Longitudinal Assessment of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific Gamma Interferon Responses during the First Year of Life in HIV-1-Infected Infants

Department of Paediatrics, University of Nairobi, Kenya.
Journal of Virology (Impact Factor: 4.44). 08/2005; 79(13):8121-30. DOI: 10.1128/JVI.79.13.8121-8130.2005
Source: PubMed


Human immunodeficiency virus type 1 (HIV-1) infection results in different patterns of viral replication in pediatric compared to adult populations. The role of early HIV-1-specific responses in viral control has not been well defined, because most studies of HIV-1-infected infants have been retrospective or cross-sectional. We evaluated the association between HIV-1-specific gamma interferon (IFN-gamma) release from the cells of infants of 1 to 3 months of age and peak viral loads and mortality in the first year of life among 61 Kenyan HIV-1-infected infants. At 1 month, responses were detected in 7/12 (58%) and 6/21 (29%) of infants infected in utero and peripartum, respectively (P = 0.09), and in approximately 50% of infants thereafter. Peaks of HIV-specific spot-forming units (SFU) increased significantly with age in all infants, from 251/10(6) peripheral blood mononuclear cells (PBMC) at 1 month of age to 501/10(6) PBMC at 12 months of age (P = 0.03), although when limited to infants who survived to 1 year, the increase in peak HIV-specific SFU was no longer significant (P = 0.18). Over the first year of life, infants with IFN-gamma responses at 1 month had peak plasma viral loads, rates of decline of viral load, and mortality risk similar to those of infants who lacked responses at 1 month. The strength and breadth of IFN-gamma responses at 1 month were not significantly associated with viral containment or mortality. These results suggest that, in contrast to HIV-1-infected adults, in whom strong cytotoxic T lymphocyte responses in primary infection are associated with reductions in viremia, HIV-1-infected neonates generate HIV-1-specific CD8+-T-cell responses early in life that are not clearly associated with improved clinical outcomes.

