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1.
Clin Infect Dis ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32020172

RESUMO

BACKGROUND: Public health action combatting HIV includes facilitating navigation through the HIV continuum of care: timely diagnosis followed by linkage to care and initiation of antiretroviral therapy to suppress viral replication. Molecular epidemiology can identify rapidly growing HIV genetic transmission clusters. How progression through the care continuum relates to transmission clusters has not been previously characterized. METHODS: We performed a retrospective study on HIV surveillance data from 5,226 adult cases in Los Angeles County diagnosed between 2010 through 2014. Genetic transmission clusters were constructed using HIV-TRACE. Cox proportional hazard models were used to estimate the impact of transmission cluster growth on the time intervals between care continuum events. Gamma frailty models incorporated the effect of heterogeneity associated with genetic transmission clusters. RESULTS: In contrast to our expectations, there were no differences in time to the care continuum events among individuals in clusters with different growth dynamics. However, upon achieving viral suppression, individuals in high growth clusters were slower to experience viral rebound (Hazard Ratio 0.83, p=0.011) compared with individuals in low growth clusters. Heterogeneity associated with cluster membership in the timing to each event in the care continuum was highly significant (p<0.001), with and without adjustment for transmission risk and demographics. CONCLUSIONS: Individuals within the same transmission cluster have more similar trajectories through the HIV care continuum than those across transmission clusters. These findings suggest molecular epidemiology can assist public health officials in identifying clusters of individuals who may benefit from assistance in navigating the HIV care continuum.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31977598

RESUMO

BACKGROUND: In the United States (U.S.), young (aged 13-24 years) men who have sex with men (MSM) bear a disproportionate burden of HIV. Transmission among MSM has been found to be disassortative by age. METHODS: We analyzed HIV-1 pol sequences reported to the U.S. National HIV Surveillance System from MSM with HIV diagnosed during 2009-2016. Using an HIV genetic transmission network, we identified persons with closely related viruses (i.e., genetic distance ≤1.5%) and used multivariable logistic regression to examine changes from 2009-2012 to 2013-2016 in proportions of MSM linked to young MSM who were > 5 years older or of the same race/ethnicity. RESULTS: Among 9,510 young MSM linked to another MSM with a closely related virus, 37% linked to an older MSM and 62% linked to a MSM of the same race/ethnicity. Comparing 2013-2016 with 2009-2012, we found increases in linkage of older MSM to young MSM, with the most substantial increases seen in Hispanic/Latinos aged 13-19 (adjusted prevalence ratio [APR]=1.31, 95% confidence interval [CI]=1.11-1.56) and blacks aged 13-19 (APR=1.23, CI=1.06-1.41) and 20-24 (APR=1.14, CI=1.02-1.28). In contrast, change in linkage patterns among racial/ethnic groups was unremarkable. CONCLUSIONS: We found evidence of increased age mixing among MSM with respect to HIV transmission over time, which coincides temporally with changes in partner-seeking behavior such as increased use of mobile applications. These findings indicate the importance of social factors on HIV sexual and transmission networks and suggest that prevention efforts need to effectively reach MSM of all ages.

3.
AIDS ; 34(3): 459-467, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31794522

RESUMO

BACKGROUND: To develop a predictive model to prioritize persons with a transmissible HIV viral load for transmission-reduction interventions. METHODS: New York City (NYC) HIV molecular surveillance data from 2010 to 2013 were used to build a model to predict the probability that the partial pol gene of the virus of a person with a transmissible HIV viral load (>1500 copies/ml) would be genetically similar to that of a person with a new HIV infection (diagnosis at stage 0 or 1 according to the revised Centers for Disease Control and Prevention classification system). Data from 2013 to 2016 were then used to validate the model and compare it with five other selection strategies that can be used to prioritize persons for transmission-reduction interventions. RESULTS: A total of 10 609 persons living with HIV (PLWH) were included in the development dataset, and 8257 were included in the validation dataset. Among the six selection strategies, the predictive model had the highest area under the receiver operating characteristic curve (AUC) [0.86, 95% confidence interval (CI) 0.84--0.88], followed by the 'Young MSM' (0.79, 95% CI 0.77--0.82), 'MSM with high viral loads' (0.74, 95% CI 0.72--0.76), 'Random sample of MSM' (0.73, 95% CI 0.71--0.76), 'Persons with high viral loads' (0.56, 95% CI 0.54--0.59), and 'Random sample' (0.50, 95% CI 0.48--0.53) strategies. CONCLUSIONS: Jurisdictions should consider applying predictive modeling to prioritize persons with a transmissible viral load for transmission-reduction interventions and to evaluate its feasibility and effectiveness.

