28 and in patients on highly active antiretroviral therapy (HAART) in whom suppression of the viral load is accompanied with concomitant enhanced numbers of naive T cells and increased TREC content.…”