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1.  The Global Transmission Network of HIV-1 
The Journal of Infectious Diseases  2013;209(2):304-313.
Human immunodeficiency virus type 1 (HIV-1) is pandemic, but its contemporary global transmission network has not been characterized. A better understanding of the properties and dynamics of this network is essential for surveillance, prevention, and eventual eradication of HIV. Here, we apply a simple and computationally efficient network-based approach to all publicly available HIV polymerase sequences in the global database, revealing a contemporary picture of the spread of HIV-1 within and between countries. This approach automatically recovered well-characterized transmission clusters and extended other clusters thought to be contained within a single country across international borders. In addition, previously undescribed transmission clusters were discovered. Together, these clusters represent all known modes of HIV transmission. The extent of international linkage revealed by our comprehensive approach demonstrates the need to consider the global diversity of HIV, even when describing local epidemics. Finally, the speed of this method allows for near-real-time surveillance of the pandemic's progression.
doi:10.1093/infdis/jit524
PMCID: PMC3873788  PMID: 24151309
human immunodeficiency virus; transmission network; molecular epidemiology
2.  Cytomegalovirus Replication in Semen Is Associated with Higher Levels of Proviral HIV DNA and CD4+ T Cell Activation during Antiretroviral Treatment 
Journal of Virology  2014;88(14):7818-7827.
ABSTRACT
Asymptomatic cytomegalovirus (CMV) replication occurs frequently in the genital tract in untreated HIV-infected men and is associated with increased immune activation and HIV disease progression. To determine the connections between CMV-associated immune activation and the size of the viral reservoir, we evaluated the interactions between (i) asymptomatic seminal CMV replication, (ii) levels of T cell activation and proliferation in blood, and (iii) the size and transcriptional activity of the HIV DNA reservoir in blood from 53 HIV-infected men on long-term antiretroviral therapy (ART) with suppressed HIV RNA in blood plasma. We found that asymptomatic CMV shedding in semen was associated with significantly higher levels of proliferating and activated CD4+ T cells in blood (P < 0.01). Subjects with detectable CMV in semen had approximately five times higher average levels of HIV DNA in blood CD4+ T cells than subjects with no CMV. There was also a trend for CMV shedders to have increased cellular (multiply spliced) HIV RNA transcription (P = 0.068) compared to participants without CMV, but it is unclear if this transcription pattern is associated with residual HIV replication. In multivariate analysis, the presence of seminal plasma CMV (P = 0.04), detectable 2-long terminal repeat (2-LTR), and lower nadir CD4+ (P < 0.01) were independent predictors of higher levels of proviral HIV DNA in blood. Interventions aimed at reducing seminal CMV and associated immune activation may be important for HIV curative strategies. Future studies of anti-CMV therapeutics will help to establish causality and determine the mechanisms underlying these described associations.
IMPORTANCE Almost all individuals infected with HIV are also infected with cytomegalovirus (CMV), and the replication dynamics of the two viruses likely influence each other. This study investigated interactions between asymptomatic CMV replication within the male genital tract, levels of inflammation in blood, and the size of the HIV DNA reservoir in 53 HIV-infected men on long-term antiretroviral therapy (ART) with suppressed HIV RNA in blood plasma. In support of our primary hypothesis, shedding of CMV DNA in semen was associated with increased activation and proliferation of T cells in blood and also significantly higher levels of HIV DNA in blood cells. These results suggest that CMV reactivation might play a role in the maintenance of the HIV DNA reservoir during suppressive ART and that it could be a target of pharmacologic intervention in future studies.