4.
Medicine (Baltimore) ; 98(50): e18232, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852085

RESUMO

Transgender people continue to be at high-risk for HIV acquisition, but little is known about the characteristics of their sexual partners. To address this gap, we examined sociodemographic and sexual characteristics of cisgender men who have sex with men (MSM) on pre-exposure prophylaxis (PrEP) reporting transgender sexual partners.A cohort of 392 MSM in southern California in a randomized clinical trial for PrEP adherence were followed from 2013 to 2016. Multivariable generalized estimating equation and logistic models identified characteristics of MSM reporting transgender sexual partners and PrEP adherence.Only 14 (4%) MSM reported having transgender sexual partners. MSM were more likely to report transgender partners if they were African American, had incident chlamydia, reported injection drug-using sexual partners, or received items for sex. Most associations remained significant in the multivariable model: African American (adjusted odds ratio [AOR] 11.20, P = .01), incident chlamydia (AOR 3.71, P = .04), and receiving items for sex (AOR 5.29, P = .04). There were no significant differences in PrEP adherence between MSM reporting transgender partners and their counterpart.MSM who report transgender sexual partners share characteristics associated with individuals with high HIV prevalence. Identifying this group distinct from larger cohorts of MSM could offer new HIV prevention opportunities for this group of MSM and the transgender community.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/prevenção & controle , Homossexualidade Masculina/psicologia , Prevenção Primária/métodos , Comportamento Sexual , Parceiros Sexuais , Pessoas Transgênero , Adulto , Seguimentos , Infecções por HIV/epidemiologia , Humanos , Incidência , Masculino , Adesão à Medicação , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologia
5.
Nat Commun ; 10(1): 5788, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31857582

RESUMO

HIV molecular epidemiology can identify clusters of individuals with elevated rates of HIV transmission. These variable transmission rates are primarily driven by host risk behavior; however, the effect of viral traits on variable transmission rates is poorly understood. Viral load, the concentration of HIV in blood, is a heritable viral trait that influences HIV infectiousness and disease progression. Here, we reconstruct HIV genetic transmission clusters using data from the United States National HIV Surveillance System and report that viruses in clusters, inferred to be frequently transmitted, have higher viral loads at diagnosis. Further, viral load is higher in people in larger clusters and with increased network connectivity, suggesting that HIV in the United States is experiencing natural selection to be more infectious and virulent. We also observe a concurrent increase in viral load at diagnosis over the last decade. This evolutionary trajectory may be slowed by prevention strategies prioritized toward rapidly growing transmission clusters.

