transmission correlates
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Publication
Journal: Molecular Biology and Evolution
October/30/2013
Abstract
Model-based analyses of natural selection often categorize sites into a relatively small number of site classes. Forcing each site to belong to one of these classes places unrealistic constraints on the distribution of selection parameters, which can result in misleading inference due to model misspecification. We present an approximate hierarchical Bayesian method using a Markov chain Monte Carlo (MCMC) routine that ensures robustness against model misspecification by averaging over a large number of predefined site classes. This leaves the distribution of selection parameters essentially unconstrained, and also allows sites experiencing positive and purifying selection to be identified orders of magnitude faster than by existing methods. We demonstrate that popular random effects likelihood methods can produce misleading results when sites assigned to the same site class experience different levels of positive or purifying selection--an unavoidable scenario when using a small number of site classes. Our Fast Unconstrained Bayesian AppRoximation (FUBAR) is unaffected by this problem, while achieving higher power than existing unconstrained (fixed effects likelihood) methods. The speed advantage of FUBAR allows us to analyze larger data sets than other methods: We illustrate this on a large influenza hemagglutinin data set (3,142 sequences). FUBAR is available as a batch file within the latest HyPhy distribution (http://www.hyphy.org), as well as on the Datamonkey web server (http://www.datamonkey.org/).
Publication
Journal: New England Journal of Medicine
January/22/2013
Abstract
BACKGROUND
The relationship between the timing of the initiation of antiretroviral therapy (ART) after infection with human immunodeficiency virus type 1 (HIV-1) and the recovery of CD4+ T-cell counts is unknown.
METHODS
In a prospective, observational cohort of persons with acute or early HIV-1 infection, we determined the trajectory of CD4+ counts over a 48-month period in partially overlapping study sets: study set 1 included 384 participants during the time window in which they were not receiving ART and study set 2 included 213 participants who received ART soon after study entry or sometime thereafter and had a suppressed plasma HIV viral load. We investigated the likelihood and rate of CD4+ T-cell recovery to 900 or more cells per cubic millimeter within 48 months while the participants were receiving viral-load-suppressive ART.
RESULTS
Among the participants who were not receiving ART, CD4+ counts increased spontaneously, soon after HIV-1 infection, from the level at study entry (median, 495 cells per cubic millimeter; interquartile range, 383 to 622), reached a peak value (median, 763 cells per cubic millimeter; interquartile range, 573 to 987) within approximately 4 months after the estimated date of infection, and declined progressively thereafter. Recovery of CD4+ counts to 900 or more cells per cubic millimeter was seen in approximately 64% of the participants who initiated ART earlier (≤4 months after the estimated date of HIV infection) as compared with approximately 34% of participants who initiated ART later (>4 months) (P<0.001). After adjustment for whether ART was initiated when the CD4+ count was 500 or more cells per cubic millimeter or less than 500 cells per cubic millimeter, the likelihood that the count would increase to 900 or more cells per cubic millimeter was lower by 65% (odds ratio, 0.35), and the rate of recovery was slower by 56% (rate ratio, 0.44), if ART was initiated later rather than earlier. There was no association between the plasma HIV RNA level at the time of initiation of ART and CD4+ T-cell recovery.
CONCLUSIONS
A transient, spontaneous restoration of CD4+ T-cell counts occurs in the 4-month time window after HIV-1 infection. Initiation of ART during this period is associated with an enhanced likelihood of recovery of CD4+ counts. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
Publication
Journal: AIDS
April/20/2014
Abstract
OBJECTIVE
Early HIV infection is characterized by a dramatic depletion of CD4 T cells in the gastrointestinal tract and translocation of bacterial products from the gut into the blood. In this study, we evaluated if gut bacterial profiles were associated with immune status before and after starting antiretroviral therapy (ART).
METHODS
We evaluated the gut microbiota of men recently infected with HIV (n = 13) who were participating in a randomized, double-blind controlled trial of combination ART and maraviroc versus placebo and who were followed for 48 weeks.
METHODS
To evaluate the gut microbiota of participants, we pyrosequenced the bacterial populations from anal swabs collected before and longitudinally after the initiation of ART. Associations of the gut flora with clinical variables (lymphocyte profiles and viral loads), activation and proliferation markers in peripheral blood mononuclear cells and gut biopsies (measured by flow cytometry) and markers of microbial translocation (lipopolysaccharide and soluble CD14) were performed by regression analyses using R statistical software.
RESULTS
Using pyrosequencing, we identified that higher proportions of Lactobacillales in the distal gut of recently HIV-infected individuals were associated with lower markers of microbial translocation, higher CD4% and lower viral loads before ART was started. Similarly, during ART, higher proportions of gut Lactobacillales were associated with higher CD4%, less microbial translocation, less systemic immune activation, less gut T lymphocyte proliferation, and higher CD4% in the gut.
