Abstract
Pediatric slow progressors (PSP) are rare ART-naïve, HIV-infected children who maintain high CD4 T-cell counts and low immune activation despite persistently high viral loads. Using a well-defined cohort of PSP, we investigated the role of regulatory T-cells (TREG) and of IL-7 homeostatic signaling in maintaining normal-for-age CD4 counts in these individuals. Compared to children with progressive disease, PSP had greater absolute numbers of TREG, skewed toward functionally suppressive phenotypes. As with immune activation, overall T-cell proliferation was lower in PSP, but was uniquely higher in central memory TREG (CM TREG), indicating active engagement of this subset. Furthermore, PSP secreted higher levels of the immunosuppressive cytokine IL-10 than children who progressed. The frequency of suppressive TREG, CM TREG proliferation, and IL-10 production were all lower in PSP who go on to progress at a later time-point, supporting the importance of an active TREG response in preventing disease progression. In addition, we find that IL-7 homeostatic signaling is enhanced in PSP, both through preserved surface IL-7receptor (CD127) expression on central memory T-cells and increased plasma levels of soluble IL-7receptor, which enhances the bioactivity of IL-7. Combined analysis, using a LASSO modeling approach, indicates that both TREG activity and homeostatic T-cell signaling make independent contributions to the preservation of CD4 T-cells in HIV-infected children. Together, these data demonstrate that maintenance of normal-for-age CD4 counts in PSP is an active process, which requires both suppression of immune activation through functional TREG, and enhanced T-cell homeostatic signaling.
Highlights
In the absence of antiretroviral therapy (ART), HIV-infected children typically progress rapidly to AIDS [1]
To examine the T-cell correlates of low immune activation observed among Pediatric slow progressors” (PSP), we divided subjects into four study groups: (i) Pediatric slow progressors, who maintained CD4 counts at >450/mm3 throughout the study period and remained ART-naïve (PSPN; n = 12); (ii) Pediatric future progressors (PFP; n = 11): children who met the criteria to be categorized as PSP at baseline, but who later experienced CD4 decline to
As previously reported [7], CD4 T-cell activation, measured by HLA-DR expression, was lower in both PSPN and PFP compared to Pediatric progressors (PP) and correlated with disease progression by CD4% (Figures 1E,F)
Summary
In the absence of antiretroviral therapy (ART), HIV-infected children typically progress rapidly to AIDS [1]. “Pediatric slow progressors” (PSP) are a subgroup of vertically HIVinfected children who maintain their CD4 counts despite being antiretroviral treatment-naive [2,3,4,5,6,7] These children share certain fundamental immunological characteristics with the natural hosts of nonpathogenic SIV infection such as sooty mangabeys, including low immune activation on CD4 T-cells in the face of persistent high viral loads [7,8,9,10]. In the nonhuman primate model of HIV infection, the rapid resolution of immune activation during acute infection distinguishes nonpathogenic infection of SIV in sooty mangabeys from pathogenic infection in rhesus macaques [15]. The importance of TREG in pediatric non-progression has not been assessed to date, but the similarities between PSP and non-progressive SIV infection suggest a possible role for these cells
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