6.
Virus Evol ; 5(2): vez041, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31616569

RESUMO

Recombination is an important driver of genetic diversity, though it is relatively uncommon in hepatitis C virus (HCV). Recent investigation of sequence data acquired from HCV clinical trials produced twenty-one full-genome recombinant viruses belonging to three putative inter-subtype forms 2b/1a, 2b/1b, and 2k/1b. The 2k/1b chimera is the only known HCV circulating recombinant form (CRF), provoking interest in its genetic structure and origin. Discovered in Russia in 1999, 2k/1b cases have since been detected throughout the former Soviet Union, Western Europe, and North America. Although 2k/1b prevalence is highest in the Caucasus mountain region (i.e., Armenia, Azerbaijan, and Georgia), the origin and migration patterns of CRF 2k/1b have remained obscure due to a paucity of available sequences. We assembled an alignment which spans the entire coding region of the HCV genome containing all available 2k/1b sequences (>500 nucleotides; n = 109) sampled in ninteen countries from public databases (102 individuals), additional newly sequenced genomic regions (from 48 of these 102 individuals), unpublished isolates with newly sequenced regions (5 additional individuals), and novel complete genomes (2 additional individuals) generated in this study. Analysis of this expanded dataset reconfirmed the monophyletic origin of 2k/1b with a recombination breakpoint at position 3,187 (95% confidence interval: 3,172-3,202; HCV GT1a reference strain H77). Phylogeography is a valuable tool used to reveal viral migration dynamics. Inference of the timed history of spread in a Bayesian framework identified Russia as the ancestral source of the CRF 2k/1b clade. Further, we found evidence for migration routes leading out of Russia to other former Soviet Republics or countries under the Soviet sphere of influence. These findings suggest an interplay between geopolitics and the historical spread of CRF 2k/1b.

7.
Bioinformatics ; 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31418766

RESUMO

SUMMARY: In exploring the epidemiology of infectious diseases, networks have been used to reconstruct contacts among individuals and/or populations. Summarizing networks using pathogen metadata (e.g., host species and place of isolation) and a phylogenetic tree is a nascent, alternative approach. In this paper, we introduce a tool for reconstructing transmission networks in arbitrary space from phylogenetic information and metadata. Our goals are to provide a means of deriving new insights and infection control strategies based on the dynamics of the pathogen lineages derived from networks and centrality metrics. We created a web-based application, called StrainHub, in which a user can input a phylogenetic tree based on genetic or other data along with characters derived from metadata using their preferred tree search method. StrainHub generates a transmission network based on character state changes in metadata, such as place or source of isolation, mapped on the phylogenetic tree. The user has the option to calculate centrality metrics on the nodes including betweenness, closeness, degree, and a new metric, the source/hub ratio. The outputs include the network with values for metrics on its nodes and the tree with characters reconstructed. All of these results can be exported for further analysis. AVAILABILITY: strainhub.io and https://github.com/abschneider/StrainHub.

9.
J Viral Hepat ; 26(11): 1351-1354, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31194901

RESUMO

Molecular epidemiological analysis of viral pathogens can identify factors associated with increased transmission risk. We investigated the frequency of genetic clustering in a large data set of NS34A, NS5A, and NS5B viral sequences from patients with chronic hepatitis C virus (HCV). Within a subset of patients with longitudinal samples, Receiver Operator Characteristic (ROC) analysis was applied which identified a threshold of 0.02 substitutions/site as most appropriate for clustering. From the 7457 patients with chronic HCV infection included in this analysis, we inferred 256 clusters comprising 541 patients (7.3%). We found that HCV/HIV co-infection, young age, and high HCV viral load were all associated with increased clustering frequency, an indicator of increased transmission risk. In light of previous work on HCV/HIV co-infection in acute HCV cohorts, our results suggest that patients with HCV/HIV co-infection may disproportionately be the source of new HCV infections and treatment efforts should be geared towards viral elimination in this vulnerable population.

10.
Curr Opin HIV AIDS ; 14(3): 205-212, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30946142

RESUMO

PURPOSE OF REVIEW: To discuss the recent HIV phylogenetic analyses examining HIV transmission patterns among and within risk groups. RECENT FINDINGS: Phylodynamic analysis has recently been applied to multiple HIV outbreaks among people who inject drugs to determine whether HIV transmission is ongoing. Large-scale analyses of datasets of HIV sequences collected for drug-resistance testing provide population-level insights into transmission patterns. One focus across world regions has been to investigate whether age-disparity is a driver of HIV transmission. In sub-Saharan Africa, researchers have examined transmission between heterosexuals and MSM and between high prevalence fishing communities and inland communities. In the US and the UK, cryptic risk groups such as nondisclosed MSM and the partners of transgender women are increasingly being uncovered based on their position in densely sampled molecular transmission networks. SUMMARY: Analysis of HIV genetic sequence can resolve viral transmission patterns between risk groups at unprecedented scales and levels of detail. Future research should focus on understanding the effect of missing data on inferences and the biases of different methods. Uncovering groups and patterns obscured from traditional epidemiolocal analyses is exciting but should not compromise the privacy of the groups in question.

