Browsing by Author "Naidoo, Shalena"
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- ItemAntibody responses to vaccination among South African HIV-exposed and unexposed uninfected infants during the first 2 years of life(American Society for Microbiology, 2013-01) Reikie, Brian A.; Naidoo, Shalena; Ruck, Candice E.; Slogrove, Amy L.; De Beer, Corena; La Grange, Heleen; Adams, Rozanne C. M.; Ho, Kevin; Smolen, Kinga; Speert, David P.; Cotton, Mark F.; Preiser, Wolfgang; Esser, Monika; Kollmann, Tobias R.HIV-exposed but uninfected (HEU) infants born to HIV-infected mothers from areas in the world with a high burden of infectious disease suffer higher infectious morbidity and mortality than their HIV unexposed uninfected (HUU) peers. Vaccination provides protection from infection. The possibility exists that altered response to vaccination contributes to the higher rate of infection in HEU than in HUU infants. While short-term, cross-sectional studies support this notion, it is unclear whether or not HEU infants develop long-term protective immune responses following theWHOextended program on immunization (EPI). Vaccine-specific antibody responses were compared between HEU and HUU infants from 2 weeks until 2 years of age in a longitudinal South African cohort. Total IgG and antibodies specific for Bordetella pertussis, Haemophilus influenzae type b (Hib), tetanus toxoid, hepatitis B virus (HepB), and measles virus were measured at multiple time points throughout the first 2 years of life. Prevaccine antibodies (maternal antibodies passively acquired) specific for tetanus were lower in HEU than in HUU infants, while prevaccine antibodies to HepB were higher in HEU than in HUU infants. Both groups responded similarly to tetanus, Hib, and HepB vaccination. HEU demonstrated stronger pertussis vaccine responses, developing protective titers 1 year earlier than HUU patients, and maintained higher anti-tetanus titers at 24 months of age. Vaccine-induced antibodies to measles virus were similar in both groups at all time points. Our results suggest that the current EPI vaccination program as practiced in South Africa leads to the development of vaccine-specific antibody responses that are equivalent in HEU and HUU infants. However, our data also suggest that a large fraction of both HEU and HUU South African infants have antibody titers for several infectious threats that remain below the level of protection for much of their first 2 years of life.
- ItemHIV‐1 DNA decay is faster in children who initiate ART shortly after birth than later(International AIDS Society, 2019-08) Veldsman, Kirsten A.; Janse van Rensburg, Anita; Isaacs, Shahieda; Naidoo, Shalena; Laughton, Barbara; Lombard, Carl; Cotton, Mark F.; Mellors, John W.; van Zyl, Gert U.Introduction: There is limited data in children on whether persistence of HIV‐1 infected cells is affected by age at initiating antiretroviral therapy (ART), its duration or any subsequent ART interruption. We therefore investigated the effects of both age of ART initiation and duration of ART interruption on HIV‐1 DNA decay in children. Methods: We investigated HIV‐1 DNA decay in three groups of children on ART: Group‐1 (n = 7) started uninterrupted ART within eight days of life; Group‐2 (n = 8) started uninterrupted ART at a median of five months of age; and Group‐3 (n = 23) started ART at a median age of 1.8 months for either 40 or 96 weeks, then interrupted ART (median of seven months), and restarted ART based on CD4 count and clinical criteria. Total HIV‐1 DNA was assayed using a sensitive HIV‐1 subtype C‐adapted quantitative PCR for integrase. The duration of ART was square root transformed to fit the observed slowing of HIV‐1 DNA decay rate. For each group, point estimates for decay rates were determined after six months of continuous suppressive ART in groups 1 and 2 or six months after restarting ART in Group‐3. Groups‐2 and 3 were combined using a mixed effect regression model to investigate covariates of HIV‐1 DNA decay rate. Results and Discussion: At six months of continuous suppressive ART, the HIV‐1 DNA t½ (95% CI) was shorter in Group‐1 (n = 7): 2.7 months (2.1 to 3.8), than 9.2 months (7.4 to 12.1) in Group‐2 (n = 8); and 9.6 months (7.6 to 12.6) in Group‐3 (n = 23) (p < 0.01). In multivariable analyses, HIV‐1 DNA before treatment (p < 0.001) and the change in HIV‐1 DNA during interruption (p < 0.01) were independent predictors of slower HIV‐1 DNA decay. Conclusions: These data suggest that ART initiation within the first week of life can reduce the persistence of long‐lived infected cells. Delaying ART is associated with slower decay of infected cells.