doi:10.1128/JVI.00831-14
PMCID: PMC4097769  PMID: 24789781
3.  High Prevalence of Hepatitis Delta Virus among Patients with Chronic Hepatitis B Virus Infection and HIV-1 in an Intermediate Hepatitis B Virus Endemic Region 
We conducted a study to investigate HIV and hepatitis delta virus (HDV) coinfection among patients with chronic hepatitis B virus (HBV) infection and the triple infection’s (HIV/HBV/HDV) clinical implications in India, an intermediate HBV endemic region, with an estimated HIV-positive population of 2.5 million. A total of 450 patients (men: 270; women: 180) with chronic HBV infections and 135 healthy volunteers were screened for HIV and HDV. The incidence of the triple infection was low (4 [0.8%]) compared with dual infections of HIV-1/HBV (7 [1.5%]) and HBV/HDV (22[4.8%]). Among 21- to 40-year-olds, HBV/HDV coinfection (45.8%) and HBV/HDV/HIV-1 triple infection was predominant (75%). Among 11 patients coinfected with HIV-1/HBV, 4 (36%) were tri-infected and were also associated with chronic hepatitis and cirrhosis. The HDV coinfection was higher among patients coinfected with HBV/HIV-1, despite the declining trend in HDV infection among HIV-negative patients, as previously reported. Thus, it is important to assess the impact of HIV, chronic HBV, and HDV tri-infection in India.
doi:10.1177/2325957413488166
PMCID: PMC4114572  PMID: 23722085
coinfection in India; hepatitis delta virus (HDV); hepatitis B virus (HBV); human immunodeficiency virus (HIV)
4.  Real-World Impact of Neurocognitive Deficits in Acute and Early HIV Infection 
Journal of neurovirology  2013;19(6):10.1007/s13365-013-0218-2.
The acute and early period of HIV-1 infection (AEH) is characterized by neuroinflammatory and immunopathogenic processes that can alter the integrity of neural systems and neurocognitive functions. However, the extent to which central nervous system changes in AEH confer increased risk of real-world functioning (RWF) problems is not known. In the present study, 34 individuals with AEH and 39 seronegative comparison participants completed standardized neuromedical, psychiatric, and neurocognitive research evaluations, alongside a comprehensive assessment of RWF that included cognitive symptoms in daily life, basic and instrumental activities of daily living, clinician-rated global functioning, and employment. Results showed that AEH was associated with a significantly increased risk of dependence in RWF, which was particularly elevated among AEH persons with global neurocognitive impairment (NCI). Among those with AEH, NCI (i.e., deficits in learning and information processing speed), mood disorders (i.e., Bipolar Disorder), and substance dependence (e.g., methamphetamine dependence) were all independently predictive of RWF dependence. Findings suggest that neurocognitively impaired individuals with AEH are at notably elevated risk of clinically significant challenges in normal daily functioning. Screening for neurocognitive, mood, and substance use disorders in AEH may facilitate identification of individuals at high risk of functional dependence who may benefit from psychological and medical strategies to manage their neuropsychiatric conditions.
doi:10.1007/s13365-013-0218-2
PMCID: PMC3865175  PMID: 24277439
Infectious disease; Disability; Substance use; Neuropsychology; AIDS-related Dementia
5.  Dual-mixed HIV-1 Coreceptor Tropism and HIV-Associated Neurocognitive Deficits 
Journal of neurovirology  2013;19(5):488-494.
Background
HIV coreceptor usage of CXCR4 (X4) is associated with decreased CD4+ T-cell counts and accelerated disease progression, but the role of X4 tropism in HIV-associated neurocognitive disorders (HAND) has not previously been described.
Methods
This longitudinal study evaluated data on 197 visits from 72 recently HIV-infected persons who had undergone up to 4 sequential neurocognitive assessments over a median of 160 days (IQR 138–192). Phenotypic tropism testing (Trofile ES, Monogram, Biosciences) was performed on stored blood samples. Multivariable mixed model repeated measures regression was used to determine the association between HAND and dual-mixed (DM) viral tropism, estimated duration of infection (EDI), HIV RNA, CD4 count and problematic methamphetamine use.
Results
Six subjects (8.3%) had dual mixed tropism (DM) at their first neurocognitive assessment and four converted to DM in subsequent sampling (for total of 10 DM) at a median EDI of 10.1 months (IQR 7.2–12.2). There were 44 (61.1%) subjects who demonstrated HAND on at least one study visit. HAND was associated with DM tropism (odds ratio 4.4, 95% CI 0.9–20.5) and shorter EDI (odds ratio 1.1 per month earlier, 95% CI 1.0–1.2).
