TNFAIP3-interacting protein 1 polymorphisms and their association with symptomatic human respiratory syncytial virus infection and bronchiolitis in infants younger than one year from South Africa: A case-control study

Objectives: This study analyzed the association of TNFAIP3-interacting protein 1 (TNIP1) polymorphisms with the symptomatic human respiratory syncytial virus (HRSV) infection and bronchiolitis in infants. Methods: A case-control study was conducted involving 129 hospitalized infants with symptomatic HRSV infection (case group) and 161 healthy infants (control group) in South Africa (2016-2018). Six TNIP1 polymorphisms (rs869976, rs4958881, rs73272842, rs3792783, rs17728338, and rs999011) were genotyped. Genetic associations were evaluated using logistic regression adjusted by age and gender. Results: Both rs73272842 G and rs999011 C alleles were associated with reduced odds for symptomatic HRSV infection (adjusted odd ratio [aOR] = 0.68 [95% confidence interval {CI} = 0.48-0.96] and aOR = 0.36 [95% CI = 0.19-0.68], respectively] and bronchiolitis (aOR = 0.71 [95% CI = 0.50-1.00] and aOR = 0.38 [95% CI = 0.22-0.66], respectively). The significance of these associations was validated using the BCa Bootstrap method (P <0.05). The haplotype GC (composed of rs73272842 and rs999011) was associated with reduced odds of symptomatic HRSV infection (aOR = 0.53 [95% CI = 0.37-0.77]) and bronchiolitis (aOR = 0.62 [95% CI = 0.46-0.84]), which were validated by the BCa Bootstrap method (P = 0.002 for both). Conclusion: TNIP1 rs73272842 G allele and rs999011 C allele were associated with reduced odds of symptomatic HRSV infection and the development of bronchiolitis in infants, suggesting that TNIP1 polymorphisms could impact susceptibility to HRSV illness.The study was funded by Poliomyelitis Research Foundation (grant # 19/27 to FKT), South Africa. The study was also funded by the CIBER -Consorcio Centro de Investigación Biomédica en Red- (CB 2021), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea – NextGenerationEU (grant #CB21/13/00044 to SR).S

Adaptive changes in HIV-1 subtype C proteins during early infection are driven by changes in HLA-associated immune pressure

It is unresolved whether recently transmitted human immunodeficiency viruses (HIV) have genetic features that specifically favour their transmissibility. To identify potential "transmission signatures", we compared 20 full-length HIV-1 subtype C genomes from primary infections, with 66 sampled from ethnically and geographically matched individuals with chronic infections. Controlling for recombination and phylogenetic relatedness, we identified 39 sites at which amino acid frequency spectra differed significantly between groups. These sites were predominantly located within Env, Pol and Gag (14/39, 9/39 and 6/39 respectively) and were significantly clustered (33/39) within known immunoreactive peptides. Within 6 months of infection, we detected reversion-to-consensus mutations at 14 sites and potential CTL escape mutations at seven. Here we provide evidence that frequent reversion mutations probably allows the virus to recover replicative fitness which, together with immune escape driven by the HLA alleles of the new hosts, differentiate sequences from chronic infections from those sampled shortly after transmission

Enterovirus D68 and other enterovirus serotypes identified in South African patients with severe acute respiratory illness, 2009-2011

BACKGROUND : Human enteroviruses (EV) have been associated with severe acute respiratory illness (SARI) in South Africa. OBJECTIVES : We aimed to describe the molecular epidemiology of EV serotypes among patients hospitalized with SARI during 2009-2011. PATIENTS/METHODS : Study samples from patients were tested for the presence of enterovirus using a polymerase chain reaction assay. RESULTS : 8.2% (842/10 260) of SARI cases tested positive for enterovirus; 16% (7/45) were species EV-A, 44% (20/45) EV-B, 18% (8/45) EV-C and 22% (10/45) EV-D. Seventeen different EV serotypes were identified within EV-A to EV-D, of which EV-D68 (22%; 10/45) and Echovirus 3 (11%; 5/45) were the most prevalent. CONCLUSIONS : EV-D68 should be monitored in South Africa to assess the emergence of highly pathogenic strains.The United States Centers for Disease Control and Prevention, Atlanta, Georgia, USA (co-operative agreement number: 5U51IP000155).http://www.wileyonlinelibrary.com/journal/irvhttp://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1750-2659am2018Medical Virolog

The role of influenza, RSV and other common respiratory viruses in severe acute respiratory infections and influenza-like illness in a population with a high HIV sero-prevalence, South Africa, 2012-2015

