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Use of an Indeterminate Range in HIV Early Infant Diagnosis: A Systematic Review and Meta-Analysis

J Acquir Immune Defic Syndr

2019 Fong, Youyi, PhD Youyi Fong

BACKGROUND: Expanded access to HIV antiretrovirals has dramatically reduced mother-to-child transmission of HIV. However, there is increasing concern around false-positive HIV test results in perinatally HIV-exposed infants but few insights into the use of indeterminate range to improve infant HIV diagnosis. METHODS: A systematic review and meta-analysis was conducted to evaluate the use of an indeterminate range for HIV early infant diagnosis. Published and unpublished studies from 2000 to 2018 were included. Study quality was evaluated using GRADE and QUADAS-2 criteria. A random-effects model compared various indeterminate ranges for identifying true and false positives. RESULTS: The review identified 32 studies with data from over 1.3 million infants across 14 countries published from 2000 to 2018. Indeterminate results accounted for 16.5% of initial non-negative test results, and 76% of indeterminate results were negative on repeat testing. Most results were from Roche tests. In the random-effects model, an indeterminate range using a polymerase chain reaction cycle threshold value of 33 captured over 93% of false positives while classifying fewer than 9% of true positives as indeterminate. CONCLUSIONS: Without the use of an indeterminate range, over 10% of infants could be incorrectly diagnosed as HIV positive if their initial test results are not confirmed. Use of an indeterminate range appears to lead to substantial improvements in the accuracy of early infant diagnosis testing and supports current recommendations to confirm all initial positive tests.

Inherited chromosomally integrated HHV-6 demonstrates tissue-specific RNA expression in vivo that correlates with increased antibody immune response

J Virol

2019 Jerome, Keith R, MD, PhD Keith Jerome

Human herpesvirus-6A and 6B (HHV-6A, HHV-6B) are human viruses capable of chromosomal integration. Approximately 1% of the human population carry one copy of HHV-6A/B integrated into every cell in their body, referred to as inherited chromosomally integrated human herpesvirus 6A/B (iciHHV-6A/B). Whether iciHHV-6A/B is transcriptionally active in vivo and how it shapes the immunological response is still unclear. Here, we screened DNA-Seq and RNA-Seq data for 650 individuals available through the Genotype-Tissue Expression (GTEx) project and identified 2 iciHHV-6A and 4 iciHHV-6B positive candidates. When corresponding tissue-specific gene expression signatures were analyzed, low levels HHV-6A/B gene expression was found across multiple tissues, with the highest levels of gene expression in the brain (specifically for HHV-6A), testis, esophagus, and adrenal gland. U90 and U100 were the most highly expressed HHV-6 genes in both iciHHV-6A and iciHHV-6B individuals. To assess whether tissue-specific gene expression from iciHHV-6A/B influences the immune response, a cohort of 15,498 subjects was screened and 85 iciHHV-6A/B+ subjects were identified. Plasma samples from iciHHV-6A/B+ and age and sex matched controls were analyzed for antibodies to control antigens (CMV, EBV, FLU) or HHV-6A/B antigens. Our results indicate that iciHHV-6A/B+ subjects have significantly more antibodies against the U90 gene product (IE1) relative to non-iciHHV-6 individuals. Antibody responses against EBV and FLU antigens or HHV-6A/B gene products either not expressed or expressed at low levels, such as U47, U57 or U72, were identical between controls and iciHHV-6A/B+ subjects. CMV seropositive individuals with iciHHV-6A/B+ have more antibodies against CMV pp150, relative to CMV seropositive controls. These results argue that spontaneous gene expression from integrated HHV-6A/B leads to an increase in antigenic burden that translates into a more robust HHV-6A/B specific antibody response.IMPORTANCE HHV-6A/B are human herpesviruses that have the unique property of being able to integrate into the telomeric regions of human chromosomes. Approximately 1% of the world's population carries integrated HHV-6A/B genome in every cell of their body. Whether viral genes are transcriptionally active in these individuals is unclear. By taking advantage of a unique tissue-specific gene expression dataset, we show the majority of tissues from iciHHV-6 individuals do not show HHV-6 gene expression. Brain and testes showed the highest tissue-specific expression of HHV-6 genes in two separate datasets. Two HHV-6 genes, U90 (immediate early 1 protein) and U100 (glycoproteins Q1 and Q2), were found to be selectively and consistently expressed across several human tissues. Expression of U90 translates into an increase in antigen-specific antibody response in iciHHV-6A/B+ subjects relative to controls. Future studies will be needed to determine the mechanism of gene expression, the effects of these genes on human gene transcription networks and the pathophysiological impact of having increased viral protein expression in tissue in conjunction with increased antigen-specific antibody production.

Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk

J Clin Invest

2019 Young, William C Youyi Fong

HVTN 505 is a preventative vaccine efficacy trial testing DNA followed by recombinant adenovirus serotype 5 (rAd5) in circumcised, Ad5-seronegative men and transgendered persons who have sex with men in the United States. Identified immune correlates of lower HIV-1 risk and a virus sieve analysis revealed that, despite lacking overall efficacy, vaccine-elicited responses exerted pressure on infecting HIV-1 viruses. To interrogate the mechanism of the antibody correlate of HIV-1 risk, we examined antigen-specific antibody recruitment of Fcγ receptors (FcγRs), antibody-dependent cellular phagocytosis (ADCP), and the role of anti-envelope (anti-Env) IgG3. In a prespecified immune correlates analysis, antibody-dependent monocyte phagocytosis and antibody binding to FcγRIIa correlated with decreased HIV-1 risk. Follow-up analyses revealed that anti-Env IgG3 breadth correlated with reduced HIV-1 risk, anti-Env IgA negatively modified infection risk by Fc effector functions, and that vaccine recipients with a specific FcγRIIa single-nucleotide polymorphism locus had a stronger correlation with decreased HIV-1 risk when ADCP, Env-FcγRIIa, and IgG3 binding were high. Additionally, FcγRIIa engagement correlated with decreased viral load setpoint in vaccine recipients who acquired HIV-1. These data support a role for vaccine-elicited anti-HIV-1 Env IgG3, antibody engagement of FcRs, and phagocytosis as potential mechanisms for HIV-1 prevention.