- ItemLongitudinal investigation of vaccine specific antibody levels and cellular markers of adaptive immune responses in HIV Exposed Uninfected (HEU) and Unexposed (UE) infants(Stellenbosch : Stellenbosch University, 2012-03) Naidoo, Shalena; De Beer, Corena; Esser, Monika; Ipp, Hayley; Stellenbosch University. Faculty of Health Sciences. Dept. of Pathology. Medical Microbiology.ENGLISH ABSTRACT: Background: In South Africa alone, 30% of women of child-bearing age are infected with HIV. With the increasing focus and success of prevention of mother-to-child transmission (PMTCT) programmes, an estimated 300 000 infants are born exposed to HIV every year. The underlying impact of in utero HIV exposure on infant immune health has not been extensively characterised. Clinical follow-up of these HIV-exposed uninfected (HEU) infants reveals increased infectious morbidity and mortality compared to their unexposed (UE) counterparts. Objectives: (i) To evaluate and characterise adaptive immune properties by measuring vaccine-specific antibody levels in children from 2 weeks to 2 years of age in the presence and absence of maternal HIV infection. (ii) To investigate specific cellular markers of immune activation, immune regulation, apoptosis and B cell memory on T and B cell populations in HEU and UE children measured at 18 and 24 months of age. Methods: This sub-investigation formed part of a collaborative pilot study between the universities of British Columbia (Vancouver, Canada) and Stellenbosch. A total of 95 HIV-positive and HIV-negative mothers were recruited after delivery at Tygerberg Hospital, and signed informed consent for their infants to be included in the study. Of these infants, only 27 HEU and 30 UE infants were eventually enrolled and followed up at various time points, starting at two weeks of age. Four of these infants were confirmed to be HIV-positive at 2 weeks and clinically followed up according to the protocol, but were excluded from statistical data analyses. Blood was collected at 2, 6 and 12 weeks and again at 6, 12, 18 and 24 months of age. Quantitative IgG-specific antibodies to Haemophilus influenzae B (Hib), Bordetella pertussis, tetanus and pneumococcus were measured at each time point, using commercially available ELISA (Enzyme-Linked ImmunoSorbent) kits. Cellular markers of immune activation, immune regulation, apoptosis and memory were measured in various populations of T and B cells at 18 and 24 months only, by using four-colour flow cytometry and validated whole-blood staining methods. In addition, a functional assay was developed to evaluate cell susceptibility to apoptosis (spontaneously) by measuring the expression of Annexin V on both CD4+ T and CD20+ B cells after 16 and 24-hour incubation periods. The statistical analysis of the antibody data was conducted by repeated-measures ANOVA (i.e. analysis of variance), using a mixed-model approach. Differences in the expression of the two groups’ cellular markers were compared by employing one-way ANOVA. An F test p value (which assumes normality) was reported, while the non-parametric Mann-Whitney U test served as confirmatory tool. Repeated-measures ANOVA was used for the evaluation of the functional spontaneous apoptosis assay at three time points (ex vivo, 16 and 24 hours) on the 18-month samples, while one-way ANOVA was used for the 24-month samples. Results: The HEU group (n = 23) displayed significantly lower levels of antibodies to pertussis (20.80 vs 28.01 Food and Drug Administration [FDA] U/ml; p = 0.0237), tetanus (0.08 vs 0.53 IU/ml; p < 0.001) and pneumococcus (31.67 vs 80.77 mg/l; p = 0.003) than the UE group (n = 23) at 2 weeks of age. No statistical differences were noted for Hib antibody levels