Abstract
Naive T cells in untreated HIV-1 infected individuals have a reduced T-cell receptor excision circle (TREC) content. Previous mathematical models have suggested that this is due to increased naive T-cell division. It remains unclear, however, how reduced naive TREC contents can be reconciled with a gradual loss of naive T cells in HIV-1 infection. We performed longitudinal analyses in humans before and after HIV-1 seroconversion, and used a mathematical model to investigate which processes could explain the observed changes in naive T-cell numbers and TRECs during untreated HIV-1 disease progression. Both CD4+ and CD8+ naive T-cell TREC contents declined biphasically, with a rapid loss during the first year and a much slower loss during the chronic phase of infection. While naive CD8+ T-cell numbers hardly changed during follow-up, naive CD4+ T-cell counts continually declined. We show that a fine balance between increased T-cell division and loss in the peripheral naive T-cell pool can explain the observed short- and long-term changes in TRECs and naive T-cell numbers, especially if T-cell turnover during the acute phase is more increased than during the chronic phase of infection. Loss of thymic output, on the other hand, does not help to explain the biphasic loss of TRECs in HIV infection. The observed longitudinal changes in TRECs and naive T-cell numbers in HIV-infected individuals are most likely explained by a tight balance between increased T-cell division and death, suggesting that these changes are intrinsically linked in HIV infection.
Highlights
Both CD4+ and CD8+ T-cell homeostasis are clearly disturbed during untreated HIV infection [1]: in the acute phase of infection, the majority of memory CD4+ T cells in the gut are lost [2,3] while in the chronic phase, peripheral CD4+ T cells are gradually lost
Based on a mathematical model, it has previously been argued that the reduced average T-cell receptor excision circle (TREC) content of T cells in HIV-1 infection is probably due to increased naive T-cell division, and provides no evidence for reduced thymic output [9]
Our longitudinal analysis of the naive CD4+ and CD8+ T-cell pools − over seroconversion and up to the chronic stage of HIV infection − shows that both CD4+ and CD8+ T-cell TREC dynamics are biphasic, with a rapid decline during the first year and a slow decline during the chronic phase of HIV infection
Summary
Both CD4+ and CD8+ T-cell homeostasis are clearly disturbed during untreated HIV infection [1]: in the acute phase of infection, the majority of memory CD4+ T cells in the gut are lost [2,3] while in the chronic phase, peripheral CD4+ T cells are gradually lost. The CD8+ T-cell pool expands during the acute stage of infection and starts to decline at the AIDS stage [4], while the percentage of naive cells in the CD8+ T-cell pool is severely reduced throughout HIV infection [5,6,7]. The causes of these changes in the CD4+ and CD8+ T-cell pools are still debated. Based on a mathematical model, it has previously been argued that the reduced average TREC content of T cells in HIV-1 infection is probably due to increased naive T-cell division, and provides no evidence for reduced thymic output [9]
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