11.
Curr Opin HIV AIDS ; 14(3): 213-220, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30882486

RESUMO

PURPOSE OF REVIEW: The purpose of this study is to summarize recent advances in public health applications of comparative methods for HIV-1 sequence analysis in real time, including genetic clustering methods. RECENT FINDINGS: Over the past 2 years, several groups have reported the deployment of established genetic clustering methods to guide public health decisions for HIV prevention in 'near real time'. However, it remains unresolved how well the readouts of comparative methods like clusters translate to events that are actionable for public health. A small number of recent studies have begun to elucidate the linkage between clusters and HIV-1 incidence, whereas others continue to refine and develop new comparative methods for such applications. SUMMARY: Although the use of established methods to cluster HIV-1 sequence databases has become a widespread activity, there remains a critical gap between clusters and public health value.

12.
MMWR Morb Mortal Wkly Rep ; 68(6): 149-152, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30763299

RESUMO

Public health interviews (i.e., partner services), during which persons with diagnosed human immunodeficiency virus (HIV) infection name their sexual or needle-sharing partners (named partners), are used to identify HIV transmission networks to guide and prioritize HIV prevention activities. HIV sequence data, generated from provider-ordered drug resistance testing, can be used to understand characteristics of molecular clusters, a group of sequences for which each sequence is highly similar (linked) to all other sequences, and assess whether named partners are plausible HIV transmission partners. Although molecular data in higher HIV-morbidity states have been analyzed (1-3), few analyses exist for lower morbidity states (4), such as Wisconsin, which reported 4.6 HIV diagnoses per 100,000 persons aged ≥13 years in 2016 (5). The Wisconsin Division of Public Health (DPH) analyzed HIV sequence data generated from provider-ordered drug resistance testing and collected through routine HIV surveillance to identify molecular clusters and describe demographic and transmission risk characteristics among pairs of persons whose sequences were highly genetically similar (i.e., molecular linkages). In addition, overlap between partner linkages identified during public health interviews and molecular linkages was assessed. Overall, characteristics of molecular clusters in Wisconsin mirrored those from states with more HIV diagnoses, particularly in that most molecular linkages were observed among persons of the same race (78.2% of non-Hispanic blacks [blacks] linked to other blacks), the same transmission risk (90.2% of men who have sex with men [MSM] linked to other MSM), and the same age group (59.2% of persons aged 20-29 years linked to other persons aged 20-29 years). Among named partner linkages identified during interviews in which both persons also had a reported sequence, overlap of named partner and molecular linkages was moderate: 33.8% of named partners were plausible transmission partners according to available molecular data. Analysis of HIV sequence data is a useful tool for characterizing transmission patterns not immediately apparent using traditional public health interview data, even in a state with lower HIV morbidity. Prevention recommendations generated from national data (e.g., targeting preexposure prophylaxis for HIV-negative persons at high risk and implementing measures to maintain viral suppression among persons with HIV infection) also are relevant in a lower HIV-morbidity state.


Assuntos
Infecções por HIV/epidemiologia , Infecções por HIV/transmissão , Vigilância da População , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Wisconsin/epidemiologia , Adulto Jovem
13.
Lancet HIV ; 6(3): e164-e172, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30765313

