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1.  Predictors of virologic response in persons who start antiretroviral therapy during recent HIV infection 
AIDS (London, England)  2014;28(6):841-849.
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.
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.
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.
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.
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.
PMCID: PMC4049563  PMID: 24401640
antiretroviral therapy; gut-associated lymphoid tissue; microbial translocation; recent HIV; virologic response
2.  Using HIV Networks to Inform Real Time Prevention Interventions 
PLoS ONE  2014;9(6):e98443.
To reconstruct the local HIV-1 transmission network from 1996 to 2011 and use network data to evaluate and guide efforts to interrupt transmission.
HIV-1 pol sequence data were analyzed to infer the local transmission network.
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.
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).
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.
PMCID: PMC4047027  PMID: 24901437
3.  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.
PMCID: PMC3838120  PMID: 24049166
4.  Etravirine in CSF is highly protein bound 
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).
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.
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.
Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS.
PMCID: PMC3625433  PMID: 23335197
HIV; antiretroviral therapy; central nervous system; CNS; protein binding; CSF
6.  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.
PMCID: PMC3588118  PMID: 23264364
liver failure; primary acute hepatitis C infection; HIV infection/AIDS; immunocompromise; men who have sex with men
7.  Mathematical Modeling of HIV Prevention Measures Including Pre-Exposure Prophylaxis on HIV Incidence in South Korea 
PLoS ONE  2014;9(3):e90080.
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.
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.
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.
This model suggests that PrEP and early diagnosis could be a very effective way to reduce HIV incidence in South Korea among MSM.
PMCID: PMC3963840  PMID: 24662776
8.  Cytomegalovirus DNA in Semen and Blood Is Associated With Higher Levels of Proviral HIV DNA 
The Journal of Infectious Diseases  2012;207(6):898-902.
Over three-fourths of human immunodeficiency virus (HIV)–infected men who have sex with men (MSM) have at least one herpesvirus detected in their semen, and cytomegalovirus (CMV) is the most prevalent. The presence of CMV is associated with higher T-cell immune activation and with HIV disease progression in treated and untreated individuals. In this study of 113 antiretroviral (ART)–naive HIV-infected MSM, we found that CMV replication in blood and semen was associated with higher levels of HIV DNA in peripheral blood mononuclear cells. These observations suggest that interventions aimed to reduce CMV replication and, thus, systemic immune activation could decrease the size of the latent HIV reservoir.
PMCID: PMC3571441  PMID: 23275608
cytomegalovirus; HIV DNA; latent reservoir; immune activation; early HIV infection
9.  Darunavir Is a Good Third-Line Antiretroviral Agent for HIV Type 1-Infected Patients Failing Second-Line Protease Inhibitor-Based Regimens in South India 
Eleven protease mutations have been associated with reduced susceptibility to darunavir. In this study of 87 HIV-1-infected patients experiencing virological failure to second-line regimens containing protease inhibitors boosted with ritonavir (viral load >1,000 HIV RNA copies/ml), we observed a low prevalence (3%) of ≥3 darunavir resistance-associated mutations, indicating that this drug may be a good option for third-line antiretroviral therapy in southern India.
PMCID: PMC3581023  PMID: 23045961
11.  Enhanced CD4+ T-Cell Recovery with Earlier HIV-1 Antiretroviral Therapy 
The New England journal of medicine  2013;368(3):218-230.
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.
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.
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.
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.)
PMCID: PMC3657555  PMID: 23323898
12.  Substance Use is a Risk Factor for Neurocognitive Deficits and Neuropsychiatric Distress in Acute and Early HIV Infection 
Journal of neurovirology  2012;19(1):65-74.
The acute and early stages of HIV infection (AEH) are characterized by substantial viral replication, immune activation, and alterations in brain metabolism. However, little is known about the prevalence and predictors of neurocognitive deficits and neuropsychiatric disturbances during this period. The present study examined the impact of demographic, HIV disease, and substance use factors on HIV-associated neurocognitive impairment and self-reported neuropsychiatric distress among 46 antiretroviral-naïve adults with median duration of infection of 75 days, relative to sample a of 21 HIV seronegative (HIV-) adults with comparable demographics and risk factors. Participants were administered a brief neurocognitive battery that was adjusted for demographics and assessed executive functions, memory, psychomotor speed, and verbal fluency, as well as the Profile of Mood States (POMS), a self-report measure of neuropsychiatric distress. Odds ratios revealed that AEH participants were nearly four times more likely than their seronegative counterparts to experience neurocognitive impairment, particularly in the areas of learning and information processing speed. Similarly, AEH was associated with a nearly five-fold increase in the odds of neuropsychiatric distress, most notably in anxiety and depression. Within the AEH sample, HIV-associated neurocognitive impairment was associated with problematic methamphetamine use and higher plasma HIV RNA levels, whereas neuropsychiatric distress was solely associated with high-risk alcohol use. Extending prior neuroimaging findings, results from this study indicate that HIV-associated neurocognitive impairment and neuropsychiatric distress are highly prevalent during AEH and are associated with high-risk substance use.