BACKGROUND : Viruses detected in patients with acute respiratory infections may be the cause of illness or colonizers. METHODS : We compared the prevalence of 10 common respiratory viruses (influenza A and B viruses, parainfluenza virus 1, 2, and 3; respiratory syncytial virus (RSV); adenovirus, rhinovirus, human metapneumovirus (hMPV) and enterovirus) in patients hospitalized with severe acute respiratory illness (SARI), outpatients with influenza-like illness (ILI), and control subjects who did not report any febrile, respiratory or gastrointestinal illness during 2012-2015 in South Africa. We estimated the attributable fraction (AF) and the detection rate attributable to illness for each of the different respiratory viruses. RESULTS : We enrolled 1959 SARI, 3784 ILI and 1793 controls. Influenza virus (AF: 86.3%; 95%CI: 77.7%-91.6%), hMPV (AF: 85.6%%; 95%CI: 72.0%-92.6%), and RSV (AF: 83.7%; 95%CI: 77.5%-88.2%) infections were highly associated with severe disease, while rhinovirus (AF: 46.9%; 95%CI: 37.6%-56.5%) and adenovirus (AF: 36.4%; 95%CI: 20.6%-49.0%) were only moderately associated. The estimated detection rate associated with severe disease was: 20.2% for rhinovirus, 16.7% for RSV, 7.0% for adenovirus, 4.9% for influenza virus and 3.8% for hMPV. Similar patterns were observed for patients with ILI. CONCLUSIONS : Influenza, RSV and hMPV can be considered likely pathogens if detected in patients with ILI and SARI while rhinovirus and adenovirus were commonly identified also among controls suggesting that they may cause only a proportion of clinical disease observed in positive patients. Nonetheless, given their high estimated detection rate attributable to illness, they may be important contributors to disease.Co-operative agreement 5U51/IP000155 with the Centers for Disease Control and Prevention, Atlanta, Georgia, USA.http://www.elsevier.com/locate/jcv2017-02-28hb2016Medical Virolog

Development of a respiratory severity score for hospitalized adults in a high HIV-prevalence setting—South Africa, 2010-2011

BACKGROUND : Acute lower respiratory tract infections (LRTI) are a frequent cause of hospitalization and mortality in South Africa; however, existing respiratory severity scores may underestimate mortality risk in HIV-infected adults in resource limited settings. A simple predictive clinical score for low-resource settings could aid healthcare providers in the management of patients hospitalized with LRTI. METHODS : We analyzed 1,356 LRTI hospitalizations in adults aged ≥18 years enrolled in Severe Acute Respiratory Illness (SARI) surveillance in three South African hospitals from January 2010 to December 2011. Using demographic and clinical data at admission, we evaluated potential risk factors for in-hospital mortality. We evaluated three existing respiratory severity scores, CURB-65, CRB-65, and Classification Tree Analysis (CTA) Score assessing for discrimination and calibration. We then developed a new respiratory severity score using a multivariable logistic regression model for in-hospital mortality and assigned points to risk factors based on the coefficients in the multivariable model. Finally we evaluated the model statistically using bootstrap resampling techniques. RESULTS : Of the 1,356 patients hospitalized with LRTI, 101 (7.4%) died while hospitalized. The CURB-65, CRB-65, and CTA scores had poor calibration and demonstrated low discrimination with c-statistics of 0.594, 0.548, and 0.569 respectively. Significant risk factors for in-hospital mortality included age ≥ 45 years (A), confusion on admission (C), HIV-infection (H), and serum blood urea nitrogen >7 mmol/L (U), which were used to create the seven-point ACHU clinical predictor score. In-hospital mortality, stratified by ACHU score was: score ≤1, 2.4%, score 2, 6.4%, score 3, 11. 9%, and score ≥ 4, 29.3%. Final models showed good discrimination (c-statistic 0.789) and calibration (chi-square 1.6, Hosmer-Lemeshow goodness-of-fit p-value = 0.904) and discriminated well in the bootstrap sample (average optimism of 0.003). CONCLUSIONS : Existing clinical predictive scores underestimated mortality in a low resource setting with a high HIV burden. The ACHU score incorporates a simple set a risk factors that can accurately stratify patients ≥18 years of age with LRTI by in-hospital mortality risk. This score can quantify in-hospital mortality risk in an HIV-endemic, resource-limited setting with limited clinical information and if used to facilitate timely treatment may improve clinical outcomes.Additional file 1: BMC Pulmonary_Severity Score Data.xlsx. Severity Score Dataset. Dataset generated and used for analysis and creation of the ACHU score. Two tabs are included 1) includes the data used for the analysis 2) includes important notes related to the analytical methods and definitions for several composite variables.Additional file 2: Table S1. CURB-65, CRB-65, Classification Tree Analysis (CTA) severity scores. Table S2. Predicted and observed risk of mortality based on CURB-65, CRB-65, Classification Tree Analysis (CTA), and CURB-45 severity scores among hospitalized adults with lower respiratory tract infections, South Africa, 2010–2011. Table S3. Predicted and observed risk of mortality based by ACHU (Age, confusion, HIV, urea) respiratory severity score among hospitalized adults with lower respiratory tract infections, South Africa, 2010–2011.The Centers for Disease Control and Preventionhttp://www.biomedcentral.com/bmccom/plementalternmedam2017Medical Virolog

