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Endothelial activation, innate immune activation, and inflammation are associated with post-bronchodilator airflow limitation and obstruction among adolescents living with HIV

J Acquir Immune Defic Syndr

2020 Richardson, Barbra A; Chung, Michael H; Crothers, Kristina; Graham, Susan M; Triplette, Matthew A

BACKGROUND: Chronic inflammation, innate immune activation, T-cell imbalance and endothelial activation have been linked with lung diseases. We sought to determine whether markers of these pathophysiologic pathways were associated with spirometry and chest CT abnormalities among adolescents living with HIV (ALWH). SETTING: Coptic Hope Center for Infectious Diseases in Nairobi, Kenya METHODS:: We performed a cross-sectional study of ALWH (10-19 years old). Participants underwent chest CT, spirometry and venipuncture for serum biomarkers. We also collected demographic, anthropometric, T-cell subset, antiretroviral therapy, and exposure data. We compared characteristics and biomarkers by airflow obstruction (post-bronchodilator FEV1/FVC z-score [zFEV1/FVC] < -1.64). We used multivariable linear regression to determine associations of log10-transformed biomarkers and chest CT abnormalities with lower post-bronchodilator zFEV1/FVC (airflow limitation). We performed exploratory principal components analysis on biomarkers, and determined associations of factors with post-bronchodilator zFEV1/FVC and chest CT abnormalities. RESULTS: Of 47 participants with acceptable quality spirometry, 21 (45%) were female, median age was 13 years and 96% had perinatally-acquired HIV. Median CD4 was 672 cells/L. Overall, 28% had airflow obstruction and 78% had a chest CT abnormality; airflow obstruction was associated with mosaic attenuation (p=0.001). Higher endothelial activation (sVCAM-1, sICAM-1), inflammation and innate immune activation (SAA, sTREM-1, sCD163), and T-cell imbalance (lower CD4/CD8) markers were associated with airflow limitation. Factors comprising endothelial and innate immune activation were associated with airflow limitation. CONCLUSIONS: Endothelial activation, innate immune activation, T-cell imbalance, and chronic inflammation are associated with airflow limitation and obstruction, providing insights into chronic lung disease pathophysiology among ALWH.

Disseminated adenovirus infection after autologous stem cell transplant

Transpl Infect Dis

2019 Pergam, Steven A; Issaka, Rachel B; Hyun, Teresa S

Adenovirus is an infrequent but challenging viral complication of transplantation that is rarely reported after autologous stem cell transplant. We present a case of disseminated adenovirus infection in a woman who received an autologous stem cell transplant for treatment of multiple sclerosis. After presenting with post-transplant episodic diarrhea and viremia, endoscopic biopsies and immunohistochemical staining confirmed the diagnosis of disseminated adenovirus infection. Her symptoms and viremia resolved after treatment with cidofovir. This case demonstrates that a high-index of suspicion, a systematic clinical approach, and immunohistochemical tissue staining are necessary to diagnose disseminated adenovirus infection in an unexpected host.

Recombinant HIV-1 vaccine candidates based on replication-defective flavivirus vector

Sci Rep

2019 Gottardo, Raphael; Bennett, Chelsey L; McElrath, Julie; Mayer, Bryan T

Multiple approaches utilizing viral and DNA vectors have shown promise in the development of an effective vaccine against HIV. In this study, an alternative replication-defective flavivirus vector, RepliVax (RV), was evaluated for the delivery of HIV-1 immunogens. Recombinant RV-HIV viruses were engineered to stably express clade C virus Gag and Env (gp120TM) proteins and propagated in Vero helper cells. RV-based vectors enabled efficient expression and correct maturation of Gag and gp120TM proteins, were apathogenic in a sensitive suckling mouse neurovirulence test, and were similar in immunogenicity to recombinant poxvirus NYVAC-HIV vectors in homologous or heterologous prime-boost combinations in mice. In a pilot NHP study, immunogenicity of RV-HIV viruses used as a prime or boost for DNA or NYVAC candidates was compared to a DNA prime/NYVAC boost benchmark scheme when administered together with adjuvanted gp120 protein. Similar neutralizing antibody titers, binding IgG titers measured against a broad panel of Env and Gag antigens, and ADCC responses were observed in the groups throughout the course of the study, and T cell responses were elicited. The entire data demonstrate that RV vectors have the potential as novel HIV-1 vaccine components for use in combination with other promising candidates to develop new effective vaccination strategies.

