An HLA-I signature favouring KIR-educated Natural Killer cells mediates immune control of HIV in children and contrasts with the HLA-B-restricted CD8+ T-cell-mediated immune control in adults.

Natural Killer (NK) cells contribute to HIV control in adults, but HLA-B-mediated T-cell activity has a more substantial impact on disease outcome. However, the HLA-B molecules influencing immune control in adults have less impact on paediatric infection. To investigate the contribution NK cells make to immune control, we studied >300 children living with HIV followed over two decades in South Africa. In children, HLA-B alleles associated with adult protection or disease-susceptibility did not have significant effects, whereas Bw4 (p = 0.003) and low HLA-A expression (p = 0.002) alleles were strongly associated with immunological and viral control. In a comparator adult cohort, Bw4 and HLA-A expression contributions to HIV disease outcome were dwarfed by those of protective and disease-susceptible HLA-B molecules. We next investigated the immunophenotype and effector functions of NK cells in a subset of these children using flow cytometry. Slow progression and better plasma viraemic control were also associated with high frequencies of less terminally differentiated NKG2A+NKp46+CD56dim NK cells strongly responsive to cytokine stimulation and linked with the immunogenetic signature identified. Future studies are indicated to determine whether this signature associated with immune control in early life directly facilitates functional cure in children.

Next-generation point-of-care testing in pediatric human immunodeficiency virus infection facilitates diagnosis and monitoring of treatment.

Point-of-care (PoC) testing facilitates early infant diagnosis (EID) and treatment initiation, which improves outcome. We present a field evaluation of a new PoC test (Cepheid Xpert® HIV-1 Qual XC RUO) to determine whether this test improves EID and assists the management of children living with human immunodeficiency virus (HIV) infection. We compared 2 PoC tests with the standard-of-care (SoC) test used to detect HIV infection from dry blood spots in newborn infants at high risk of in utero infection. We also evaluated the ability of the PoC tests to detect HIV total nucleic acid (TNA) in children living with HIV infection who had maintained undetectable plasma viremia following very early combination antiretroviral therapy (cART) initiation. Qualitative (Qual) detection of HIV using the Xpert® HIV-1 Qual XC RUO ("RUO") and Xpert® HIV-1 Qual ("Qual") PoC tests was compared in 224 infants with the SoC DBS Roche COBAS® HIV-1/HIV-2 qualitative test. The same 2 PoC tests were also evaluated in 35 older children who had initiated cART before 21 days of age and maintained undetectable plasma viremia for a mean of 25 months. No discrepancies were observed in detection of HIV infection via the 2 PoC tests or the SoC test in the 224 neonates studied, but only 95% of the SoC test results were generated compared with 100% of the PoC test results (P = .0009). The cycle threshold values for the research use only (RUO) assay were the lowest of the 3 assays (P < .0001 in each case). In 6 of the 35 early-treated aviremic children, HIV TNA was detected by RUO but not Qual. The RUO assay outperforms Qual in detecting HIV-1 infection. RUO would therefore potentially improve EID and assist in identifying cART-adherent early-treated children with the lowest HIV TNA levels and the highest HIV cure potential.

Robust HIV-specific CD4+ and CD8+ T-cell responses distinguish elite control in adolescents living with HIV from viremic nonprogressors.

BACKGROUND: Elite controllers are therapy-naive individuals living with HIV capable of spontaneous control of plasma viraemia for at least a year. Although viremic nonprogressors are more common in vertical HIV-infection than in adults' infection, elite control has been rarely characterized in the pediatric population. DESIGN: We analyzed the T-cell immunophenotype and the HIV-specific response by flow cytometry in four pediatric elite controllers (PECs) compared with age-matched nonprogressors (PNPs), progressors and HIV-exposed uninfected (HEUs) adolescents. RESULTS: PECs T-cell populations had lower immune activation and exhaustion levels when compared with progressors, reflected by a more sustained and preserved effector function. The HIV-specific T-cell responses among PECs were characterized by high-frequency Gag-specific CD4+ T-cell activity, and markedly more polyfunctional Gag-specific CD8+ activity, compared with PNPs and progressors. These findings were consistently observed even in the absence of protective HLA-I molecules such as HLA-B∗27/57/81. CONCLUSION: Pediatric elite control is normally achieved after years of infection, and low immune activation in PNPs precedes the increasing ability of CD8+ T-cell responses to achieve immune control of viraemia over the course of childhood, whereas in adults, high immune activation in acute infection predicts subsequent CD8+ T-cell mediated immune control of viremia, and in adult elite controllers, low immune activation is therefore the consequence of the rapid CD8+ T-cell mediated immune control generated after acute infection. This distinct strategy adopted by PECs may help identify pathways that facilitate remission in posttreatment controllers, in whom protective HLA-I molecules are not the main factor.