Quantification of naive and memory T-cell turnover during HIV-1 infection

Abstract

The average lifespan of both naive and memory CD4 and CD8 T cells decreased during untreated chronic HIV-1 infection. Although the turnover of the memory T-cell populations nearly normalized during effective treatment, the turnover of naive CD4 and CD8 T cells did not seem to normalize completely.

Quantifying T lymphocyte turnover

“…A large variety of techniques, varying from Ki67 staining [37, 71, 193, 247], BrdU labeling [46, 121, 132, 162], deuterium labeling [103, 105, 134, 163, 224], TREC analysis [60, 62, 102, 140, 187], telomere analysis [173, 238, 239] and various combinations thereof [61, 89, 172] have unequivocally established that T lymphocytes are turning over more rapidly in chronically infected patients and macaques than in healthy controls. It has been difficult to precisely quantify the fold increase in T lymphocyte turnover because (1) the estimation of turnover rates from this data can be challenging, (2) studies have not always separated naive from memory T cells, and (3) the rates of cell division, i.e., the fraction of Ki67 + T cells, depend on the viral load and the density of CD4 + T cells [37, 193].…”

“…It has been difficult to precisely quantify the fold increase in T lymphocyte turnover because (1) the estimation of turnover rates from this data can be challenging, (2) studies have not always separated naive from memory T cells, and (3) the rates of cell division, i.e., the fraction of Ki67 + T cells, depend on the viral load and the density of CD4 + T cells [37, 193]. Long-term deuterium labeling in volunteers and HIV-1 infected patients suggests that the turnover rate of memory CD4 + and CD8 + T cells is approximately 3-fold increased in patients with CD4 + T cell counts between 180 to 450 cells per μ l blood [224]. The variation in the turnover rate of naive T cells was higher, with a similar 3-fold increase in the naive CD4 + T cell compartment, and a 12-fold increase for CD8 + naive T cells [224].…”

“…We recently found that these labeling data from human naive T cells are well described by the single compartment version of Eq. (21), arguing that human naive T cells form a homogeneous population of long-lived cells [224]. However, the data from the memory T cells in that study [223] required at least two compartments to obtain a good fit to the labeling data, suggesting that memory T cells form a heterogeneous population [231].…”

“…Estimates of the death rate are available from studies using deuterium labeling of CD4 + naive T cells in healthy volunteers [223] and HIV + patients [224], which suggested average loss rates of d = 0.0005 day −1 and d = 0.00152 day −1 , respectively (i.e., life spans of 5.6 and 1.8 years, respectively; just exceeding a 3-fold difference). Naive T cell counts are depleted during HIV-1 infection, and after one or two years of HIV-1 infection one readily observes a 5-fold TREC dilution and a 2-fold reduction of the number of naive CD4 + T cells in the blood.…”

A genotypic method for determining HIV-2 coreceptor usage enables epidemiological studies and clinical decision support

“…X4-R5 reversions have already been reported in HIV-1-infected patients after immune reconstitution [51–54]. Because recent findings indicate that X4-capable HIV-1 viruses are less susceptible to neutralization by autologous antibodies than R5-using viruses from the same host [55], X4-R5 reversions could result from the normalization of naïve T-cell turnover following immunological recovery [56], after which the infection of naïve T-cells by X4-capable variants may not be productive enough [51]. Since X4-capable HIV-2 also seem to be less susceptible to neutralization than CCR5-using strains [19], X4-R5 reversions in HIV-2 could be explained by the same mechanism.…”