CONCLUSIONS
Shaping the gut microbiome, especially proportions of Lactobacillales, could help to preserve immune function during HIV infection.
Publication
Journal: Journal of Virology
July/28/2013
Abstract
Coronaviruses are found in a diverse array of bat and bird species, which are believed to act as natural hosts. Molecular clock dating analyses of coronaviruses suggest that the most recent common ancestor of these viruses existed around 10,000 years ago. This relatively young age is in sharp contrast to the ancient evolutionary history of their putative natural hosts, which began diversifying tens of millions of years ago. Here, we attempted to resolve this discrepancy by applying more realistic evolutionary models that have previously revealed the ancient evolutionary history of other RNA viruses. By explicitly modeling variation in the strength of natural selection over time and thereby improving the modeling of substitution saturation, we found that the time to the most recent ancestor common for all coronaviruses is likely far greater (millions of years) than the previously inferred range.
Publication
Journal: Journal of Infectious Diseases
December/18/2014
Abstract
BACKGROUND
Early initiation of combination antiretroviral therapy (cART) to human immunodeficiency virus type 1 (HIV-1)-infected infants controls HIV-1 replication and reduces mortality.
METHODS
Plasma viremia (lower limit of detection, <2 copies/mL), T-cell activation, HIV-1-specific immune responses, and the persistence of cells carrying replication-competent virus were quantified during long-term effective combination antiretroviral therapy (cART) in 4 perinatally HIV-1-infected youth who received treatment early (the ET group) and 4 who received treatment late (the LT group). Decay in peripheral blood mononuclear cell (PBMC) proviral DNA levels was also measured over time in the ET youth.
RESULTS
Plasma viremia was not detected in any ET youth but was detected in all LT youth (median, 8 copies/mL; P = .03). PBMC proviral load was significantly lower in ET youth (median, 7 copies per million PBMCs) than in LT youth (median, 181 copies; P = .03). Replication-competent virus was recovered from all LT youth but only 1 ET youth. Decay in proviral DNA was noted in all 4 ET youth in association with limited T-cell activation and with absent to minimal HIV-1-specific immune responses.
CONCLUSIONS
Initiation of early effective cART during infancy significantly limits circulating levels of proviral and replication-competent HIV-1 and promotes continuous decay of viral reservoirs. Continued cART with reduction in HIV-1 reservoirs over time may facilitate HIV-1 eradication strategies.
Publication
Journal: PLoS ONE
April/23/2014
Abstract
OBJECTIVE
Characterize intra-individual HIV-1 subtype B pol evolution in antiretroviral naive individuals.
METHODS
Longitudinal cohort study of individuals enrolled during primary infection.
METHODS
Eligible individuals were antiretroviral naïve participants enrolled in the cohort from December 1997-December 2005 and having at least two blood samples available with the first one collected within a year of their estimated date of infection. Population-based pol sequences were generated from collected blood samples and analyzed for genetic divergence over time in respect to dual infection status, HLA, CD4 count and viral load.
RESULTS
93 participants were observed for a median of 1.8 years (Mean = 2.2 years, SD =1.9 years). All participants classified as mono-infected had less than 0.7% divergence between any two of their pol sequences using the Tamura-Nei model (TN93), while individuals with dual infection had up to 7.0% divergence. The global substitution rates (substitutions/nucleotide/year) for mono and dually infected individuals were significantly different (p<0.001); however, substitution rates were not associated with HLA haplotype, CD4 or viral load.
CONCLUSIONS
Even after a maximum of almost 9 years of follow-up, all mono-infected participants had less than 1% divergence between baseline and longitudinal sequences, while participants with dual infection had 10 times greater divergence. These data support the use of HIV-1 pol sequence data to evaluate transmission events, networks and HIV-1 dual infection.
Publication
Journal: Clinical Infectious Diseases
October/18/2017
Publication
Journal: AIDS and Behavior
May/10/2015
Abstract
Our objective here is to demonstrate the population-level effects of individual-level post-diagnosis behavior change (PDBC) in Southern Californian men who have sex with men (MSM), recently diagnosed with HIV. While PDBC has been empirically documented, the population-level effects of such behavior change are largely unknown. To examine these effects, we develop network models derived from the exponential random graph model family. We parameterize our models using behavioral data from the Southern California Acute Infection and Early Disease Research Program, and biological data from a number of published sources. Our models incorporate vital demographic processes, biology, treatment and behavior. We find that without PDBC, HIV prevalence among MSM would be significantly higher at any reasonable frequency of testing. We also demonstrate that higher levels of HIV risk behavior among HIV-positive men relative to HIV-negative men observed in some cross-sectional studies are consistent with individual-level PDBC.
