Diversity and Tropism of HIV-1 Plasma Rebound Virus After Treatment Discontinuation

Modern antiretroviral therapies can confer effective suppression of HIV-1 infection. However, HIV-infected people discontinuing antiretroviral therapy experience a rebound of virus from a persistent reservoir. Characterizing this reservoir constitutes a crucial step towards developing a cure, and we hypothesized that assessing the diversity and tropism of rebound virus would provide insight into the types of cells that likely house the viral reservoir as well as reservoir diversity. We examined 10 rebound samples from a project within the large-scale AIDS Clinical Trials Group and used single genome amplification and Primer ID deep sequencing to assess the genetic diversity of the env gene, which encodes the HIV-1 envelope protein, among rebounding virus. Samples from the same patients with viral suppression due to antiretroviral therapy were also available. Most rebound virus populations showed significant diversity. All env genes examined were isoforms that would require cells to express high surface levels of the CD4 receptor for entry, consistent with the current hypothesis that virus is selectively replicated in CD4+ T cells. These results indicate that most people discontinuing therapy release a diverse population of virus, and this released virus targets CD4+ T cells rather than myeloid cells, which tend to last longer. Research indicates that a small proportion of viruses have evolved to efficiently enter myeloid cells. Current HIV-1 cure strategies focus on reactivating latent HIV-1 and targeting the resultant virus. It is essential to understand the features of rebound viruses because they are the first such targets.Bachelor of Science in Public Healt

Assessing Factors Associated with Option B+ Initiation, Retention, and Infant Follow Up in Lilongwe, Malawi

Background: Malawi launched Option B+ in July 2011, a program for all pregnant or breastfeeding HIV-positive women to begin lifelong combination antiretroviral therapy (cART). This study characterizes the continuum of care within an antenatal setting in Lilongwe. Methods: Women testing HIV-positive at Bwaila Antenatal Clinic from July 2013 to January 2014 were included. HIV testing and counseling logs were examined, and HIV-infected women were linked to HIV mastercards and infant test records. Logistic regression models were used to analyze relationships between characteristics recorded on the logs and maternal cART initiation, retention, and return for infant testing. Results: During this period, 578 women tested HIV-positive. Of these women, 490 (85%) were linked to an ART initiation record; of these women, 398 (81%) had at least one follow-up record; and of these women, 197 (49%) were retained with full adherence to antiretroviral therapy for three months. Two hundred twenty (38%) were linked to a record of infant testing. Women without an ART record (aOR = 0.19; 95% CI: 0.10, 0.35), women with no follow-up visits (aOR = 0.20; 95% CI: 0.11, 0.36), and women not fully adherent for three months (aOR = 0.56; 95% CI: 0.37, 0.84) were less likely to return for infant testing than women who were retained and adherent for three months. Discussion: Even with a test-and-treat program, many women did not initiate cART, remain in care, or bring their infant for testing. Women lost are at highest risk for transmission and were least likely to bring infants for testing. Facilitating care-seeking at all steps of the continuum remains an important unmet need. Ensuring maternal health has the potential to make major contributions towards maintaining environmental health, thus augmenting the importance of this research.Bachelor of Science in Public Healt

The effect of HIV counselling and testing on HIV acquisition in sub-Saharan Africa: a systematic review

Annually, millions of people in sub-Saharan Africa (SSA) receive HIV counselling and testing (HCT), a service designed to inform persons of their HIV status and, if HIV-uninfected, reduce HIV acquisition risk. However, the impact of HCT on HIV acquisition has not been systematically evaluated. We conducted a systematic review to assess this relationship in SSA

Deep Sequencing of the HIV-1 env Gene Reveals Discrete X4 Lineages and Linkage Disequilibrium between X4 and R5 Viruses in the V1/V2 and V3 Variable Regions