PMCID: PMC3568179  PMID: 23250704
HIV; substance abuse; viral load; neuropsychiatry; AIDS dementia complex
13.  Role of Seminal Shedding of Herpesviruses in HIV Type 1 Transmission 
The Journal of Infectious Diseases  2012;207(2):257-261.
To investigate the role of genital shedding of herpesviruses in human immunodeficiency virus type 1 (HIV) transmission, we compared 20 HIV-infected men who did and 26 who did not transmit HIV to their sex partners. As described previously, HIV transmission was associated with the potential source partner having higher levels of HIV RNA in blood and semen, having lower CD4+ T cell counts, having bacterial coinfections in the genital tract, and not using antiretroviral therapy. This study extended these findings by observing significant associations between HIV transmission and the following characteristics, especially among therapy-naive potential source partners: seminal cytomegalovirus (CMV) shedding, seminal Epstein-Barr virus shedding, and levels of anti CMV immunoglobulin in blood plasma.
PMCID: PMC3532824  PMID: 23148284
Herpes viruses; HIV-1 transmission; genital coinfections; men who have sex with men; antiretroviral therapy
14.  The Use of High Performance Liquid Chromatography to Speciate and Characterize the Epidemiology of Mycobacteria 
Laboratory medicine  2011;42(10):612-617.
We evaluated high-performance liquid chromatography (HPLC) for species identification of mycobacteria from various clinical specimens in an urban hospital in South Korea between January 2005 and December 2009.
In the study period 24,774 cultures were completed, yielding the 3215 clinical isolates cultivated for mycobacteria and positive cultures that had mycolic acid investigated by HPLC. For species identification, we compared HPLC patterns of clinical isolates with 33 standard Mycobacterium species.
There were 3 different HPLC groups with single, double, and triple-cluster patterns representing 9, 20, and 4 mycobacterial species, respectively. Species identification rates of HPLC for Mycobacterium tuberculosis and nontuberculous mycobacteria (NTM) were found to be 100% and 95.6%, respectively. Among mycobacterial isolates, 12.1% were NTM-positive. There were 20 different NTM species with frequencies of 0.3%~15.5%.
The HPLC method was highly sensitive identifying NTM isolated from clinical specimens.
PMCID: PMC3892985  PMID: 24443588
mycobacteria; Mycobacterium tuberculosis; nontuberculous mycobacteria; HPLC
15.  Herpesviruses and HIV-1 drug resistance mutations influence the virologic and immunologic milieu of the male genital tract 
AIDS (London, England)  2013;27(1):39-47.
To further understand the role that chronic viral infections of the male genital tract play on HIV-1 dynamics and replication.
Retrospective, observational study including236 paired semen and blood samples collected from 115 recently HIV-1 infected antiretroviral naïve men who have sex with men (MSM).
In this study, we evaluated the association ofseminal HIV-1 shedding to coinfections with seven herpesviruses, blood plasma HIV-1 RNA levels, CD4+ T-cell counts, presence of transmitted drug resistance mutations (DRM) in HIV-1 pol, participants’ age and stage of HIV-infection using multivariate generalized estimating equation methods (GEE). Associations between herpesvirus shedding, seminal HIV-1 levels, number and immune activation of seminal T-cells was also investigated (Mann Whitney).
Seminal herpesvirus shedding was observed in 75.7% of subjects. Blood HIV-1 RNA levels (p<0.01), and seminal CMV and HHV-8 levels (p<0.05) were independent predictors of detectable seminal HIV-1 RNA, and higher seminal HIV-1 levelswere associated with CMV and EBV seminal shedding,and absence of DRM (p < 0.05). CMV and EBV seminal shedding was associated with higher number of seminalT-lymphocytes, but onlypresence of seminal CMV DNA was associated withincreasedimmune activation of T-lymphocytes in semen and blood.
Despite high median CD4cells number, we found a high frequency of herpesviruses seminal shedding in our cohort. Shedding of CMV, EBV and HHV-8 and absence of DRM were associated with increased frequency of HIV-1 shedding and/or higher levels of HIV-1 RNA in semen, which are likely important co-factors for HIV-1 transmission.