The ability of single genes vs full genomes to resolve time and space in outbreak analysis

BMC Evol Biol

2019 Bedford, Trevor; Dudas, Gytis

BACKGROUND: Inexpensive pathogen genome sequencing has had a transformative effect on the field of phylodynamics, where ever increasing volumes of data have promised real-time insight into outbreaks of infectious disease. As well as the sheer volume of pathogen isolates being sequenced, the sequencing of whole pathogen genomes, rather than select loci, has allowed phylogenetic analyses to be carried out at finer time scales, often approaching serial intervals for infections caused by rapidly evolving RNA viruses. Despite its utility, whole genome sequencing of pathogens has not been adopted universally and targeted sequencing of loci is common in some pathogen-specific fields. RESULTS: In this study we highlighted the utility of sequencing whole genomes of pathogens by re-analysing a well-characterised collection of Ebola virus sequences in the form of complete viral genomes (19 kb long) or the rapidly evolving glycoprotein (GP, 2 kb long) gene. We have quantified changes in phylogenetic, temporal, and spatial inference resolution as a result of this reduction in data and compared these to theoretical expectations. CONCLUSIONS: We propose a simple intuitive metric for quantifying temporal resolution, i.e. the time scale over which sequence data might be informative of various processes as a quick back-of-the-envelope calculation of statistical power available to molecular clock analyses.

Publisher Correction: Orchestrating single-cell analysis with Bioconductor

Nat Methods

2019 Gottardo, Raphael; Becht, Etienne K; Carpp, Lindsay N; Pages, Herve; Amezquita, Robert A

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics


2019 Goo, Leslie

Eliciting broadly neutralizing antibodies (bNAbs) against the four dengue virus serotypes (DENV1-4) that are spreading into new territories is an important goal of vaccine design. To define bNAb targets, we characterized 28 antibodies belonging to expanded and hypermutated clonal families identified by transcriptomic analysis of single plasmablasts from DENV-infected individuals. Among these, we identified J9 and J8, two somatically related bNAbs that potently neutralized DENV1-4. Mutagenesis studies showed that the major recognition determinants of these bNAbs are in E protein domain I, distinct from the only known class of human bNAbs against DENV with a well-defined epitope. B cell repertoire analysis from acute-phase peripheral blood suggested that J9 and J8 followed divergent somatic hypermutation pathways, and that a limited number of mutations was sufficient for neutralizing activity. Our study suggests multiple B cell evolutionary pathways leading to DENV bNAbs targeting a new epitope that can be exploited for vaccine design.

Clinically significant drug interaction: letermovir and voriconazole

J Antimicrob Chemother

2019 Boeckh, Michael J; Hill, Joshua A; Liu, Catherine; Pergam, Steven A


Anal intercourse, HIV-1 risk, and efficacy in a trial of a dapivirine-containing vaginal ring for HIV-1 prevention