ABSTRACT HIV-1 requires the CD4 receptor and a coreceptor (CCR5 [R5 phenotype] or CXCR4 [X4 phenotype]) to enter cells. Coreceptor tropism can be assessed by either phenotypic or genotypic analysis, the latter using bioinformatics algorithms to predict tropism based on the env V3 sequence. We used the Primer ID sequencing strategy with the MiSeq sequencing platform to reveal the structure of viral populations in the V1/V2 and C2/V3 regions of the HIV-1 env gene in 30 late-stage and 6 early-stage subjects. We also used endpoint dilution PCR followed by cloning of env genes to create pseudotyped virus to explore the link between genotypic predictions and phenotypic assessment of coreceptor usage. We found out that the most stringently sequence-based calls of X4 variants (Geno2Pheno false-positive rate [FPR] of ≤2%) formed distinct lineages within the viral population, and these were detected in 24 of 30 late-stage samples (80%), which was significantly higher than what has been seen previously by using other approaches. Non-X4 lineages were not skewed toward lower FPR scores in X4-containing populations. Phenotypic assays showed that variants with an intermediate FPR (2 to 20%) could be either X4/dual-tropic or R5 variants, although the X4 variants made up only about 25% of the lineages with an FPR of <10%, and these variants carried a distinctive sequence change. Phylogenetic analysis of both the V1/V2 and C2/V3 regions showed evidence of recombination within but very little recombination between the X4 and R5 lineages, suggesting that these populations are genetically isolated. IMPORTANCE Primer ID sequencing provides a novel approach to study genetic structures of viral populations. X4 variants may be more prevalent than previously reported when assessed by using next-generation sequencing (NGS) and with a greater depth of sampling than single-genome amplification (SGA). Phylogenetic analysis to identify lineages of sequences with intermediate FPR values may provide additional information for accurately predicting X4 variants by using V3 sequences. Limited recombination occurs between X4 and R5 lineages, suggesting that X4 and R5 variants are genetically isolated and may be replicating in different cell types or that X4/R5 recombinants have reduced fitness

Diversity and Tropism of HIV-1 Rebound Virus Populations in Plasma Level After Treatment Discontinuation

Human immunodeficiency virus–infected people discontinuing therapy experience a rebound in the virus level (hereafter, “rebound virus”) from a persistent reservoir. We examined 10 samples from patients in AIDS Clinical Trials Group study A5068 with rebound virus, using single-genome amplification and Primer ID deep sequencing, to assess env genetic diversity of the virus population. Most rebound-virus populations showed significant diversity. All env examined required high levels of CD4 for entry, consistent with selection of replication in CD4+ T cells. These results indicate that most people discontinuing therapy release a diverse population of virus and that this released virus has entry features of virus selected for replication in CD4+ T cells, rather than in myeloid cells

Cosmic Background dipole measurements with Planck-High Frequency Instrument

This paper discusses the Cosmic Background (CB) dipoles observations in the framework of the Planck mission. Dipoles observations can be used in three ways: (i) It gives a measurement of the peculiar velocity of our Galaxy which is an important observation in large scale structures formation model. (ii) Measuring the dipole can give unprecedent information on the monopole (that can be in some cases hard to obtain due to large foreground contaminations). (iii) The dipole can be an ideal absolute calibrator, easily detectable in cosmological experiments. Following the last two objectives, the main goal of the work presented here is twofold. First, we study the accuracy of the Planck-HFI calibration using the Cosmic Microwave Background (CMB) dipole measured by COBE as well as the Earth orbital motion dipole. We show that we can reach for HFI, a relative calibration between rings of about 1% and an absolute calibration better than 0.4% for the CMB channels (in the end, the absolute calibration will be limited by the uncertainties on the CMB temperature). We also show that Planck will be able to measure the CMB dipole direction at better than 1.7 arcmin and improve on the amplitude. Second, we investigate the detection of the Cosmic Far-Infrared Background (FIRB) dipole. Measuring this dipole could give a new and independent determination of the FIRB for which a direct determination is quite difficult due to Galactic dust emission contamination. We show that such a detection would require a Galactic dust emission removal at better than 1%, which will be very hard to achieve.Comment: 10 pages, 13 figures, submitted to A&A, uses aa.sty V5.

The Epigenomics of Pituitary Adenoma

Background: The vast majority of pituitary tumors are benign and behave accordingly; however, a fraction are invasive and are more aggressive, with a very small fraction being frankly malignant. The cellular pathways that drive transformation in pituitary neoplasms are poorly characterized, and current classification methods are not reliable correlates of clinical behavior. Novel techniques in epigenetics, the study of alterations in gene expression without changes to the genetic code, provide a new dimension to characterize tumors, and may hold implications for prognostication and management.Methods: We conducted a review of primary epigenetic studies of pituitary tumors with a focus on histone modification, DNA methylation, and transcript modification.Results: High levels of methylation have been identified in invasive and large pituitary tumors. DNA methyltransferase overexpression has been detected in pituitary tumors, especially in macroadenomas. Methylation differences at CpG sites in promoter regions may distinguish several types of tumors from normal pituitary tissue. Histone modifications have been linked to increased p53 expression and longer progression-free survival in pituitary tumors; sirtuins are expressed at higher values in GH-expressing compared to nonfunctional adenomas and correlate inversely with size in somatotrophs. Upregulation in citrullinating enzymes may be an early pathogenic marker of prolactinomas. Numerous genes involved with cell growth and signaling show altered methylation status for pituitary tumors, including cell cycle regulators, components of signal transduction pathways, apoptotic regulators, and pituitary developmental signals.Conclusions: The limited clinical predictive capacity of the current pituitary tumor classification system suggests that tumor subclasses likely remain to be discovered. Ongoing epigenetic studies could provide a basis for adding methylation and/or acetylation screening to standard pituitary tumor workups. Identifying robust correlations between tumor epigenetics and corresponding histological, radiographic, and clinical course information could ultimately inform clinical decision-making