Immunoglobulin M, more than just an early responder to malaria

Immunology and cell biology

2019 Taylor, Justin J, PhD Justin Taylor


The Brief Case: Inherited Chromosomally Integrated Human Herpesvirus 6 (HHV-6) in the Age of Multiplex HHV-6 Testing

Journal of clinical microbiology

2019 Jerome, Keith R, MD, PhD Keith Jerome


Closing the Brief Case: Inherited Chromosomally Integrated Human Herpesvirus 6 (HHV-6) in the Age of Multiplex HHV-6 Testing

Journal of clinical microbiology

2019 Jerome, Keith R, MD, PhD Keith Jerome


Human herpesvirus 6 in transplant recipients: an update on diagnostic and treatment strategies

Curr Opin Infect Dis

2019 Hill, Joshua A, MD Joshua Hill

PURPOSE OF REVIEW: The current review article focuses on recent advances in the approach to the diagnosis and treatment of human herpesvirus 6B (HHV-6B) in hematopoietic cell and solid organ transplant recipients. RECENT FINDINGS: Over the past few years, key studies have broadened our understanding of best practices for the prevention and treatment of HHV-6B encephalitis after transplantation. Moreover, important data have been reported that support a potential role of HHV-6B reactivation in the development of acute graft-versus-host disease and lower respiratory tract disease in transplant recipients. Finally, increasing recognition of inherited chromosomally integrated HHV-6 (iciHHV-6) and an expanding array of diagnostic tools have increased our understanding of the potential for complications related to viral reactivation originating from iciHHV-6 in donors or recipients. SUMMARY: Recent advances in diagnostic tools, disease associations, and potential treatments for HHV-6B present abundant opportunities for improving our understanding and management of this complex virus in transplant recipients.

Multilevel Measures of Education and Pathways to Incident Herpes Simplex Virus Type 2 in Adolescent Girls and Young Women in South Africa

J Adolesc Health

2019 Hughes, James P, PhD Jim Hughes

PURPOSE: Schooling is associated with a lower risk of Herpes simplex virus type 2 (HSV-2) in adolescent girls and young women, but there is little understanding of the pathways underlying this relationship. METHODS: We used data from adolescent girls and young women in South Africa enrolled in the HIV Prevention Trials Network 068 study. We tested a structural equation model where individual household and community education measures were associated directly and indirectly with incident HSV-2 through HIV knowledge, future aspirations, age-disparate partnerships, sex in the last 12months, and condomless sex. RESULTS: Community, household, and individual measures of schooling were all associated with incident HSV-2 infection through mediated pathways that increased the likelihood of having sex. Low school attendance (<80% of school days) increased the likelihood of having sex through increased age-disparate partnerships and reduced future aspirations. Fewer community years of education increased the likelihood of having sex through increased age-disparate partnerships. Parental education level was indirectly associated with HSV-2 overall, although we could not identify the individual pathways that were responsible for this association. CONCLUSIONS: Community and individual schooling interventions may reduce the risk of HSV-2 infection by influencing the likelihood of having sex, partner age, and future aspirations.

FliC's Hypervariable D3 Domain Is Required for Robust Anti-Flagellin Primary Antibody Responses


2019 Strong, Roland K, PhD Roland K Strong

Bacterial flagellin is a well-known agonist of the innate immune system that induces proinflammatory responses through the TLR5 and Naip5/6 recognition pathways. Several clinical trials investigating flagellin fusion proteins have demonstrated promising results for inducing protective immunity toward influenza virus, which has been largely attributed to flagellin's ability to activate TLR5. Our laboratory previously demonstrated that the Salmonella enterica serovar Typhimurium flagellin protein, FliC, induces Ab responses in mice through a third pathway that is independent of TLR5, Casp1/11, and MyD88. In this study, we further define the structural features of FliC that contribute to this unknown third pathway. By destroying the Naip5/6 and TLR5 recognition sites, we demonstrate that neither were required for the TLR5-, inflammasome- and MyD88-independent Ab responses toward FliC. In contrast, deletion of FliC's D3 or D0/D1 domains eliminated primary anti-flagellin Ab responses. For optimal primary and secondary anti-flagellin Ab responses we show that TLR5, inflammasome recognition, and the D3 domain of FliC are essential for flagellin's robust immunogenicity. Our data demonstrate that the D3 domain of FliC influences immunogenicity independent of the known innate recognition sites in the D0/D1 domains to augment Ab production. Our results suggest full-length FliC is critical for optimal immunogenicity and Ab responses in flagellin-based vaccines.

Guidelines from the 2017 European Conference on Infections in Leukaemia for management of HHV-6 infection in patients with hematological malignancies and after hematopoietic stem cell transplantation


2019 Hill, Joshua A, MD Joshua Hill

HHV-6B encephalitis is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant. Guidelines for the management of HHV-6 infections in patients with hematological malignancies or post-transplant were prepared a decade ago but there have been no other guidelines since then despite significant advances in the understanding of HHV-6 encephalitis, its therapy, and other aspects of HHV-6 disease in this patient population. Revised guidelines prepared at the 2017 European Conference on Infections in Leukaemia covering diagnosis, preventative strategies and management of HHV-6 disease are now presented.