RESUMO

BACKGROUND: Transgender women are among the groups at highest risk for HIV infection, with a prevalence of 27·7% in the USA; and despite this known high risk, undiagnosed infection is common in this population. We set out to identify transgender women and their partners in a molecular transmission network to prioritise public health activities. METHODS: Since 2006, HIV protease and reverse transcriptase gene (pol) sequences from drug resistance testing have been reported to the Los Angeles County Department of Public Health and linked to demographic data, gender, and HIV transmission risk factor data for each case in the enhanced HIV/AIDS Reporting System. We reconstructed a molecular transmission network by use of HIV-TRAnsmission Cluster Engine (with a pairwise genetic distance threshold of 0·015 substitutions per site) from the earliest pol sequences from 22 398 unique individuals, including 412 (2%) self-identified transgender women. We examined the possible predictors of clustering with multivariate logistic regression. We characterised the genetically linked partners of transgender women and calculated assortativity (the tendency for people to link to other people with the same attributes) for each transmission risk group. FINDINGS: 8133 (36·3%) of 22 398 individuals clustered in the network across 1722 molecular transmission clusters. Transgender women who indicated a sexual risk factor clustered at the highest frequency in the network, with 147 (43%) of 345 being linked to at least one other person (adjusted odds ratio [aOR] 2·0, p=0·0002). Transgender women were assortative in the network (assortativity 0·06, p<0·001), indicating that they tended to link to other transgender women. Transgender women were more likely than expected to link to other transgender women (OR 4·65, p<0·001) and cisgender men who did not identify as men who have sex with men (MSM; OR 1·53, p<0·001). Transgender women were less likely than expected to link to MSM (OR 0·75, p<0·001), despite the high prevalence of HIV among MSM. Transgender women were distributed across 126 clusters, and cisgender individuals linked to one transgender woman were 9·2 times more likely to link to a second transgender woman than other individuals in the surveillance database. Reconstruction of the transmission network is limited by sample availability, but sequences were available for more than 40% of diagnoses. INTERPRETATION: Clustering of transgender women and the observed tendency for linkage with cisgender men who did not identify as MSM, shows the potential to use molecular epidemiology both to identify clusters that are likely to include undiagnosed transgender women with HIV and to improve the targeting of public health prevention and treatment services to transgender women. FUNDING: California HIV and AIDS Research Program and National Institutes of Health-National Institute of Allergy and Infectious Diseases.

14.
Bioinformatics ; 35(11): 1852-1861, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30395173

RESUMO

MOTIVATION: The ability to simulate epidemics as a function of model parameters allows insights that are unobtainable from real datasets. Further, reconstructing transmission networks for fast-evolving viruses like Human Immunodeficiency Virus (HIV) may have the potential to greatly enhance epidemic intervention, but transmission network reconstruction methods have been inadequately studied, largely because it is difficult to obtain 'truth' sets on which to test them and properly measure their performance. RESULTS: We introduce FrAmework for VIral Transmission and Evolution Simulation (FAVITES), a robust framework for simulating realistic datasets for epidemics that are caused by fast-evolving pathogens like HIV. FAVITES creates a generative model to produce contact networks, transmission networks, phylogenetic trees and sequence datasets, and to add error to the data. FAVITES is designed to be extensible by dividing the generative model into modules, each of which is expressed as a fixed API that can be implemented using various models. We use FAVITES to simulate HIV datasets and study the realism of the simulated datasets. We then use the simulated data to study the impact of the increased treatment efforts on epidemiological outcomes. We also study two transmission network reconstruction methods and their effectiveness in detecting fast-growing clusters. AVAILABILITY AND IMPLEMENTATION: FAVITES is available at https://github.com/niemasd/FAVITES, and a Docker image can be found on DockerHub (https://hub.docker.com/r/niemasd/favites). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

15.
Virus Evol ; 4(2): vey030, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30538823

RESUMO

Understanding genetic variation in human immunodeficiency virus (HIV) is clinically and immunologically important for patient treatment and vaccine development. We investigated the longitudinal intra-host genetic variation of HIV in over 3,000 individuals in the US National HIV Surveillance System with at least four reported HIV-1 polymerase (pol) sequences. In this population, we identified 149 putative instances of superinfection (i.e. an individual sequentially infected with genetically divergent, polyphyletic viruses). Unexpectedly, we discovered a group of 240 individuals with consecutively sampled viral strains that were >0.015 substitutions/site divergent, despite remaining monophyletic in the phylogeny. Viruses in some of these individuals had a maximum genetic divergence approaching that found between two random, unrelated HIV-1 subtype-B pol sequences within the US population. Individuals with these highly divergent viruses tended to be diagnosed nearly a decade earlier in the epidemic than people with superinfection or virus with less intra-host genetic variation, and they had distinct transmission risk factor profiles. To better understand this genetic variation in cases with extremely divergent, monophyletic viruses, we performed molecular clock phylogenetic analysis. Our findings suggest that, like Hepatitis C virus, extremely divergent HIV lineages can be maintained within an individual and reemerge over a period of years.