Rationally designed immunogens enable immune focusing following SARS-CoV-2 spike imprinting

Eliciting antibodies to surface-exposed viral glycoproteins can generate protective responses that control and prevent future infections. Targeting conserved sites may reduce the likelihood of viral escape and limit the spread of related viruses with pandemic potential. Here we leverage rational immunogen design to focus humoral responses on conserved epitopes. Using glycan engineering and epitope scaffolding in boosting immunogens, we focus murine serum antibody responses to conserved receptor binding motif (RBM) and receptor binding domain (RBD) epitopes following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike imprinting. Although all engineered immunogens elicit a robust SARS-CoV-2-neutralizing serum response, RBM-focusing immunogens exhibit increased potency against related sarbecoviruses, SARS-CoV, WIV1-CoV, RaTG13-CoV, and SHC014-CoV; structural characterization of representative antibodies defines a conserved epitope. RBM-focused sera confer protection against SARS-CoV-2 challenge. Thus, RBM focusing is a promising strategy to elicit breadth across emerging sarbecoviruses without compromising SARS-CoV-2 protection. These engineering strategies are adaptable to other viral glycoproteins for targeting conserved epitopes

R5 Macrophage-Tropic HIV-1 in the Male Genital Tract

The entry tropism of HIV-1 Env proteins from virus isolated from the blood and genital tract of five men with compartmentalized lineages was determined. The Env proteins isolated from the genital tract of subject C018 were macrophage-tropic proteins, while the remaining cloned env genes encoded R5 T cell-tropic proteins. The detection of a macrophage-tropic lineage of HIV-1 within the male genital tract strongly suggests that evolution of macrophage-tropic viruses can occur in anatomically isolated sites outside the central nervous system

Exploration of Deaf people’s health information sources and techniques for information delivery in Cape Town: A qualitative study for the design and development of a mobile health application

BACKGROUND: Many cultural and linguistic Deaf people in South Africa face disparity when accessing health information because of social and language barriers. The number of certified South African Sign Language interpreters (SASLIs) is also insufficient to meet the demand of the Deaf population in the country. Our research team, in collaboration with the Deaf communities in Cape Town, devised a mobile health app called SignSupport to bridge the communication gaps in health care contexts. We consequently plan to extend our work with a Health Knowledge Transfer System (HKTS) to provide Deaf people with accessible, understandable, and accurate health information. We conducted an explorative study to prepare the groundwork for the design and development of the system. OBJECTIVES: To investigate the current modes of health information distributed to Deaf people in Cape Town, identify the health information sources Deaf people prefer and their reasons, and define effective techniques for delivering understandable information to generate the groundwork for the mobile health app development with and for Deaf people. METHODS: A qualitative methodology using semistructured interviews with sensitizing tools was used in a community-based codesign setting. Twenty-three Deaf people and 10 health professionals participated in this study. Inductive and deductive coding was used for the analysis. RESULTS: Deaf people currently have access to 4 modes of health information distribution through: Deaf and other relevant organizations, hearing health professionals, personal interactions, and the mass media. Their preferred and accessible sources are those delivering information in signed language and with communication techniques that match Deaf people’s communication needs. Accessible and accurate health information can be delivered to Deaf people by 3 effective techniques: using signed language including its dialects, through health drama with its combined techniques, and accompanying the information with pictures in combination with simple text descriptions. CONCLUSIONS: We can apply the knowledge gained from this exploration to build the groundwork of the mobile health information system. We see an opportunity to design an HKTS to assist the information delivery during the patient-health professional interactions in primary health care settings. Deaf people want to understand the information relevant to their diagnosed disease and its self-management. The 3 identified effective techniques will be applied to deliver health information through the mobile health app