Altered Toll-Like Receptor-4 Response to Lipopolysaccharides in Infants Exposed to HIV-1 and Its Preventive Therapy

Abstract

Pathogen sensing and recognition through pattern recognition receptors, and subsequent production of pro-inflammatory cytokines, is the cornerstone of the innate immune system. Despite the fact that HIV-exposed uninfected (HEU) infants are prone to serious bacterial infections, no study has focused on the functionality of their bacteria recognition system. This is the first study to investigate baseline levels of three critically important immune response molecules in this population: complement component (C)-3, toll-like receptor (TLR)-4, and C-reactive protein (CRP). We enrolled 16 HEU and 6 HIV-unexposed (HU) infants. TLR4 function was investigated by stimulating whole blood with increasing concentrations of TLR4-agonist ultrapure lipopolysaccharides. TLR4/TLR4-agonist dose response were assessed by measuring IL-6 secretion. Complement C3 and CRP were measured by photo spectrometry. Data showed no significant differences in baseline concentration of CRP between HEU and HU infants. Complement C3 was significantly higher in HEU infants than HU infants. TLR4 anergy was observed in 7 of 12 HEU infants, whereas the rest of HEU infants (n = 4) and the control HU infants tested (n = 3) showed responsive TLR4. None of the HEU infants investigated in this study had severe infections in the year after their birth. In conclusion, TLR4 anergy can occur in HEU infants without necessarily translating to increased vulnerability to infectious diseases.

Immune and Metabolic Alterations in Children with Perinatal HIV Exposure

“…Children who are HEU have been found to have up to two-fold fewer neutrophils than their HUU counterparts, possibly as a consequence of in utero exposure to ART, and this reduced neutrophil count can persist up to 8 years of age [ 44 ]. Importantly, impaired neutrophil responses have also been noted in some CHEU [ 45 , 46 , 47 ]. Although a link between in utero ART-exposure and defective neutrophil oxidative burst has been observed [ 46 ] further studies are required in order to determine the effect of exposure to ART on impaired neutrophil function in CHEU.…”

Association of Maternal Factors and HIV Infection With Innate Cytokine Responses of Delivering Mothers and Newborns in Mozambique

“…We previously found higher TNF, IL-6, and IL-12 concentrations in myeloid dendritic cells (DC) and monocytes in response to bacterial PRR ligands in South African children, particularly at 2 and 6 weeks of age, but no differences in plasmacytoid DC (Reikie et al, 2013). However, other studies reported a reduced IL-12 production by cord monocytes in HEU infants (Chougnet et al, 2000) and no IL-6 responses upon TLR4 stimulation in some HEU infants (Maloupazoa Siawaya et al, 2018). Another study showed no differences upon TLR9 stimulation on DC (Velilla et al, 2008).…”