Publication
Journal: Current Opinion in HIV and AIDS
July/21/2013
Abstract
OBJECTIVE
Measurements of HIV burden have relied upon quantification of viral nucleic acids by real-time PCR (qPCR). To develop and test strategies for eradication, new methods are needed to better characterize residual cellular reservoirs in patients on suppressive antiretroviral therapy (ART). This review summarizes recent advances that may lead to clinically useful tests with improved sensitivity, reproducibility and throughput.
RESULTS
HIV DNA remains the most sensitive measure of residual infection, but its low levels are difficult to differentiate from assay noise by qPCR. Digital PCR has begun to improve the precision of existing real-time assays, but there remains a need to distinguish replication-competent proviruses. Rapid technological progress in single-cell analysis is beginning to offer new approaches, notably CyTOF and microengraving, which could provide vastly more information about the composition of the latent reservoir.
CONCLUSIONS
To investigate and assess therapies directed towards eradication, improved assays that simultaneously offer high sensitivity, precision and information content will be needed.
Publication
Journal: AIDS
September/23/2017
Abstract
Assays for classifying HIV infections as 'recent' or 'nonrecent' for incidence surveillance fail to simultaneously achieve large mean durations of 'recent' infection (MDRIs) and low 'false-recent' rates (FRRs), particularly in virally suppressed persons. The potential for optimizing recent infection testing algorithms (RITAs), by introducing viral load criteria and tuning thresholds used to dichotomize quantitative measures, is explored.
The Consortium for the Evaluation and Performance of HIV Incidence Assays characterized over 2000 possible RITAs constructed from seven assays (Limiting Antigen, BED, Less-sensitive Vitros, Vitros Avidity, BioRad Avidity, Architect Avidity, and Geenius) applied to 2500 diverse specimens.
MDRIs were estimated using regression, and FRRs as observed 'recent' proportions, in various specimen sets. Context-specific FRRs were estimated for hypothetical scenarios. FRRs were made directly comparable by constructing RITAs with the same MDRI through the tuning of thresholds. RITA utility was summarized by the precision of incidence estimation.
All assays produce high FRRs among treated patients and elite controllers (10-80%). Viral load testing reduces FRRs, but diminishes MDRIs. Context-specific FRRs vary substantially by scenario - BioRad Avidity and Limiting Antigen provided the lowest FRRs and highest incidence precision in scenarios considered.
The introduction of a low viral load threshold provides crucial improvements in RITAs. However, it does not eliminate nonzero FRRs, and MDRIs must be consistently estimated. The tuning of thresholds is essential for comparing and optimizing the use of assays. The translation of directly measured FRRs into context-specific FRRs critically affects their magnitudes and our understanding of the utility of assays.
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Publication
Journal: Scientific Reports
February/23/2017
Abstract
Expert guidelines for antiretroviral therapy (ART) now recommend ART as soon as possible in all HIV infected persons to reduce the risk of disease progression and prevent transmission. The goal of this observational study was to evaluate the impact of very early ART initiation and regimen type on time to viral suppression. We evaluated time to viral suppression among 86 persons with newly-diagnosed HIV infection who initiated ART within 30 days of diagnosis. A total of 36 (42%) had acute, 27 (31%) early, and 23 (27%) had established HIV infection. The median time from an offer of immediate ART to starting ART was 8 days. A total of 56/86 (65%) initiated an integrase inhibitor-based regimen and 30/86 (35%) a protease inhibitor-based regimen. The time to viral suppression was significantly shorter in those receiving an integrase inhibitor- versus a protease inhibitor-based regimen (p = 0.022). Twenty-two (26%) initiated ART at their HIV care intake visit and 79% of these participants achieved viral suppression at week 12, 82% at week 24 and 88% at week 48. ART initiated at the intake visit led to rapid and reliable viral suppression in acute, early and chronic HIV infection, in particular when integrase inhibitor-based regimens were used.
Publication
Journal: PLoS ONE
September/16/2012
Abstract
BACKGROUND
To develop a low cost method to screen for virologic failure of antiretroviral therapy (ART) and HIV-1 drug resistance, we performed a retrospective evaluation of a screening assay using serial dilutions of HIV-1 RNA-spiked blood plasma and samples from patients receiving >6 months of first-line ART.
METHODS
Serial dilution testing was used to assess sensitivity of a simple PCR-based assay (targeted at ≥1,000 HIV RNA copies/mL). We created blood plasma minipools of five samples, extracted HIV RNA from the pools, PCR amplified the reverse transcriptase (RT) coding region of the HIV-1 pol gene from extracted RNA, sequenced PCR product of positive pools, and used sequences to determine drug resistance. Sensitivity, specificity, and predictive values were determined for different levels of virologic failure based on maximum viral loads of individual samples within a pool.