Conclusion
This study found that recency of HIV-1 infection and the development of DM tropism may be associated with HAND in the relatively early stage of infection. Together these data suggest that viral interaction with cellular receptors may play an important role in the early manifestation of HAND.
doi:10.1007/s13365-013-0203-9
PMCID: PMC3921071  PMID: 24078557
HIV-associated neurocognitive disorders; coreceptor tropism; methamphetamine
6.  IDEPI: Rapid Prediction of HIV-1 Antibody Epitopes and Other Phenotypic Features from Sequence Data Using a Flexible Machine Learning Platform 
PLoS Computational Biology  2014;10(9):e1003842.
Since its identification in 1983, HIV-1 has been the focus of a research effort unprecedented in scope and difficulty, whose ultimate goals — a cure and a vaccine – remain elusive. One of the fundamental challenges in accomplishing these goals is the tremendous genetic variability of the virus, with some genes differing at as many as 40% of nucleotide positions among circulating strains. Because of this, the genetic bases of many viral phenotypes, most notably the susceptibility to neutralization by a particular antibody, are difficult to identify computationally. Drawing upon open-source general-purpose machine learning algorithms and libraries, we have developed a software package IDEPI (IDentify EPItopes) for learning genotype-to-phenotype predictive models from sequences with known phenotypes. IDEPI can apply learned models to classify sequences of unknown phenotypes, and also identify specific sequence features which contribute to a particular phenotype. We demonstrate that IDEPI achieves performance similar to or better than that of previously published approaches on four well-studied problems: finding the epitopes of broadly neutralizing antibodies (bNab), determining coreceptor tropism of the virus, identifying compartment-specific genetic signatures of the virus, and deducing drug-resistance associated mutations. The cross-platform Python source code (released under the GPL 3.0 license), documentation, issue tracking, and a pre-configured virtual machine for IDEPI can be found at https://github.com/veg/idepi.
doi:10.1371/journal.pcbi.1003842
PMCID: PMC4177671  PMID: 25254639
7.  Cerebrospinal fluid can be used for HIV genotyping when it fails in blood 
Arquivos de neuro-psiquiatria  2014;72(7):506-509.
Blood plasma specimens are the clinical standard for HIV-1 pol gene genotyping from viral populations; however, it is not always successful, often from low viral loads or the presence of polymerase chain reaction (PCR) inhibitors.
Objective
To describe the successful of HIV-1 genotyping in two samples of cerebrospinal fluid (CSF), after genotype procedures failed from blood.
Method
Two HIV-infected patients enrolled in a neurocognitive research study were evaluated when standard HIV-1 genotyping failed from blood plasma samples. Genotyping was performed using the commercial system TRUGENE® HIV-1 Genotyping Kit and the OpenGene® DNA Sequencing System (Siemens Healthcare Diagnostics, Tarrytown, NY, USA).
Results
CSF genotyping was performed via the same commercial platform and was successful in both cases.
Conclusion
This report demonstrates that CSF could be used as an alternate clinical specimen for HIV-1 genotyping when it fails from blood.
PMCID: PMC4139176  PMID: 25054982
HIV-1; clades; genotyping; cerebrospinal fluid; central nervous system
8.  Reply to Mounzer and DiNubile 
The Journal of Infectious Diseases  2013;208(4):711-712.
doi:10.1093/infdis/jit218
PMCID: PMC3719903  PMID: 23667136
9.  Shedding of HIV and Human Herpesviruses in the Semen of Effectively Treated HIV-1–Infected Men Who Have Sex With Men 
The study aimed to understand the associations between coinfections and HIV RNA shedding in the genital tract of men receiving antiretroviral therapy with suppressed blood plasma viral load.
Background. Current antiretroviral therapy (ART) suppresses human immunodeficiency virus (HIV) in blood to undetectable levels in most infected individuals; however, some men shed HIV in semen despite suppressed levels in blood.
Methods. This study included 114 chronically HIV type 1–infected men who have sex with men, who were receiving ART with blood plasma HIV <500 copies/mL. Asymptomatic participants were screened for bacterial sexually transmitted infections (STIs) and nonspecific genital inflammation. Levels of HIV and 7 human herpesviruses were measured by real-time polymerase chain reaction in seminal plasma. Predictors of HIV seminal shedding were determined for the entire cohort, and on the subset of 100 subjects with blood plasma HIV <50 copies/mL.