Genetic diversity and molecular epidemiology of human rhinoviruses in South Africa

BACKGROUND Rhinoviruses (RV) are a well-established cause of respiratory illness. RV-C has been associated with more severe illness. We aimed to characterize and compare the clinical presentations and disease severity of different RV type circulating in South Africa. METHOD We performed two analyses of RV-positive specimens identified through surveillance in South Africa across all age groups. First, RV-positive specimens identified through severe acute respiratory illness (SARI) surveillance in four provinces was randomly selected from 2009 to 2010 for molecular characterization. Second, RV-positive specimens identified through SARI, influenzalike illness (ILI) and control surveillance at hospitals and outpatient clinics in during 2012–2013 were used to determine the association of RV type with severe disease. Selected specimens were sequenced, and phylogenetic analysis was performed. RESULTS Among the 599 sequenced specimens from 2009 to 2010 and 2012 to 2013, RV-A (285, 48%) and RV-C (247, 41%) were more commonly identified than RV-B (67, 11%), with no seasonality and a high genetic diversity. A higher prevalence of RV infection was identified in cases with SARI [515/962 (26%); aRRR = 1 6; 95% CI 1 21; 2 2] and ILI [356/962 (28%); aRRR = 1 9; 95% CI 1 37; 2 6] compared with asymptomatic controls (91/962, 22%). There was no difference in disease severity between the different type when comparing SARI, ILI and controls. CONCLUSION All three type of RV were identified in South Africa, although RV-A and RV-C were more common than RV-B. RV was associated with symptomatic respiratory illness; however, there was no association between RV type and disease severity.http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1750-2659http://www.influenzajournal.comam201

The performance of different case definitions for severe influenza surveillance among HIV-infected and HIV-uninfected children aged <5 years in South Africa, 2011–2015

In 2014, the World Health Organization (WHO) proposed a new severe influenza surveillance case definition, which has not been evaluated in a high human immunodeficiency virus (HIV) prevalence setting. Our study aimed to assess the performance of this proposed case definition in identifying influenza among HIV-uninfected and HIV-infected children aged <5 years in South Africa. We prospectively enrolled children aged <5 years hospitalised with physician-diagnosed lower respiratory tract infection (LRTI) at two surveillance sites from January 2011 to December 2015. Epidemiologic and clinical data were collected. We tested nasopharyngeal aspirates for influenza using reverse transcription polymerase chain reaction. We used logistic regression to assess factors associated with influenza positivity among HIV-infected and HIV-uninfected children. We calculated sensitivity and specificity for different signs and symptoms and combinations of these for laboratory-confirmed influenza. We enrolled 2,582 children <5 years of age with LRTI of whom 87% (2,257) had influenza and HIV results, of these 14% (318) were HIV-infected. The influenza detection rate was 5% (104/1,939) in HIV-uninfected and 5% (16/318) in HIV-infected children. Children with measured fever (≥38°C) were two times more likely to test positive for influenza than those without measured fever among the HIV-uninfected (OR 2.2, 95% Confidence Interval (CI) 1.5–3.4; p<0.001). No significant association was observed between fever and influenza infection among HIV-infected children. Cough alone had sensitivity of 95% (95% CI 89–98%) in HIV-uninfected and of 100% (95% CI 79–100%) in HIV-infected children but low specificity: 7% (95% CI 6–8%) and 6% (95% CI 3–9%) in HIV-uninfected and HIV-infected children, respectively. The WHO post-2014 case definition for severe acute respiratory illness (SARI—an acute respiratory infection with history of fever or measured fever of ≥ 38°C and cough; with onset within the last ten days and requires hospitalization), had a sensitivity of 66% (95% CI 56–76%) and specificity of 46% (95% CI 44–48%) among HIV-uninfected and a sensitivity of 63% (95% CI 35–84%) and a specificity of 42% (95% CI 36–48%) among HIV-infected children. The sensitivity and specificity of the WHO post-2014 case definition for SARI were similar among HIV-uninfected and HIV-infected children. Our findings support the adoption of the 2014 WHO case definition for children aged <5 years irrespective of HIV infection status.MassGenicshttps://journals.plos.org/plosonehj2020School of Health Systems and Public Health (SHSPH

Rapid, complex adaption of transmitted HIV-1 full-length genomes in subtype C-infected individuals with differing disease progression.