RESULTS
Of 295 samples analyzed, 43 (15%) had virologic failure at ≥50 copies/mL (range 50-10,500 copies/mL, four at ≥1,000 copies/mL). The assay demonstrated 100% sensitivity to detect virus from these four samples, requiring only one round of PCR, and 56% and 89% sensitivity to detect samples with ≥50 and ≥500 copies/mL using two rounds. Amplified PCR products of all positive pools were successfully sequenced and 30% harbored ≥1 major resistance mutation. This method would have cost 10% of the combined costs of individual viral load and resistance testing.
CONCLUSIONS
We present a novel method that can screen for both virologic failure of first-line ART and drug resistance. The method is much less expensive than current methods, which may offer sustainability in resource-limited settings.
Publication
Journal: Journal of Infectious Diseases
April/17/2013
Publication
Journal: Journal of Immunology
September/19/2012
Abstract
To subvert host defenses, some microbial pathogens produce proteins that interact with conserved motifs in V regions of B cell Ag receptor shared by large sets of lymphocytes, which define the properties of a superantigen. Because the clonal composition of the lymphocyte pool is a major determinant of immune responsiveness, this study was undertaken to examine the in vivo effect on the host immune system of exposure to a B cell superantigen, protein L (PpL), a product of the common commensal bacterial species, Finegoldia magna, which is one of the most common pathogenic species among Gram-positive anaerobic cocci. Libraries of Vκ L chain transcripts were generated from the spleens of control and PpL-exposed mice, and the expressed Vκ rearrangements were characterized by high-throughput sequencing. A total of 120,855 sequencing reads could be assigned to a germline Vκ gene, with all 20 known Vκ subgroups represented. In control mice, we found a recurrent and consistent hierarchy of Vκ gene usage, as well as patterns of preferential Vκ-Jκ pairing. PpL exposure induced significant targeted global shifts in repertoire with reduction of Vκ that contain the superantigen binding motif in all exposed mice. We found significant targeted reductions in the expression of clonotypes encoded by 14 specific Vκ genes with the predicted PpL binding motif. These rigorous surveys document the capacity of a microbial protein to modulate the composition of the expressed lymphocyte repertoire, which also has broad potential implications for host-microbiome and host-pathogen relationships.
Publication
Journal: Clinical and Vaccine Immunology
July/16/2014
Abstract
Inflammation during HIV infection is associated with worse disease outcomes and progression. Many mechanisms have been indicted, including HIV itself, coinfections, and gut microbial translocation. Concerning microbial translocation, we hypothesized that adaptive immune responses to a specific bacterial species known to be present in gut-associated lymphoid tissue are higher among HIV-infected individuals than among HIV-uninfected controls and are associated with T cell activation and lower CD4 T cell counts. By characterizing the IgG response to Achromobacter xylosoxidans, we found that HIV-infected participants who were immunoresponsive (n = 48) had significantly lower CD4 percentages (P = 0.01), greater CD4 activation (percentages of RA(-) CD38(+)) (P = 0.03), and higher soluble CD14 (P = 0.01). HIV-positive individuals had higher anti-A. xylosoxidans IgG titers than HIV-uninfected individuals (P = 0.04). The results suggest an abnormal adaptive immune activation to gut microflora during HIV infection.
Publication
Journal: Journal of Infectious Diseases
September/29/2013
Publication
Journal: Journal of Infectious Diseases
September/14/2014
Publication
Journal: Scientific Reports
April/2/2017
Abstract
It remains unclear what proportions of HIV-infected and uninfected people should receive effective antiretroviral therapy (ART) to control local HIV epidemics. We developed a flexible model to evaluate the impact of treatment as prevention (TasP) and pre-exposure prophylaxis (PrEP) on HIV incidence in local communities. We evaluated this tool for determining what TasP and PrEP targets are needed to substantially reduce the HIV epidemic in San Diego, which is predominately comprised of men who have sex with men. By increasing the proportion of HIV-infected individuals on ART from 30% to 50%, 686 new infections would be prevented over five years in San Diego. By providing PrEP to 30% of MSM to the age group that account for 90% of local HIV incident cases (21-52 years), we could prevent 433 infections over five years. When combining these initiatives, a PrEP coverage rate of 40% and TasP coverage rate of 34% would be expected to decrease the number of new infections by over half in one year. This online tool is designed to help local public health planners and policy makers to estimate program outcomes and costs that may lead to better control of their local HIV epidemics.