Results. Eleven subjects (9.6%) had detectable levels of seminal HIV (median, 2.1 log10 copies/mL), and 72 (63.2%) had at least 1 herpesvirus detected in their seminal plasma. Detectable levels of seminal HIV were present more often in persons with plasma HIV between 50 and 500 copies/mL compared to those <50 copies/mL (P values adjusted for false discovery rate [FDR] = 0.08). There was a trend for high-level cytomegalovirus (CMV; >4 log10 DNA copies/mL; FDR-adjusted P = .08), and presence of Epstein-Barr virus (FDR-adjusted P = .06) in semen to be associated with detectable seminal HIV levels. In a subanalysis of 100 subjects with blood plasma HIV <50 copies/mL, high levels of CMV in semen was the only significant predictor for seminal HIV shedding.
Conclusions. Low-level HIV replication in blood and high-level seminal CMV shedding, but not presence of asymptomatic STIs, is associated with seminal shedding of HIV in men receiving ART, conferring a potential risk for HIV transmission.
doi:10.1093/cid/cit252
PMCID: PMC3703105  PMID: 23595831
cytomegalovirus; HIV shedding; semen; antiretroviral therapy; HIV transmission
10.  Gut Lactobacillales are associated with higher CD4 and less microbial translocation during HIV infection 
AIDS (London, England)  2013;27(12):1921-1931.
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).
Design
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.
Conclusion
Shaping the gut microbiome, especially proportions of Lactobacillales, could help to preserve immune function during HIV infection.
PMCID: PMC3816380  PMID: 24180001
gut-associated lymphoid tissue; gut microbiome; immune activation; microbial translocation; pyrosequencing
11.  Enhanced CD4+ T-Cell Recovery with Earlier HIV-1 Antiretroviral Therapy 
The New England journal of medicine  2013;368(3):218-230.
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.)
doi:10.1056/NEJMoa1110187
PMCID: PMC3657555  PMID: 23323898
12.  Using Ultradeep Pyrosequencing to Study HIV-1 Coreceptor Usage in Primary and Dual Infection 
The Journal of Infectious Diseases  2013;208(2):271-274.
HIV-1 dual infection (DI) and CXCR4 (X4) coreceptor usage are associated with accelerated disease progression but frequency and dynamics of coreceptor usage during DI is unknown. Ultradeep sequencing was used to interrogate for DI and infer coreceptor usage in longitudinal blood samples of 102 subjects. At baseline, X4 usage was high (23 subjects harbored X4 variants) and was not associated with infection duration or DI. Coreceptor usage changed over time in 12 of 47 participants, and X4 usage emerged in 4 of 41 monoinfections vs 2 of 5 superinfections (P = .12), suggesting a weak statistical trend toward occurrence of superinfection and acquiring X4 usage.
doi:10.1093/infdis/jit168
PMCID: PMC3685231  PMID: 23599311
HIV-1 dual infection; HIV-1 coinfection; HIV-1 superinfection; coreceptor tropism; coreceptor usage; ultradeep pyrosequencing; next-generation sequencing; genotypic tropism prediction; genotypic coreceptor usage prediction
14.  Antibody Response to Achromobacter xylosoxidans during HIV Infection Is Associated with Lower CD4 Levels and Increased Lymphocyte Activation 
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.
doi:10.1128/CVI.00553-13
PMCID: PMC3910916  PMID: 24173027
15.  The use of pooled viral load testing to identify antiretroviral treatment failure 
AIDS (London, England)  2009;23(16):2151-2158.
Background
To develop less costly methods to virologically monitor patients receiving antiretroviral therapy, we evaluated methods that use pooled blood samples and quantitative information available from viral load assays to monitor a cohort of patients on first-line antiretroviral therapy for virologic failure.