PMCID: PMC3769229  PMID: 22739399
cytomegalovirus; genital tract; herpesvirus; HIV; HIV drug resistance; men who have sex with men; seminal shedding
16.  The price of tenofovir-emtricitabine undermines the cost-effectiveness and advancement of pre-exposure prophylaxis 
AIDS (London, England)  2011;25(18):10.1097/QAD.0b013e32834d3cab.
PMCID: PMC3874210  PMID: 22067201
17.  Sexual Transmission of predicted CXCR4-tropic HIV-1 likely originating from the Source Partner’s Seminal Cells 
Virology  2012;434(1):2-4.
We present a case of sexual transmission of HIV-1 predicted to have CXCR4-tropism during male-to-male sexual exposure. Phylogenetic analyses exclude cell-free virus in the seminal plasma of the source partner and possibly point to the seminal cells as the origin of the transmission event.
PMCID: PMC3485073  PMID: 23040890
18.  Unusual Insertion and Deletion at Codon 67 and 69 of HIV Type 1 Subtype C Reverse Transcriptase Among First-Line Highly Active Antiretroviral Treatment-Failing South Indian Patients: Association with Other Resistance Mutations 
AIDS Research and Human Retroviruses  2012;28(12):1763-1765.
We report a high frequency of drug resistance mutations among patients with unusual insertions or deletions at the β3–β4 hairpin-loop-coding region of HIV-1 subtype C reverse transcriptase, during failure of first-line antiretroviral therapy containing only reverse transcriptase inhibitors in Chennai, India.
PMCID: PMC3505055  PMID: 22404052
19.  Higher HIV-1 Genetic Diversity is Associated with AIDS and Neuropsychological Impairment 
Virology  2012;433(2):498-505.
Standard methods used to estimate HIV-1 population diversity are often resource intensive (e.g., single genome amplification, clonal amplification and pyrosequencing) and not well suited for large study cohorts. Additional approaches are needed to address the relationships between intraindividual HIV-1 genetic diversity and disease. With a small cohort of individuals, we validated three methods for measuring diversity: Shannon entropy and average pairwise distance (APD) using single genome sequences, and counts of mixed bases (i.e. ambiguous nucleotides) from population-based sequences. In a large cohort, we then used the mixed base approach to determine associations between measure HIV-1 diversity and HIV associated disease. Normalized counts of mixed bases correlated with Shannon Entropy at both the nucleotide (rho=0.72, p=0.002) and amino acid level (rho=0.59, p=0.015), and APD (rho=0.75, p=0.001). Among participants who underwent neuropsychological and clinical assessments (n=187), increased HIV-1 population diversity was associated with both a diagnosis of AIDS and neuropsychological impairment.
PMCID: PMC3466337  PMID: 22999095
HIV; AIDS; genetic diversity; neuropsychological impairment; viral population dynamics
20.  Impact of Seminal Cytomegalovirus Replication on HIV-1 Dynamics between Blood and Semen 
Journal of medical virology  2012;84(11):1703-1709.
The genital tract of individuals infected with HIV-1 is an anatomic compartment that supports local HIV-1 and CMV replication. This study investigated the association of seminal CMV replication with changes in HIV-1 clonal expansion, evolution and phylogenetic compartmentalization between blood and semen. Fourteen paired blood and semen samples were analyzed from four untreated subjects. Clonal sequences (n=607) were generated from extracted HIV-1 RNA (env C2-V3 region), and HIV-1 and CMV levels were measured in the seminal plasma by real-time PCR. Sequence alignments were evaluated for: (i) viral compartmentalization between semen and blood samples using Slatkin-Maddison and FST methods, (ii) different nucleotide substitution rates in semen and blood, and (iii) association between proportions of clonal HIV-1 sequences in each compartment and seminal CMV levels. Half of the semen samples had detectable CMV DNA, with at least one CMV positive sample for each patient. Seminal CMV DNA levels correlated positively with seminal HIV-1 RNA levels (Spearman p=0.05). A trend towards an association between compartmentalization of HIV-1 sequences sampled from blood and semen and presence of seminal CMV was observed (Cochran Q test p=0.12). Evolutionary rates between semen and blood HIV-1 populations did not differ significantly, and there was no significant association between seminal CMV DNA levels and the frequency of non-unique clonal HIV-1 sequences in the semen. In conclusion, the effects of CMV replication on HIV-1 viral and immunologic dynamics within the male genital tract are not significant enough to perturb evolution or disrupt compartmentalization in the genital tract.