16.
J Acquir Immune Defic Syndr ; 79(5): 543-550, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30222659

RESUMO

BACKGROUND: Detecting recent and rapid spread of HIV can help prioritize prevention and early treatment for those at highest risk of transmission. HIV genetic sequence data can identify transmission clusters, but previous approaches have not distinguished clusters of recent, rapid transmission. We assessed an analytic approach to identify such clusters in the United States. METHODS: We analyzed 156,553 partial HIV-1 polymerase sequences reported to the National HIV Surveillance System and inferred transmission clusters using 2 genetic distance thresholds (0.5% and 1.5%) and 2 periods for diagnoses (all years and 2013-2015, ie, recent diagnoses). For rapidly growing clusters (with ≥5 diagnoses during 2015), molecular clock phylogenetic analysis estimated the time to most recent common ancestor for all divergence events within the cluster. Cluster transmission rates were estimated using these phylogenies. RESULTS: A distance threshold of 1.5% identified 103 rapidly growing clusters using all diagnoses and 73 using recent diagnoses; at 0.5%, 15 clusters were identified using all diagnoses and 13 using recent diagnoses. Molecular clock analysis estimated that the 13 clusters identified at 0.5% using recent diagnoses had been diversifying for a median of 4.7 years, compared with 6.5-13.2 years using other approaches. The 13 clusters at 0.5% had a transmission rate of 33/100 person-years, compared with previous national estimates of 4/100 person-years. CONCLUSIONS: Our approach identified clusters with transmission rates 8 times those of previous national estimates. This method can identify groups involved in rapid transmission and help programs effectively direct and prioritize limited public health resources.


Assuntos
Análise por Conglomerados , Monitoramento Epidemiológico , Genótipo , Infecções por HIV/epidemiologia , Infecções por HIV/transmissão , HIV-1/isolamento & purificação , Epidemiologia Molecular/métodos , Adulto , Idoso , Feminino , HIV-1/classificação , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Estados Unidos/epidemiologia , Adulto Jovem , Produtos do Gene pol do Vírus da Imunodeficiência Humana/genética
17.
J Biol Chem ; 293(40): 15678-15690, 2018 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-30135209

RESUMO

Protein trafficking in the endosomal system involves the recognition of specific signals within the cytoplasmic domains (CDs) of transmembrane proteins by clathrin adaptors. One such signal is the phosphoserine acidic cluster (PSAC), the prototype of which is in the endoprotease furin. How PSACs are recognized by clathrin adaptors has been controversial. We reported previously that HIV-1 Vpu, which modulates cellular immunoreceptors, contains a PSAC that binds to the µ subunits of clathrin adaptor protein (AP) complexes. Here, we show that the CD of furin binds the µ subunits of AP-1 and AP-2 in a phosphorylation-dependent manner. Moreover, we identify a potential PSAC in a cytoplasmic loop of the cellular transmembrane Serinc3, an inhibitor of the infectivity of retroviruses. The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the µ subunits in vitro The sites of these serines vary among mammals in a manner suggesting host-pathogen conflict, yet the Serinc3 PSAC seems dispensable for anti-HIV activity and for counteraction by HIV-1 Nef. The CDs of Vpu and furin and the PSAC-containing loop of Serinc3 each bind the µ subunit of AP-2 (µ2) with similar affinities, but they appear to utilize different basic regions on µ2. The Serinc3 loop requires a region previously reported to bind the acidic plasma membrane lipid phosphatidylinositol 4,5-bisphosphate. These data suggest that the PSACs within different proteins recognize different basic regions on the µ surface, providing the potential to inhibit the activity of viral proteins without necessarily affecting cellular protein trafficking.