Methods
We evaluated 150 blood samples collected after 6 months of therapy from participants enrolled in a San Diego primary infection program between January 1998 and January 2007. Samples were screened for virologic failure with individual viral load testing, 10 × 10 matrix pools and minipools of five samples. For the pooled platforms (matrix and minipools), we used a search and retest algorithm based on the quantitative viral load data to resolve samples that remained ambiguous for virologic failure. Viral load thresholds were more than 500 and more than 1500 copies/ml for the matrix and more than 250 and more than 500 copies/ml for the minipool. Efficiency, accuracy and result turnaround times were evaluated.
Results
Twenty-three percent of cohort samples were detectable at more than 50 HIV RNA copies/ml. At an algorithm threshold of more than 500 HIV RNA copies/ml, both minipool and matrix methods used less than half the number of viral load assays to screen the cohort, compared with testing samples individually. Both pooling platforms had negative predictive values of 100% for viral loads of more than 500 HIV RNA copies/ml and at least 94% for viral loads of more than 250 HIV RNA copies/ml.
Conclusion
In this cohort, both pooling methods improved the efficiency of virologic monitoring over individual testing with a minimal decrease in accuracy. These methods may allow for the induction and sustainability of the virologic monitoring of patients receiving antiretroviral therapy in resource-limited settings.
doi:10.1097/QAD.0b013e3283313ca9
PMCID: PMC2915784  PMID: 19730348
antiretroviral therapy; drug resistance; HIV; monitoring; pooling; viral load
16.  Predictors of virologic response in persons who start antiretroviral therapy during recent HIV infection 
AIDS (London, England)  2014;28(6):841-849.
Objective
Despite evidence supporting antiretroviral therapy (ART) in recent HIV infection, little is known about factors that are associated with successful ART. We assessed demographic, virologic, and immunologic parameters to identify predictors of virologic response.
Design
A 24-week observational study of ART on persons enrolled within 6 months of their estimated date of infection (EDI) evaluated baseline demographics and the collection of blood and gut specimens.
Methods
Flow cytometry analyses of blood and gut lymphocytes allowed characterization of CD4+ and CD8+ T cells at study entry and end. Additional assessments included soluble CD14 (sCD14), lipopolysaccharide, CD4+ T-cell counts, and HIV RNA levels.
Results
Twenty nine participants initiated ART, and 17 achieved undetectable HIV RNA by study end. A longer time from EDI to ART, older age, higher sCD14, lower proportions of central memory CD4+ T cells, and higher proportions of activated CD8+ T cells were associated with detectable viremia. Multivariable logistic regression found only older age and elevated sCD14 were independently associated with persistent viremia. Additionally, we observed that ART in recent infection did not result in discernible recovery of CD4+ T cells in the gut.
Conclusion
In persons who started ART within 3–33 weeks from EDI, age and microbial translocation were associated with detectable HIV RNA. As observed in other cohorts, ART in recent infection did not improve proportions of total CD4+ T cells in gut-associated lymphoid tissue (GALT). This lends support to further evaluate the use of more potent ART or regimens that protect the GALT in recent HIV infection.
doi:10.1097/QAD.0000000000000149
PMCID: PMC4049563  PMID: 24401640
antiretroviral therapy; gut-associated lymphoid tissue; microbial translocation; recent HIV; virologic response
17.  Using HIV Networks to Inform Real Time Prevention Interventions 
PLoS ONE  2014;9(6):e98443.
Objective
To reconstruct the local HIV-1 transmission network from 1996 to 2011 and use network data to evaluate and guide efforts to interrupt transmission.
Design
HIV-1 pol sequence data were analyzed to infer the local transmission network.
Methods
We analyzed HIV-1 pol sequence data to infer a partial local transmission network among 478 recently HIV-1 infected persons and 170 of their sexual and social contacts in San Diego, California. A transmission network score (TNS) was developed to estimate the risk of HIV transmission from a newly diagnosed individual to a new partner and target prevention interventions.
