Torque teno virus: a potential marker of immune reconstitution in youths with vertically acquired HIV

Abstract

Torque teno virus (TTV) viral load (VL), a component of the human virome, increases during immune suppression or dysregulation. This study aimed to explore TTV VL in youths living with vertically acquired HIV (YWVH) and its potential as an immunovirological marker. We performed an observational, retrospective study involving YWVH under antiretroviral treatment (ART) from the Spanish Cohort of HIV-infected children, adolescents, and vertically HIV-infected patients transferred to Adult Units (CoRISpe-FARO), compared to HIV-negative healthy donors (HD). Plasma TTV VL was assessed by qPCR. T-cell phenotype was analysed on cryopreserved peripheral blood mononuclear cells by flow cytometry. Correlations with baseline CD4 and CD8 and long-term virological evolution were examined. A total of 57 YWVH were compared with 23 HD. YWVH had a median CD4 T-cells of 736 cells/mm³ [IQR: 574-906], a median of 17 years [IQR: 14-20.5] since ART initiation, and 65 months [IQR: 39-116] under HIV-RNA virological control. TTV VL was higher among YWVH and in males compared with females (p < 0.05). Among YWVH, TTV VL correlated with CD4 and CD8 counts and the CD4/CD8 ratio (p = 0.002; r = - 0.39, p = 0.037; r = 0.277, p = 0.005; r = - 0.37 respectively). TTV VL correlated with activation expression markers (HLA-DR+/CD38+) on CD4 (p = 0.007, r = 0.39) and the soluble proinflammatory cytokine IL-6 (p = 0.006, r = 0.38).

Keywords: Antiretroviral treatment; CD4/CD8 ratio; Immune reconstitution; TTV; Youths with vertically acquired HIV.

Fig. 1

Plasma TTV viral load and correlations with %CD4 T-cell, %CD8 T-cells and CD4/CD8 ratio. TTV viral load in YWVH and HD (A) and differences in both groups depending on sex (B) in all participants (B, left), YWVH (B, middle) and HD (B, right). TTV correlations with %CD4 (C, left), %CD8 T-cells (C, middle) and CD4/CD8 ratio (C, right) in YWVH (red) and HD (blue) (n = 49 for %CD8 in YWVH). Variables are taken at sampling. Abbreviations: YWVH, youths living with vertically acquired HIV; HD, healthy donors. A viral load of 0.69 log10 copies/mL was assigned to HD with undetectable viral load which is the lowest limit of detection. Mann-Whitney U-test was used for groups’ comparisons. The Spearman rho correlation coefficient test was used for correlations. ***p-value < 0.001; *0.01 < p-value < 0.05.

Fig. 2

TTV viral load correlations with HIV-related data, soluble inflammatory markers and activation, senescence, and exhaustion markers’ expression in T-cells. Correlations between TTV viral load and Nadir CD4 (A), time since ART initiation (B) and time under HIV viral control (undetectable viral load < 20 copies/ml) (C). Correlations between TTV viral load and soluble IL-6 levels (n = 23 for HD in blue dots and n = 29 for YWVH in red dots) (D), HLADR+CD38 + co-expression in CD4 T-cells (n = 23 for HD in blue dots and n = 25 for YWVH in red dots) (E), TIM-3 + expression in CD8 T-cells (F) and PD1+ (G) and CD57+ and (H) expression in EM CD4 and CD8 T-cells (n = 23 for HD in blue dots and n = 28 for YWVH in red dots). A viral load of 0.69 log10 copies/mL was assigned to HD with undetectable viral load which is the lowest limit of detection. Variables are taken at sampling. Abbreviations: YWVH, youths living with vertically acquired HIV; HD, healthy donors; ART, antiretroviral treatment; EM, Effector Memory. The Spearman rho correlation coefficient test was used.

Fig. 3

TTV viral load associations with viral and immune evolution in YWVH. Differences in TTV viral load at sampling in YWVH that developed VF (A) or blips (B) during the follow-up compared to YWVH that maintained persistent HIV-RNA viral control. Correlation between TTV viral load at sampling and time until the first blip appearance in the subgroup of YWVH that developed blips during the follow-up (n = 18) (C). Abbreviations: YWVH, youths living with vertically HIV; VF, viral failure. Mann-Whitney U-test was used for groups’ comparisons. The Spearman rho correlation coefficient test was used. *0.01 < p-value < 0.05.