Assuntos
Complexo 1 de Proteínas Adaptadoras/química , Complexo 2 de Proteínas Adaptadoras/química , Furina/química , HIV-1/genética , Proteínas de Neoplasias/química , Fosfosserina/química , Receptores de Superfície Celular/química , Complexo 1 de Proteínas Adaptadoras/genética , Complexo 1 de Proteínas Adaptadoras/metabolismo , Complexo 2 de Proteínas Adaptadoras/genética , Complexo 2 de Proteínas Adaptadoras/metabolismo , Motivos de Aminoácidos , Animais , Sítios de Ligação , Clonagem Molecular , Escherichia coli/genética , Escherichia coli/metabolismo , Furina/genética , Furina/metabolismo , Expressão Gênica , HIV-1/metabolismo , Proteínas do Vírus da Imunodeficiência Humana/química , Proteínas do Vírus da Imunodeficiência Humana/genética , Proteínas do Vírus da Imunodeficiência Humana/metabolismo , Humanos , Células Jurkat/metabolismo , Células Jurkat/virologia , Cinética , Mamíferos , Modelos Moleculares , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Fosfatidilinositol 4,5-Difosfato/química , Fosfatidilinositol 4,5-Difosfato/metabolismo , Fosfosserina/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Subunidades Proteicas/química , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Proteínas Virais Reguladoras e Acessórias/química , Proteínas Virais Reguladoras e Acessórias/genética , Proteínas Virais Reguladoras e Acessórias/metabolismo , Vírion/genética , Vírion/metabolismo , Produtos do Gene nef do Vírus da Imunodeficiência Humana/química , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética , Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo
18.
J Infect Dis ; 218(12): 1943-1953, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30010850

RESUMO

Background: HIV-1 genetic sequences can be used to infer viral transmission history and dynamics. Throughout the United States, HIV-1 sequences from drug resistance testing are reported to local public health departments. Methods: We investigated whether inferred HIV transmission network dynamics can identify individuals and clusters of individuals most likely to give rise to future HIV cases in a surveillance setting. We used HIV-TRACE, a genetic distance-based clustering tool, to infer molecular transmission clusters from HIV-1 pro/RT sequences from 65736 people in the New York City surveillance registry. Logistic and LASSO regression analyses were used to identify correlates of clustering and cluster growth, respectively. We performed retrospective transmission network analyses to evaluate individual- and cluster-level prioritization schemes for identifying parts of the network most likely to give rise to new cases in the subsequent year. Results: Individual-level prioritization schemes predicted network growth better than random targeting. Across the 3600 inferred molecular transmission clusters, previous growth dynamics were superior predictors of future transmission cluster growth compared to individual-level prediction schemes. Cluster-level prioritization schemes considering previous cluster growth relative to cluster size further improved network growth predictions. Conclusions: Prevention efforts based on HIV molecular epidemiology may improve public health outcomes in a US surveillance setting.


Assuntos
Infecções por HIV/transmissão , Infecções por HIV/virologia , HIV-1/genética , Adolescente , Adulto , Análise por Conglomerados , Feminino , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Cidade de Nova Iorque/epidemiologia , Vigilância da População , Sensibilidade e Especificidade , Adulto Jovem
19.
Mol Biol Evol ; 35(7): 1812-1819, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29401317