between the two groups at this time point. At 6 weeks of age, HEU infants displayed lower mean levels of all antibodies measured; however, these differences did not reach statistical significance. Following vaccination, compared to UE controls, the HEU group presented with statistically significantly higher antibody levels to pertussis at 6 months (155.49 vs 63.729 FDA U/ml; p = 0.0013), 12 months (26.54 vs 8.50 FDA U/ml; p < 0.001) and 18 months of age (1658.94 vs 793.03 FDA U/ml; p = 0.0362). A significant difference in tetanus antibody levels between the two groups was only evident at 24 months, with the HEU group displaying higher levels (3.28 vs 1.70 IU/ml; p = 0.018) than the UE group. No differences were observed between the two groups following vaccination for Hib. At 18 and 24 months, the HEU group showed increased expression of cellular markers of immune activation (CD69 and CD40L) on CD4+ T cells compared to UE controls. The two groups showed similar expression of the cellular marker of activation CD38 on CD8+ T cells. The HEU group displayed significantly higher levels of CD127, the interleukin (IL) 7 receptor, on CD4+ T cells compared to UE controls at 18 months of age. The HEU group also showed increased expression of cellular markers of apoptosis on both CD4+ T and CD8+ T cells. No statistical significance was noted for the expression of Fas on CD4+ T cells at 18 and 24 months of age. However, at 24 months, the HEU group showed significantly increased expression of FasL on both CD4+ T and CD8+ T cells. During cell culture experiments, the HEU group displayed increased susceptibility to spontaneous apoptosis shown by increased Annexin V expression on CD4+ T cells after a 16-hour incubation period at both 18 and 24 months. At 18 and 24 months, no difference was noted in the two groups’ immune regulation as measured by the expression of CTLA-4. The HEU group displayed increased levels of the cellular markers of immune activation CD80 on CD20+ B cells at 18 and 24 months of age. The HEU group also showed significantly increased levels of CD69 on CD19+ B cells at 24 months. No statistical significance was reached for the expression of CD62L and CD10 at either 18 or 24 months. Although the HEU group displayed increased levels of apoptosis (Fas) on CD20+ B cells, no statistical significance was reached at 18 or 24 months of age. In addition, the HEU group showed no difference in the expression of programmed death 1 (PD-1) at 18 and 24 months. HEU and UE groups showed similar expression of Annexin V after 16 hours of incubation in the 18 and 24-month samples. The expression of the biomarker of B cell memory CD27 on CD20+ B and CD19+ B cells was comparable between the two groups at both time points. Conclusion: At 2 and 6 weeks, lower mean antibody responses in HEU infants suggest poor placental transfer due to maternal HIV infection, while increased responses to specific antibodies may reflect an exaggerated immune response to immunisation. These robust responses may be due to the lack of competition with maternal antibodies, or may be ascribed to indirect stimulation of B cells via the activation of T cells. A hyper-inflammatory state is an imminent danger, with increased expression of cellular markers of immune activation and apoptosis that may be consistent with early HIV exposure that persists following infancy. These observations may serve as contributing factors to the extensively documented increased susceptibility to infections in the HEU population. Although these findings are consistent with a primed immune system, larger studies are required to confirm these observations in relation to clinical outcomes and to assess further whether these differences persist in later years.