CAPRISA 2013.Objective(s): There is limited information on full-length genome sequences and the early evolution of transmitted HIV-1 subtype C viruses, which constitute the majority of viruses spread in Africa. The purpose of this study was to characterize the earliest changes across the genome of subtype C viruses following transmission, to better understand early control of viremia. Design: We derived the near full-length genome sequence responsible for clinical infection from five HIV subtype C-infected individuals with different disease progression profiles and tracked adaptation to immune responses in the first 6 months of infection. Methods: Near full-length genomes were generated by single genome amplification and direct sequencing. Sequences were analyzed for amino acid mutations associated with cytotoxic T lymphocyte (CTL) or antibody-mediated immune pressure, and for reversion. Results: Fifty-five sequence changes associated with adaptation to the new host were identified, with 38% attributed to CTL pressure, 35% to antibody pressure, 16% to reversions and the remainder were unclassified. Mutations in CTL epitopes were most frequent in the first 5 weeks of infection, with the frequency declining over time with the decline in viral load. CTL escape predominantly occurred in nef, followed by pol and env. Shuffling/toggling of mutations was identified in 81% of CTL epitopes, with only 7% reaching fixation within the 6-month period. Conclusion: There was rapid virus adaptation following transmission, predominantly driven by CTL pressure, with most changes occurring during high viremia. Rapid escape and complex escape pathways provide further challenges for vaccine protection

Transmission of HIV-1 CTL escape variants provides HLA - mismatched recipients with a survival advantage.

One of the most important genetic factors known to affect the rate of disease progression in HIV-infected individuals is the genotype at the Class I Human Leukocyte Antigen (HLA) locus, which determines the HIV peptides targeted by cytotoxic T-lymphocytes (CTLs). Individuals with HLA-B*57 or B*5801 alleles, for example, target functionally important parts of the Gag protein. Mutants that escape these CTL responses may have lower fitness than the wild-type and can be associated with slower disease progression. Transmission of the escape variant to individuals without these HLA alleles is associated with rapid reversion to wild-type. However, the question of whether infection with an escape mutant offers an advantage to newly infected hosts has not been addressed. Here we investigate the relationship between the genotypes of transmitted viruses and prognostic markers of disease progression and show that infection with HLA-B*57/B*5801 escape mutants is associated with lower viral load and higher CD4+ counts

Increased memory differentiation is associated with decreased polyfunctionality for HIV but not for CMV-specific CD8+ T cells.

The generation of polyfunctional CD8+ T cells, in response to vaccination or natural infection, has been associated with improved protective immunity. However, it is unclear whether the maintenance of polyfunctionality is related to particular cellular phenotypic characteristics. To determine whether the cytokine expression profile is linked to the memory differentiation stage, we analyzed the degree of polyfunctionality of HIV-specific CD8+ T cells within different memory subpopulations in 20 antiretroviral therapy-naive HIV-1–infected individuals at ∼34 wk postinfection. These profiles were compared with CMV-specific CD8+ T cell responses in HIV-uninfected control subjects and in individuals chronically infected with HIV. Our results showed that the polyfunctional abilities of HIV-specific CD8+ T cells differed according to their memory phenotype. Early-differentiated cells (CD45RO+CD27+) exhibited a higher proportion of cells positive for three or four functions (p < 0.001), and a lower proportion of monofunctional cells (p < 0.001) compared with terminally differentiated (TD; CD45RO-CD27-) HIV-specific CD8+ T cells. The majority of TD HIV-specific CD8+ T cells were monofunctional (median 69% [interquartile range: 57–83]), producing predominantly CD107a or MIP1b. Moreover, proportions of HIV-specific monofunctional CD8+ T cells positively associated with proportions of TD HIV-specific CD8+ T cells (p = 0.019, r = 0.54). In contrast, CMV-specific CD8+ T cell polyfunctional capacities were similar across all memory subpopulations, with terminally and early-differentiated cells endowed with comparable polyfunctionality. Overall, these data show that the polyfunctional abilities of HIV-specific CD8+ T cells are influenced by the stage of memory differentiation, which is not the case for CMV-specific responses