J Acquir Immune Defic Syndr

2019 Brown, Elizabeth R

OBJECTIVES: To describe receptive anal intercourse (RAI) behaviors and correlates in a cohort of sub-Saharan African women, evaluate the association of RAI with HIV-1 risk, and evaluate whether the HIV-1 prevention efficacy of a dapivirine-containing vaginal ring differs among women who reported RAI. DESIGN: Secondary analysis of the MTN-020/ASPIRE trial, a randomized, double-blind, placebo-controlled trial evaluating a dapivirine-containing vaginal ring for HIV-1 prevention. METHODS: At enrollment and month three, women reported RAI in the prior three months in audio computer-assisted self-interviews. We evaluated associations between RAI and participant characteristics with chi-square and t-tests adjusted for study site. Cox proportional hazards models stratified by study site tested the association of RAI with HIV-1 acquisition and effect modification by RAI. RESULTS: Nineteen percent of women reported any RAI at enrollment and/or month 3, with a median of 2 (IQR: 1, 4) RAI acts in the prior three months, accounting for 1.5% of total sex acts. RAI prevalence was higher among women with lower educational attainment and those reporting transactional sex. In adjusted models, RAI was not associated with HIV-1 acquisition (aHR: 0.93, 95% CI: 0.57, 1.54). The ring reduced HIV-1 risk by 27% (95% CI: -5, 49) among women reporting no RAI and by 18% (95% CI: -57, 57) among women reporting any RAI (interaction p-value=0.77). CONCLUSIONS: RAI was modestly infrequent and was not associated with reduced HIV-1 protection from the ring, suggesting that, in populations with rates of RAI similar to this cohort, RAI may not appreciably reduce the population-level impact of the dapivirine vaginal ring.

Identification of the optimal treatment regimen in the presence of missing covariates

Stat Med

2019 Huang, Ying

Covariates associated with treatment-effect heterogeneity can potentially be used to make personalized treatment recommendations towards best clinical outcomes. Methods for treatment-selection rule development that directly maximize treatment-selection benefits have attracted much interest in recent years, due to the robustness of these methods to outcome modeling. In practice, the task of treatment-selection rule development can be further complicated by missingness in data. Here, we consider the identification of optimal treatment-selection rules for a binary disease outcome when measurements of an important covariate from study participants are partly missing. Under the missing at random assumption, we develop a robust estimator of treatment-selection rules under the direct-optimization paradigm. This estimator targets the maximum selection benefits to the population under correct specification of at least one mechanism from each of the two sets-missing data or conditional covariate distribution, and treatment assignment or disease outcome model. We evaluate and compare performance of the proposed estimator with alternative direct-optimization estimators through extensive simulation studies. We demonstrate the application of the proposed method through a real data example from an Alzheimer's disease study for developing covariate combinations to guide the treatment of Alzheimer's disease.

Activated PD-1+ CD4 T cells represent a short-lived part of the viral reservoir and predict poor immunologic recovery upon initiation of ART


2019 McElrath, Julie

OBJECTIVE: Activated (CD38+HLA-DR+) PD-1+ CD4 T cells are strongly associated with virus replication and disease progression in untreated HIV-1 infection, and viral persistence in individuals on ART. Few studies have examined cell associated viral load (CAVL) in different activated CD4 T cell populations to measure relative contributions to viral reservoirs. DESIGN: Longitudinal assessment of HIV-1 chronically infected Ugandans initiating ART, to investigate activated CD4 T cell populations and their contribution to viral reservoirs. METHODS: We followed 32 HIV-1 chronically infected individuals from Kampala, Uganda, and determined their CD4 T cell counts and viral load at baseline, 6, and 12 months after the initiation of ART. T cell populations were sorted based on activation profiles and gag DNA was measured to determine CAVL within these populations. Soluble factors associated with inflammation were measured in plasma using a multiplexed platform. RESULTS: Concomitant with viral load decline and CD4 T cell count rebound, the activated PD-1+ CD4 T cell population contracted upon initiation of ART. Baseline levels of activated PD-1+ CD4 T cells correlated with plasma levels of IP-10 and TNFRII. Interestingly, higher baseline level of activated PD-1+ CD4 T cells was associated with poorer CD4 T cell recovery after 12 months of ART. This population contributed significantly to the cell-associated HIV DNA load at baseline, whereas their contribution declined on ART, indicating high turnover. CONCLUSION: Activated PD-1+ CD4 T cells are predictors of poor immunologic recovery on ART and may represent a short-lived component of HIV-1 reservoirs.