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    • "However, these responses seem to be insufficient to control viremia, as there is typically no rapid decline in viral load in pediatric HIV infection as opposed to the decline in viral load after acute infection in adults [see above and Ref. (25)]. In infants, neither breadth nor magnitude of HIV-specific CD8 T-cell responses at 1 month of age correlate with viremic control or survival at 12 months (93), but Gag-specific CD8 T cell responses are higher in infants who survive to 1 year of age (94). The magnitude and breadth of Gag-specific CD8 T cell responses correlated negatively with viral load in one study (95), but not in another (96). "
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    ABSTRACT: The developing immune system is adapted to the exposure to a plethora of pathogenic and non-pathogenic antigens encountered in utero and after birth, requiring a fine balance between protective immunity and immune tolerance. In early stages of life, this tolerogenic state of the innate and adaptive immune system and the lack of immunological memory render the host more susceptible to infectious pathogens like HIV. HIV pathogenesis is different in children, compared to adults, with more rapid disease progression and a substantial lack of control of viremia compared to adults. Plasma viral load remains high during infancy and only declines gradually over several years in line with immune maturation, even in rare cases where children maintain normal CD4 T-lymphocyte counts for several years without antiretroviral therapy (ART). These pediatric slow progressors also typically show low levels of immune activation despite persistently high viremia, resembling the phenotype of natural hosts of SIV infection. The lack of immunological memory places the fetus and the newborn at higher risk of infections; however, it may also provide an opportunity for unique interventions. Frequencies of central memory CD4+ T-lymphocytes, one of the main cellular reservoirs of HIV, are very low in the newborn child, so immediate ART could prevent the establishment of persistent viral reservoirs and result in "functional cure." However, as recently demonstrated in the case report of the "Mississippi child" who experienced viral rebound after more than 2 years off ART, additional immunomodulatory strategies might be required for sustained viral suppression after ART cessation. In this review, we discuss the interactions between HIV and the developing immune system in children and the potential implications for therapeutic and prophylactic interventions.
    Frontiers in Immunology 08/2014; 5:391. DOI:10.3389/fimmu.2014.00391
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    • "Cryopreserved peripheral blood mononuclear cells (PBMCs) were tested for IFN-γ responses using T-SPOT.TB, following the manufacturers' instructions on assay procedure and interpretation of results which have been previously described [2]. The methods used for PBMC isolation in this cohort have been previously described [15]. Cells were isolated within 8 hours and were preserved in freezing medium containing 90% fetal calf serum and 10% dimethyl sulfoxide (DMSO) using a temperature rate controlled freezing unit overnight at −80 • C and transferred to liquid nitrogen storage tank within 3 days for long-term storage. "
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    ABSTRACT: We determined the consistency of positive interferon-gamma (IFN-γ) release assays (IGRAs) to detect latent TB infection (LTBI) over one-year postpartum in HIV-1-infected women. Women with positive IGRAs during pregnancy had four 3-monthly postpartum IGRAs. Postpartum change in magnitude of IFN-γ response was determined using linear mixed models. Among 18 women with positive pregnancy IGRA, 15 (83%) had a subsequent positive IGRA; 9 (50%) were always positive, 3 (17%) were always negative, and 6 (33%) fluctuated between positive and negative IGRAs. Women with pregnancy IGRA IFN-γ>8 spot forming cells (SFCs)/well were more likely to have consistent postpartum IGRA response (odds ratio: 10.0; 95% confidence interval (CI): 0.9-117.0). Change in IFN-γ response over postpartum was 10.2 SFCs/well (95% CI: -1.5-21.8 SFCs/well). Pregnancy positive IGRAs were often maintained postpartum with increased consistency in women with higher baseline responses. There were modest increases in magnitude of IGRA responses postpartum.
    Infectious Diseases in Obstetrics and Gynecology 03/2012; 2012:950650. DOI:10.1155/2012/950650
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    • "Since the infants' immune system is immature and developing, the immune responses generated against HIV-1 cannot contain the virus (Tiemessen and Kuhn, 2006). Contrary to HIV-1-infected adults where strong CTL responses are associated with reductions in viremia, HIV-1-infected neonates generate HIV-1-specific CD8 + -T-cell responses early in life that are not clearly associated with reduction in viremia and improved clinical outcomes (Lohman et al., 2005). In contrast to X4 viruses associated with AIDS progression in adults, rapidly progressing HIV-1-infected infants generally harbor viruses of R5 phenotype that is associated with high viral load (Cao et al., 1997). "
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    ABSTRACT: HIV-1 mother-to-child transmission (MTCT) occurs mainly at three stages, including prepartum, intrapartum and postpartum. Several maternal factors, including low CD4+ lymphocyte counts, high viral load, immune response, advanced disease status, smoking and abusing drugs have been implicated in an increased risk of HIV-1 MTCT. While use of antiretroviral therapy (ART) during pregnancy has significantly reduced the rate of MTCT, selective transmission of ART resistant mutants has been reported. Based on HIV-1 sequence comparison, the maternal HIV-1 minor genotypes with R5 phenotypes are predominantly transmitted to their infants and initially maintained in the infants with the same properties. Several HIV-1 structural, regulatory and accessory genes were highly conserved following MTCT. In addition, HIV-1 sequences from non-transmitting mothers are less heterogeneous compared with transmitting mothers, suggesting that a higher level of viral heterogeneity influences MTCT. Analysis of the immunologically relevant epitopes showed that variants evolved to escape the immune response that influenced HIV-1 MTCT. Several cytotoxic T-lymphocyte (CTL) epitopes were identified in various HIV-1 genes that were conserved in HIV-1 mother-infant sequences, suggesting a role in MTCT. We have shown that HIV-1 replicates more efficiently in neonatal T-lymphocytes and monocytes/macrophages compared with adult cells, and this differential replication is influenced at the level of HIV-1 gene expression, which was due to differential expression of host factors, including transcriptional activators, signal transducers and cytokines in neonatal than adult cells. In addition, HIV-1 integration occurs in more actively transcribed genes in neonatal compared with adult cells, which may influence HIV-1 gene expression. The increased HIV-1 gene expression and replication in neonatal target cells contribute to a higher viral load and more rapid disease progression in neonates/infants than adults. These findings may identify targets, viral and host, for developing strategies for HIV-1 prevention and treatment.
    Life sciences 09/2010; 88(21-22):980-6. DOI:10.1016/j.lfs.2010.09.023 · 2.70 Impact Factor
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