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A timely recovery of T-cell numbers following haematopoietic stem-cell transplantation (HSCT) is essential for preventing complications, such as increased risk of infection and disease relapse. In analogy to the occurrence of lymphopenia-induced proliferation in mice, T-cell dynamics in humans are thought to be homeostatically regulated in a cell density-dependent manner. The idea is that T cells divide faster and/or live longer when T-cell numbers are low, thereby helping the reconstitution of the T-cell pool. T-cell reconstitution after HSCT is, however, known to occur notoriously slowly. In fact, the evidence for the existence of homeostatic mechanisms in humans is quite ambiguous, since lymphopenia is often associated with infectious complications and immune activation, which confound the study of homeostatic regulation. This calls into question whether homeostatic mechanisms aid the reconstitution of the T-cell pool during lymphopenia in humans. Here we review the changes in T-cell dynamics in different situations of T-cell deficiency in humans, including the early development of the immune system after birth, healthy ageing, HIV infection, thymectomy and hematopoietic stem cell transplantation (HSCT). We discuss to what extent these changes in T-cell dynamics are a side-effect of increased immune activation during lymphopenia, and to what extent they truly reflect homeostatic mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Baliu-Piqué, Tesselaar and Borghans.)

HIV-1 cell entry is mediated by binding to the CD4-receptor and chemokine co-receptors CCR5 (R5) or CXCR4 (X4). R5-tropic viruses are predominantly detected during early infection. A switch to X4-tropism often occurs during the course of infection. X4-tropism switching is strongly associated with accelerated disease progression and jeopardizes CCR5-based HIV-1 cure strategies. It is unclear whether host immunological factors play a causative role in tropism switching. We investigated the relationship between immunological factors and X4-tropism in a cross-sectional study in HIV-1 subtype C (HIV-1C)-infected patients and in a longitudinal HIV-1 subtype B (HIV-1B) seroconverter cohort. Principal component analysis identified a cluster of immunological markers (%HLA-DR + CD4 + T-cells, %CD38 + HLA-DR + CD4 + T-cells, %CD38 + HLA-DR + CD8 + T-cells, %CD70 + CD4 + T-cells, %CD169 + monocytes, and absolute CD4 + T-cell count) in HIV-1C patients that was independently associated with X4-tropism (aOR 1.044, 95% CI 1.003-1.087, p = 0.0392). Analysis of individual cluster contributors revealed strong correlations of two markers of T-cell activation (%HLA-DR + CD4 + T-cells, %HLA-DR + CD38 + CD4 + T-cells) with X4-tropism, both in HIV-1C patients (p = 0.01;p = 0.03) and HIV-1B patients (p = 0.0003;p = 0.0001). Follow-up data from HIV-1B patients subsequently revealed that T-cell activation precedes and independently predicts X4-tropism switching (aHR 1.186, 95% CI 1.065-1.321, p = 0.002), providing novel insights into HIV-1 pathogenesis and CCR5-based curative strategies.

Both healthy aging and human immunodeficiency virus (HIV) infection lead to a progressive decline in naive CD8 + T-cell numbers and expansion of the CD8 + T-cell memory and effector compartments. HIV infection is therefore often considered a condition of premature aging. Total CD8 + T-cell numbers of HIV-infected individuals typically stay increased even after long-term (LT) combination antiretroviral treatment (cART), which is associated with an increased risk of non-AIDS morbidity and mortality. The causes of these persistent changes in the CD8 + T-cell pool remain debated. Here, we studied the impact of age, CMV infection, and LT successful cART on absolute cell numbers in different CD8 + T-cell subsets. While naïve CD8 + T-cell numbers in cART-treated individuals ( N  = 38) increased to healthy levels, central memory (CM), effector memory (EM), and effector CD8 + T-cell numbers remained higher than in (unselected) age-matched healthy controls ( N  = 107). Longitudinal analysis in a subset of patients showed that cART did result in a loss of memory CD8 + T-cells, mainly during the first year of cART, after which memory cell numbers remained relatively stable. As CMV infection is known to increase CD8 + T-cell numbers in healthy individuals, we studied whether any of the persistent changes in the CD8 + T-cell pools of cART-treated patients could be a direct reflection of the high CMV prevalence among HIV-infected individuals. We found that EM and effector CD8 + T-cell numbers in CMV + healthy individuals ( N  = 87) were significantly higher than in CMV - ( N  = 170) healthy individuals. As a result, EM and effector CD8 + T-cell numbers in successfully cART-treated HIV-infected individuals did not deviate significantly from those of age-matched CMV + healthy controls ( N  = 39). By contrast, CM T-cell numbers were quite similar in CMV + and CMV - healthy individuals across all ages. The LT expansion of the CM CD8 + T-cell pool in cART-treated individuals could thus not be attributed directly to CMV and was also not related to residual HIV RNA or to the presence of HIV-specific CM T-cells. It remains to be investigated why the CM CD8 + T-cell subset shows seemingly irreversible changes despite years of effective treatment.