PMCID: PMC3472447  PMID: 22997072
HIV-1; Cytomegalovirus; compartmentalization; evolution; semen
21.  Clinical, Virologic, and Immunologic Correlates of HIV-1 Intraclade B Dual Infection among Men who Have Sex with Men 
AIDS (London, England)  2012;26(2):10.1097/QAD.0b013e32834dcd26.
To investigate the susceptibilities to and consequences of HIV-1 dual infection (DI).
We compared clinical, virologic, and immunologic factors between participants who were dually infected with HIV-1 subtype B, and monoinfected (MI) controls who were matched by ongoing HIV risk factor.
The viral load and CD4 progressions of dually and singly infected participant groups were compared with linear mixed-effects models, and individual dynamics before and after superinfection were assessed with a structural change test (Chow test). Recombination breakpoint analysis (GARD), HLA frequency analysis, and cytotoxic T-lymphocyte (CTL) epitope mapping were also performed (HIV LANL Database).
The viral loads of DI participants increased more over 3 years of follow-up than the viral loads of MI controls, while CD4 progressions of the two groups did not differ. Viral escape from CTL responses following superinfection was observed in two participants whose superinfecting strain completely replaced the initial strain. This pattern was not seen among participants whose superinfecting virus persisted in a recombinant form with the initial virus or was only detected transiently. Several HLA types were overrepresented in DI participants as compared to MI controls.
These results identify potential factors for DI susceptibility and further define its clinical consequences.
PMCID: PMC3807679  PMID: 22045341
HIV-1 dual infection; viral load; CD4 count; HLA; CTL
22.  Characterizing HIV Transmission Networks Across the United States 
Genetic relatedness of human immunodeficiency virus type 1 sequences was used to assess variables associated with transmission and characteristics of transmission networks in a large, diverse cohort. Such assessments may be useful in identifying risks for expanding epidemics and targeting effective public health responses.
Background. Clinically, human immunodeficiency virus type 1 (HIV-1) pol sequences are used to evaluate for drug resistance. These data can also be used to evaluate transmission networks and help describe factors associated with transmission risk.
Methods. HIV-1 pol sequences from participants at 5 sites in the CFAR Network of Integrated Clinical Systems (CNICS) cohort from 2000–2009 were analyzed for genetic relatedness. Only the first available sequence per participant was included. Inferred transmission networks (“clusters”) were defined as ≥2 sequences with ≤1.5% genetic distance. Clusters including ≥3 patients (“networks”) were evaluated for clinical and demographic associations.
Results. Of 3697 sequences, 24% fell into inferred clusters: 155 clusters of 2 individuals (“dyads”), 54 clusters that included 3–14 individuals (“networks”), and 1 large cluster that included 336 individuals across all study sites. In multivariable analyses, factors associated with being in a cluster included not using antiretroviral (ARV) drugs at time of sampling (P < .001), sequence collected after 2004 (P < .001), CD4 cell count >350 cells/mL (P < .01), and viral load 10 000–100 000 copies/mL (P < .001) or >100 000 copies/mL (P < .001). In networks, women were more likely to cluster with other women (P < .001), and African Americans with other African Americans (P < .001).
Conclusions. Molecular epidemiology can be applied to study HIV transmission networks in geographically and demographically diverse cohorts. Clustering was associated with lack of ARV use and higher viral load, implying transmission may be interrupted by earlier diagnosis and treatment. Observed female and African American networks reinforce the importance of diagnosis and prevention efforts targeted by sex and race.
PMCID: PMC3529609  PMID: 22784872
23.  The use of pooled viral load testing to identify antiretroviral treatment failure 
AIDS (London, England)  2009;23(16):2151-2158.
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.
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.
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.
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.
PMCID: PMC2915784  PMID: 19730348
antiretroviral therapy; drug resistance; HIV; monitoring; pooling; viral load
24.  Pleocytosis Is Associated with Disruption of HIV Compartmentalization between Blood and Cerebral Spinal Fluid Viral Populations 
Virology  2008;385(1):204-208.
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.
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.
Pleocytosis was strongly associated with disruption of viral compartmentalization.
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.
PMCID: PMC2794037  PMID: 19100592
HIV; Neurovirulence; Neuroadaptation; Cerebrospinal fluid; Pleocytosis
25.  A Public Health Model for the Molecular Surveillance of HIV Transmission in San Diego, California 
AIDS (London, England)  2009;23(2):225-232.
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.
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).
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.
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.
PMCID: PMC2644048  PMID: 19098493
molecular epidemiology; HIV; surveillance; contact tracing; drug resistance

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