- ItemA Longitudinal Perspective on the Impact of Immune Status on the HIV-1 Latent Reservoir and Neurocognitive Outcomes in Virologically Suppressed Children(Stellenbosch : Stellenbosch University, 2022-04) Naidoo, Shalena; Glashoff, Richard; De Beer, Corena; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology.ENGLISH SUMMARY: Background: Children remain the most vulnerable population affected by the Human Immunodeficiency Virus-1 (HIV-1) pandemic whose reliance on lifelong therapy is accompanied by several immune abnormalities. In the absence of an effective vaccine, there is currently a strong emphasis on HIV-1 “cure” and although cART leads to viral suppression the virus is still able to establish latent reservoirs within host cells and this is considered the major barrier to achieving cure. Immune factors are considered critically important for the establishment and maintenance of HIV-1 latent reservoirs, but these factors are not well characterised, particularly in children. Delineating and understanding the immunological mechanisms that drive HIV-1 persistence and other chronic diseases such as metabolic, cardiovascular and neurodegenerative diseases is important in children approaching adolescence. Longitudinal studies evaluating the relationship between immune status, the HIV-1 latent reservoir and neurocognitive outcomes are limited, and inadequately studied, specifically within the South African subtype C context. The aim of this study was to longitudinally investigate and characterise host immune status before and after early initiated, delayed and interrupted cART in relation to HIV-1 latent reservoir size and neurocognitive outcomes in perinatally HIV-1 infected children. Methods: Study participants originated from the well-characterised Children with HIV Early AntiRetroviral Therapy (CHER) randomised controlled trial. This was a descriptive study that employed both a longitudinal (birth to 8 years of age) and cross-sectional study design and analysed samples collected retrospectively and prospectively. For the extensive longitudinal evaluation of immunological biomarker (cytokine, chemokine and receptor antagonist) profiling, we utilised Luminex® Multiplex Assays as well as Enzyme Linked ImmunoSorbent Assays (ELISAs). Multiparameter flow cytometry was utilised for the analysis of monocyte subset distribution. The quantitative viral outgrowth assay (QVOA) was implemented on a subset of participants for measuring of the HIV-1 replication-competent viral reservoir in conjunction with a novel highly sensitive RT-qPCR single copy assay targeted at HIV-1 integrase (iSCA). In addition, HIV-1 cell-associated DNA, specific for integrase (iCAD), were measured longitudinally as a molecular biomarker of HIV-1 persistence and correlated to immune and neurocognitive parameters. Longitudinal neurocognitive assessments were completed independently and correlated to immune, virological and clinical parameters. Age and demographically matched HIV exposed uninfected (HEU) and HIV unexposed uninfected (HUU) were included at the last time point (8 years of age). Key Findings: HIV-1 infected (HIV+) children showed significantly higher levels of biomarkers associated with generalised chronic inflammation, particularly those associated with myeloid cell activation compared to HEU and HUU controls at 8 years of age. These included hsCRP (p=0.01), MIP-1β (p=0.03), IL-1α (p<0.001), INF-α (p<0.001), CD40L (p<0.001), sCD14, sCD163, IL-18, IL-17F (p<0.001) and PDGF-BB (p<0.00001). We also observed a significant elevation of soluble calcium binding alarmin protein involved in the regulation of the inflammatory process and immune response, s100A8/A9, in the HIV+ group compared to the two study control groups (p<0.001). Within the HIV+ group, significant elevation of biomarkers associated with gut epithelial damage was observed at 8 years of age. IL-18 was the only immune biomarker that significantly correlated with HIV-1 CAD at baseline (r = +0.35; p=0.04) and at the 8-year follow-up (r = +0.38; p=0.02) and associated to the innate IL-1 family of immune biomarkers including IL-1RA (r = +0.33; p<0.01), IL-1α (r = +0.22; p<0.01), IL-1β (r = +0.26; p<0.01), and IL-1RA (r = +0.32; p<0.01). IL-18 also significantly correlated with biomarkers of monocyte/macrophage activation and gut damage, including: sCD14 (r = +0.50; p<0.01), sCD163 (r = +0.40; p<0.01), LBP (r = +0.26; p<0.01) and MIP-1β (r = +0.19; p=0.02). IL-18 showed significant negative associations (p<0.01) with CD4 % at baseline, longitudinal CD4 count and CD4:CD8 ratio at 8 years (r = +0.35; p=0.04). For longitudinal cytokine analysis, principal component analysis indicated that about 36% of the soluble biomarkers measured including: IL-15, TNFβ, GCSF, IL-1RA, IL-5, IL-4, IL-8, IL-10 and RANTES contributed to the largest parameter change over time across all treatment groups. The key early clinical predictors of plasma biomarker expression over time include time to therapy initiation, time to viral suppression, longitudinal CD4% and absolute count and CD4 and CD8% and absolute counts at birth. Neurocognitive outcomes can be predicted by early immunological, virological and clinical parameters. Conclusion: By investigating and profiling participants from the CHER randomised control trial cohort, we were able to provide important insights into immunological mechanisms that contribute to driving HIV-1 persistence during long-term suppressive therapy. The findings reported in this thesis have highlighted some key features of immune abnormalities that persists after early initiated long-term ART in paediatric populations. The evaluation of the persistence of any of the key associations through and beyond adolescence will aid in building a lifelong profile of immune changes in the MTCT-infected children. This research also provides important knowledge to further exploring PHIV children as potential “cure” and remission candidates.