Results
HIV-1 pol sequences from 339 individuals (52.3%) were highly similar to sequences from at least one other participant (i.e., clustered). A high TNS (top 25%) was significantly correlated with baseline risk behaviors (number of unique sexual partners and insertive unprotected anal intercourse (p = 0.014 and p = 0.0455, respectively) and predicted risk of transmission (p<0.0001). Retrospective analysis of antiretroviral therapy (ART) use, and simulations of ART targeted to individuals with the highest TNS, showed significantly reduced network level HIV transmission (p<0.05).
Conclusions
Sequence data from an HIV-1 screening program focused on recently infected persons and their social and sexual contacts enabled the characterization of a highly connected transmission network. The network-based risk score (TNS) was highly correlated with transmission risk behaviors and outcomes, and can be used identify and target effective prevention interventions, like ART, to those at a greater risk for HIV-1 transmission.
doi:10.1371/journal.pone.0098443
PMCID: PMC4047027  PMID: 24901437
18.  Pleocytosis Is Associated with Disruption of HIV Compartmentalization between Blood and Cerebral Spinal Fluid Viral Populations 
Virology  2008;385(1):204-208.
Introduction
We hypothesized that pleocytosis, which is a marker of central nervous system (CNS) inflammation, would result in viral genetic equilibration or de-compartmentalization between HIV populations in the blood and cerebrospinal fluid (CSF), suggesting lymphocyte trafficking.
Methods
Study subjects, who started or interrupted their antiretroviral treatment, had viral loads measured and clonal viral env sequences generated from HIV RNA extracted from paired blood and CSF samples. White blood counts in CSF were also measured at each timepoint. Degree of inter-compartment segregation was calculated by posterior probability using linear discriminant analysis and multidimensional scaling. Co-receptor usage was determined using a trained support vector machine.
Results
Pleocytosis was strongly associated with disruption of viral compartmentalization.
Conclusions
Inflammation in the CNS, marked by pleocytosis, allows HIV populations to mix between blood and CSF, which may increase the overall viral genetic diversity within the CSF.
doi:10.1016/j.virol.2008.11.010
PMCID: PMC2794037  PMID: 19100592
HIV; Neurovirulence; Neuroadaptation; Cerebrospinal fluid; Pleocytosis
19.  Dynamics of Viral Evolution and Neutralizing Antibody Response after HIV-1 Superinfection 
Journal of Virology  2013;87(23):12737-12744.
Investigating the incidence and prevalence of HIV-1 superinfection is challenging due to the complex dynamics of two infecting strains. The superinfecting strain can replace the initial strain, be transiently expressed, or persist along with the initial strain in distinct or in recombined forms. Various selective pressures influence these alternative scenarios in different HIV-1 coding regions. We hypothesized that the potency of the neutralizing antibody (NAb) response to autologous viruses would modulate viral dynamics in env following superinfection in a limited set of superinfection cases. HIV-1 env pyrosequencing data were generated from blood plasma collected from 7 individuals with evidence of superinfection. Viral variants within each patient were screened for recombination, and viral dynamics were evaluated using nucleotide diversity. NAb responses to autologous viruses were evaluated before and after superinfection. In 4 individuals, the superinfecting strain replaced the original strain. In 2 individuals, both initial and superinfecting strains continued to cocirculate. In the final individual, the surviving lineage was the product of interstrain recombination. NAb responses to autologous viruses that were detected within the first 2 years of HIV-1 infection were weak or absent for 6 of the 7 recently infected individuals at the time of and shortly following superinfection. These 6 individuals had detectable on-going viral replication of distinct superinfecting virus in the env coding region. In the remaining case, there was an early and strong autologous NAb response, which was associated with extensive recombination in env between initial and superinfecting strains. This extensive recombination made superinfection more difficult to identify and may explain why the detection of superinfection has typically been associated with low autologous NAb titers.
doi:10.1128/JVI.02260-13
PMCID: PMC3838120  PMID: 24049166
20.  A Public Health Model for the Molecular Surveillance of HIV Transmission in San Diego, California 
AIDS (London, England)  2009;23(2):225-232.
Background
Current public health efforts often use molecular technologies to identify and contain communicable disease networks, but not for HIV. Here, we investigate how molecular epidemiology can be used to identify highly-related HIV networks within a population and how voluntary contact tracing of sexual partners can be used to selectively target these networks.