RESUMO

In modern applications of molecular epidemiology, genetic sequence data are routinely used to identify clusters of transmission in rapidly evolving pathogens, most notably HIV-1. Traditional 'shoe-leather' epidemiology infers transmission clusters by tracing chains of partners sharing epidemiological connections (e.g., sexual contact). Here, we present a computational tool for identifying a molecular transmission analog of such clusters: HIV-TRACE (TRAnsmission Cluster Engine). HIV-TRACE implements an approach inspired by traditional epidemiology, by identifying chains of partners whose viral genetic relatedness imply direct or indirect epidemiological connections. Molecular transmission clusters are constructed using codon-aware pairwise alignment to a reference sequence followed by pairwise genetic distance estimation among all sequences. This approach is computationally tractable and is capable of identifying HIV-1 transmission clusters in large surveillance databases comprising tens or hundreds of thousands of sequences in near real time, that is, on the order of minutes to hours. HIV-TRACE is available at www.hivtrace.org and from www.github.com/veg/hivtrace, along with the accompanying result visualization module from www.github.com/veg/hivtrace-viz. Importantly, the approach underlying HIV-TRACE is not limited to the study of HIV-1 and can be applied to study outbreaks and epidemics of other rapidly evolving pathogens.


Assuntos
Infecções por HIV/transmissão , HIV-1/genética , Epidemiologia Molecular/métodos , Biologia Computacional , Infecções por HIV/epidemiologia , Humanos , Software
20.
J Virol ; 92(3)2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29142136

RESUMO

Residual viremia is common during antiretroviral therapy (ART) and could be caused by ongoing low-level virus replication or by release of viral particles from infected cells. ART intensification should impact ongoing viral propagation but not virion release. Eighteen acutely infected men were enrolled in a randomized controlled trial and monitored for a median of 107 weeks. Participants started ART with (n = 9) or without (n = 9) intensification with maraviroc (MVC) within 90 days of infection. Levels of HIV DNA and cell-free RNA were quantified by droplet digital PCR. Deep sequencing of C2-V3 env, gag, and pol (454 Roche) was performed on longitudinally collected plasma and peripheral blood mononuclear cell (PBMC) samples while on ART. Sequence data were analyzed for evidence of evolution by (i) molecular diversity analysis, (ii) nonparametric test for panmixia, and (iii) tip date randomization within a Bayesian framework. There was a longitudinal decay of HIV DNA after initiation of ART with no difference between MVC intensification groups (-0.08 ± 0.01 versus -0.09 ± 0.01 log10 copies/week in MVC+ versus MVC- groups; P = 0.62). All participants had low-level residual viremia (median, 2.8 RNA copies/ml). Across participants, medians of 56 (interquartile range [IQR], 36 to 74), 29 (IQR, 25 to 35), and 40 (IQR, 31 to 54) haplotypes were generated for env, gag, and pol regions, respectively. There was no clear evidence of viral evolution during ART and no difference in viral diversity or population structure from individuals with or without MVC intensification. Further efforts focusing on elucidating the mechanism(s) of viral persistence in various compartments using recent sequencing technologies are still needed, and potential low-level viral replication should always be considered in cure strategies.IMPORTANCE Residual viremia is common among HIV-infected people on ART. It remains controversial if this viremia is a consequence of propagating infection. We hypothesized that molecular evolution would be detectable during viral propagation and that therapy intensified with the entry inhibitor maraviroc would demonstrate less evolution. We performed a randomized double-blinded treatment trial with 18 acutely infected men (standard ART versus standard ART plus maraviroc). From longitudinally collected blood plasma and cells, levels of HIV DNA and cell-free HIV RNA were quantified by droplet digital PCR, and HIV DNA (env, gag, and pol coding regions) was deep sequenced (454 Roche). Investigating people who started ART during the earliest stages of their HIV infection, when viral diversity is low, provides an opportunity to detect evidence of viral evolution. Despite using a battery of analytical techniques, no clear and consistent evidence of viral propagation for over 90 weeks of observation could be discerned.


Assuntos
Antagonistas dos Receptores CCR5/uso terapêutico , Cicloexanos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Triazóis/uso terapêutico , Viremia/tratamento farmacológico , Replicação Viral/efeitos dos fármacos , Adulto , Terapia Antirretroviral de Alta Atividade , Teorema de Bayes , California , DNA Viral/sangue , Método Duplo-Cego , Feminino , Infecções por HIV/virologia , HIV-1/genética , HIV-1/fisiologia , Humanos , Masculino , Maraviroc , RNA Viral/sangue , Carga Viral , Adulto Jovem
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