- ItemNeurodevelopment at 11 months after starting antiretroviral therapy within 3 weeks of life(AOSIS, 2019-10-03) Laughton, Barbara; Naidoo, Shalena; Dobbels, Els; Boivin, Michael J.; Janse van Rensburg, Anita; Glashoff, Richard H.; Van Zyl, Gert U.; Kruger, Mariana; Cotton, Mark F.Background: Antiretroviral therapy (ART) started between 7 and 12 weeks of age improves neurodevelopmental outcomes in HIV-infected (HIV+) infants, but the impact of even earlier initiation is not yet described. Objectives: We assessed the early neurodevelopment of HIV+ infants who started ART within 21 days of life. Method: Participants were enrolled from the public sector birth HIV-diagnosis programme. Inclusion criteria included the following: birth weight > 2000 g, infant commencing ART < 6 weeks and no infant cytomegalovirus disease. Antiretroviral therapy included Zidovudine/Lamivudine/Nevirapine for the first 2 weeks, the latter then replaced by Lopinavir/Ritonavir. Once body weight > 3 kg and gestational age > 44 weeks, Abacavir replaced Zidovudine. The Griffiths mental development scales (GMDS) were administered at 10–12 months. Results: Of 29 infants assessed, 23 (79%) were girls. Mean birth weight was 3002 ± 501 g. Twenty-four mothers (83%) received ART during pregnancy. Seven (24%) infants were diagnosed HIV+ within 48 h of birth. Median [interquartile range] viral load (VL) at diagnosis was 3904 [259–16 922] copies/mL, age starting ART was 6.0 [3–10] days and age at VL suppression was 19.1 [15–36] weeks. At the GMDS assessment, nine (31%) participants had detectable VL and 26 (90%) had World Health Organization (WHO) clinical stage I disease. The GMDS was performed at a mean age of 11.5 ± 0.8 months. Mean quotients were within the average range: Global Griffiths score was 103.6 ± 10.9 and mean quotients on the subscales ranged from lowest 95.9 ± 13.4 for locomotor to highest 112.8 ± 11.3 for hearing-and-language. Conclusion: Preliminary findings in this small group suggest that early neurodevelopmental scores are within the normal range in infants with perinatal HIV infection who started ART at a median of 6 days.
- ItemOntogeny of toll-like receptor mediated cytokine responses of South African infants throughout the first year of life(Public Library of Science, 2012-09-13) Reikie, Brian A.; Adams, Rozanne C. M.; Ruck, Candice E.; Ho, Kevin; Leligdowicz, Aleksandra; Pillay, Santoshan; Naidoo, Shalena; Fortuno III, Edgardo S.; De Beer, Corena; Preiser, Wolfgang; Cotton, Mark F.; Speert, David P.; Esser, Monika; Kollmann, Tobias R.The first year of life represents a time of marked susceptibility to infections; this is particularly true for regions in sub-Saharan Africa. As innate immunity directs the adaptive immune response, the observed increased risk for infection as well as a suboptimal response to vaccination in early life may be due to less effective innate immune function. In this study, we followed a longitudinal cohort of infants born and raised in South Africa over the first year of life, employing the most comprehensive analysis of innate immune response to stimulation published to date. Our findings reveal rapid changes in innate immune development over the first year of life. This is the first report depicting dramatic differences in innate immune ontogeny between different populations in the world, with important implications for global vaccination strategies.