Increased Regulatory T-Cell Activity and Enhanced T-Cell Homeostatic Signaling in Slow Progressing HIV-infected Children

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 (T REG ) 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 T REG , skewed toward functionally suppressive phenotypes. As with immune activation, overall T-cell proliferation was lower in PSP, but was uniquely higher in central memory T REG (CM T REG ), 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 T REG , CM T REG 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 T REG 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 T REG 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 T REG , and enhanced T-cell homeostatic signaling.

Delineation of Homeostatic Immune Signatures Defining Viremic Non-progression in HIV-1 Infection

“…To be noted however, Treg expansion seems insufficient to suppress systemic immune activation in VNPs, as previously reported in studies of untreated chronic HIV infection associated with high viral replication [reviewed in Chevalier and Weiss (55)]. In contrast to our study, Roider et al (56) has delineated a possible role for Treg-mediated suppression of immune activation in a pediatric cohort resembling VNPs. The discordance in the relationship between Tregs and immune activation observed in VNPs and pediatric slow progressors may reflect the disparate immune responses to viral infection observed in a developing vis-à-vis mature immune system (57).…”

Asymptomatic and Mild SARS-CoV-2 Infections Elicit Lower Immune Activation and Higher Specific Neutralizing Antibodies in Children Than in Adults

“…Tregs inhibit the activation of both innate and adaptive immune response via inhibitory surface molecules (like CTLA-4 and LAG-3) and by the secretion of immunosuppressive cytokines (i.e., IL-10, TGF-β, and IL-35) ( 38 , 39 ). It has been recently reported that slow-progressors HIV-infected children secreted higher levels of IL-10 compared to those who progressed and had higher proliferation of Tregs ( 40 ). Similarly, it is possible that Tregs and Bregs in SARS-CoV-2-infected children constrains inflammation/immune activation, likely through the release of IL-10.…”

Differences in inducibility of the latent HIV reservoir in perinatal and adult infection

“…Studies on integration sites of proviral genomes have shown that long-term virologic suppression is associated with changes in the composition of the viral reservoir, favoring sites associated with maintenance of deep viral latency (8,43,44). The immune-selective pressure driving the establishment of the latent reservoir may be differentially affected by the underdeveloped immune system of infancy (45). Other factors that can account for the differences in reactivation are the immune landscape in which HIV infection is established, including hyporesponsiveness due to higher proportions of T regulatory cells in early infancy and childhood (46)(47)(48); as well as differences in the distribution of the latent HIV reservoir in different memory T cell subsets (49,50).…”