Methods
We evaluated the use of HIV-1 pol sequences obtained from participants of a community-recruited cohort (n=268) and a primary infection research cohort (n=369) to define highly related transmission clusters and the use of contact tracing to link other individuals (n=36) within these clusters. The presence of transmitted drug resistance was interpreted from the pol sequences (Calibrated Population Resistance v3.0).
Results
Phylogenetic clustering was conservatively defined when the genetic distance between any two pol sequences was <1%, which identified 34 distinct transmission clusters within the combined community-recruited and primary infection research cohorts containing 160 individuals. Although sequences from the epidemiologically-linked partners represented approximately 5% of the total sequences, they clustered with 60% of the sequences that clustered from the combined cohorts (O.R. 21.7; p=<0.01). Major resistance to at least one class of antiretroviral medication was found in 19% of clustering sequences.
Conclusions
Phylogenetic methods can be used to identify individuals who are within highly related transmission groups, and contact tracing of epidemiologically-linked partners of recently infected individuals can be used to link into previously-defined transmission groups. These methods could be used to implement selectively targeted prevention interventions.
doi:10.1097/QAD.0b013e32831d2a81
PMCID: PMC2644048  PMID: 19098493
molecular epidemiology; HIV; surveillance; contact tracing; drug resistance
21.  Comparison of algorithms that interpret genotypic HIV-1 drug resistance to determine the prevalence of transmitted drug resistance 
AIDS (London, England)  2008;22(7):835-839.
Objective
We compared eight genotypic interpretation methods to determine whether the method used would affect the rates of reported transmitted drug resistance.
Design
Retrospective cohort study.
Methods
For the International AIDS Society-USA method we classified a mutation as resistant if it was a ‘major’ resistance-associated mutation. For the Stanford algorithm, we classified a mutation as resistant if the score was at least 60 (Stanford 60), and alternatively, if the score was at least 30 (Stanford 30). For Agence Nationale de Recherches sur le SIDA and Rega, we interpreted resistance as either ‘intermediate resistance’ or ‘resistance’ (ANRS 1 and Rega 1), and ‘resistance’ only (ANRS 2 and Rega 2). We also used the calibrated population resistance algorithm. We then determined the rates of transmitted drug resistance within the Acute Infection Early Disease Research Program cohort (n = 1311) enrolled between March 1995 and August 2006 using each method; agreement was assessed using kappa coefficients.
Results
Differences in estimated rates of transmitted drug resistance using International AIDS Society-USA, calibrated population resistance, Stanford 30, ANRS 1, Rega 1 and Rega 2 methods were mostly minor for resistance to protease and non-nucleoside reverse transcriptase inhibitors (1% range) and more pronounced for nucleoside reverse transcriptase inhibitors (5% range). For these methods kappa agreement was substantial or almost perfect across all drug classes. The Stanford 60 was most conservative.
Conclusions
The persistent high rates of transmitted drug resistance support the need for continued genotypic surveillance. The currently available interpretation algorithms can be used for this purpose.
doi:10.1097/QAD.0b013e3282f5ff71
PMCID: PMC2716722  PMID: 18427201
algorithms; HIV; prevalence; transmitted drug resistance
22.  Etravirine in CSF is highly protein bound 
Objectives
Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α1-acid glycoprotein, which limits the amount of unbound etravirine available to enter the CNS. The objective of this study was to compare total and unbound etravirine concentrations in CSF with plasma concentrations and the in vitro median inhibitory concentration (IC50) for wild-type HIV (0.9 ng/mL).
Methods
Total and bound etravirine concentrations were measured in 17 CSF and plasma pairs by isotope-dilution liquid chromatography tandem mass spectroscopy, radioligand displacement and ultracentrifugation. Unbound etravirine concentrations were calculated from the bound fraction. The dynamic range of the assay was 7.8–2000 (plasma) and 0.78–200 (CSF) ng/mL.
Results
Subjects were mostly middle-aged (median 43 years) white (78%) men (89%). All CSF etravirine concentrations were above the limit of quantification. Total and unbound median etravirine concentrations in CSF were 9.5 (IQR 6.4, 26.4) and 0.13 (IQR 0.08, 0.27) ng/mL, respectively. Etravirine was 96% (IQR 94.5, 97.2) protein bound in plasma and 98.4% (IQR 97.8, 98.8) in CSF. Total etravirine in CSF was 4.3% (IQR 3, 5.9) of total and 101% (IQR 76, 160) of unbound etravirine in plasma. There were no significant correlations between unbound etravirine concentrations and concentrations of albumin in plasma or CSF. Unbound etravirine concentrations in CSF did not reach the wild-type IC50 in any of the specimens.
Conclusions
Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS.
doi:10.1093/jac/dks517
PMCID: PMC3625433  PMID: 23335197
HIV; antiretroviral therapy; central nervous system; CNS; protein binding; CSF
24.  Rapid Progression to Decompensated Cirrhosis, Liver Transplant, and Death in HIV-Infected Men After Primary Hepatitis C Virus Infection 
Four men from a cohort of HIV-infected men who did not achieve cure after primary hepatitis C virus infection developed decompensated cirrhosis within 17 months to 6 years after infection, with subsequent rapid progression to liver transplant and death.
Background. We and others have shown that primary hepatitis C (HCV) infection in men infected with human immunodeficiency virus (HIV) causes early-onset liver fibrosis; however, little is known about the long-term natural history of the liver disease in these HIV-infected men.
Methods. We followed a cohort of HIV-infected men with primary HCV infection in New York City.
Results. Four men who were not cured after their primary HCV infection developed decompensated cirrhosis within 17 months to 6 years after primary HCV infection. Three died within 8 years of primary HCV infection, and 1 survived after liver transplant done 2 years after primary HCV infection. Three of the 4 men had AIDS at the time of primary HCV infection, and the most rapid progression occurred in the 2 men with the lowest CD4 counts at the time of HCV infection. Liver histopathology was most consistent with HCV-induced damage even though some had exposures to other potential hepatotoxins.
Conclusions. Primary HCV infection resulted in decompensated cirrhosis and death within 2–8 years in 4 HIV-infected men. The rapid onset of fibrosis due to primary HCV infection in HIV-infected men cannot therefore be considered benign. The rate of continued progression to liver failure may be proportional to the degree of underlying immunocompromise caused by HIV infection. More research is needed to better define the mechanisms behind accelerated liver damage.
doi:10.1093/cid/cis1206
PMCID: PMC3588118  PMID: 23264364
liver failure; primary acute hepatitis C infection; HIV infection/AIDS; immunocompromise; men who have sex with men
25.  Mathematical Modeling of HIV Prevention Measures Including Pre-Exposure Prophylaxis on HIV Incidence in South Korea 
PLoS ONE  2014;9(3):e90080.
Background
Multiple prevention measures have the possibility of impacting HIV incidence in South Korea, including early diagnosis, early treatment, and pre-exposure prophylaxis (PrEP). We investigated how each of these interventions could impact the local HIV epidemic, especially among men who have sex with men (MSM), who have become the major risk group in South Korea. A mathematical model was used to estimate the effects of each these interventions on the HIV epidemic in South Korea over the next 40 years, as compared to the current situation.
Methods
We constructed a mathematical model of HIV infection among MSM in South Korea, dividing the MSM population into seven groups, and simulated the effects of early antiretroviral therapy (ART), early diagnosis, PrEP, and combination interventions on the incidence and prevalence of HIV infection, as compared to the current situation that would be expected without any new prevention measures.
Results
Overall, the model suggested that the most effective prevention measure would be PrEP. Even though PrEP effectiveness could be lessened by increased unsafe sex behavior, PrEP use was still more beneficial than the current situation. In the model, early diagnosis of HIV infection was also effectively decreased HIV incidence. However, early ART did not show considerable effectiveness. As expected, it would be most effective if all interventions (PrEP, early diagnosis and early treatment) were implemented together.
Conclusions
This model suggests that PrEP and early diagnosis could be a very effective way to reduce HIV incidence in South Korea among MSM.
doi:10.1371/journal.pone.0090080
PMCID: PMC3963840  PMID: 24662776

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