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1.  Alterations in HIV-1 gp120 V3 Region Are Necessary but Not Sufficient for Coreceptor Switching in CRF07_BC in China 
PLoS ONE  2014;9(3):e93426.
The most predominant HIV-1 strains in China's current epidemic is the Circulating Recombinant Form 07_BC (CRF07_BC). CRF07_BC is mainly considered as a CCR5-tropic (R5) virus, since CXCR4-tropic (X4) viruses have thus far not been found in this subtype, and the molecular determinants of coreceptor switching remain unknown. To investigate the mechanisms underlying coreceptor requirement in CRF07_BC viruses, we characterized a panel of pNL4-3-based chimeric viruses with mutated V3 loop regions derived from an HIV-1 CRF07_BC infectious clone pXJDC13. Among 17 chimeric viruses, seven were dual-tropic and induced syncytium formation in MT-2 cells. Two amino acid insertions between positions 13 and 14, as well as arginine substitution at position 11 or 16 (IG insertion and P16R mutation or MG insertion and S11R mutation), conferred the chimeric viruses CXCR4-tropic features, which were same as subtype C X4 viruses. Next, to construct CRF07_BC X4 variants, mutated V3 loops were cloned into the CRF07_BC infectious clone pXJDC13. These V3 loops, which in the pNL4-3 backbone conferred chimeric viruses with CXCR4-using ability, abrogated infectivity completely in the CRF07_BC pXJDC13 genetic background. Similarly, IG insertion or MG insertion and S11R mutation dramatically diminished or completely abolished viral infectivity in other envelopes of subtype C or CRF07_BC. These results suggest that the effects of IG insertion and P16R mutation or MG insertion and S11R mutation on CXCR4 usage are context dependent, and additional mutations elsewhere in the envelope are needed to compensate for these fitness-reducing alterations.
PMCID: PMC3968174  PMID: 24676404
2.  Modeling the Impact on HIV Incidence of Combination Prevention Strategies among Men Who Have Sex with Men in Beijing, China 
PLoS ONE  2014;9(3):e90985.
To project the HIV/AIDS epidemics among men who have sex with men (MSM) under different combinations of HIV testing and linkage to care (TLC) interventions including antiretroviral therapy (ART) in Beijing, China.
Mathematical modeling.
Using a mathematical model to fit prevalence estimates from 2000–2010, we projected trends in HIV prevalence and incidence during 2011–2020 under five scenarios: (S1) current intervention levels by averaging 2000–2010 coverage; (S2) increased ART coverage with current TLC; (S3) increased TLC/ART coverage; (S4) increased condom use; and (S5) increased TLC/ART plus increased condom use.
The basic reproduction number based upon the current level of interventions is significantly higher than 1 ( confidence interval (CI), 1.83–2.35), suggesting that the HIV epidemic will continue to increase to 2020. Compared to the 2010 prevalence of 7.8%, the projected HIV prevalence in 2020 for the five prevention scenarios will be: (S1) Current coverage: 21.4% (95% CI, 9.9–31.7%); (S2) Increased ART: 19.9% (95% CI, 9.9–28.4%); (S3) Increased TLC/ART: 14.5% (95% CI, 7.0–23.8%); (S4) Increased condom use: 13.0% (95% CI, 9.8–28.4%); and (S5) Increased TLC/ART and condom use: 8.7% (95% CI, 5.4–11.5%). HIV epidemic will continue to rise () for S1–S4 even with hyperbolic coverage in the sensitivity analysis, and is expected to decline () for S5.
Our transmission model suggests that Beijing MSM will have a rapidly rising HIV epidemic. Even enhanced levels of TLC/ART will not interrupt epidemic expansion, despite optimistic assumptions for coverage. Promoting condom use is a crucial component of combination interventions.
PMCID: PMC3953201  PMID: 24626165
3.  Alcohol Use among Chinese Men Who Have Sex with Men: An Epidemiological Survey and Meta-Analysis 
BioMed Research International  2014;2014:414381.
The HIV/AIDS epidemic among Chinese men who have sex with men (MSM) has become a significant public health concern. Knowledge of alcohol consumption in this population is limited. In this study, 1,155 Chinese MSM were surveyed to assess alcohol use and its correlates. A meta-analysis was also performed to aggregate pooled prevalence of current alcohol use. MSM who were unmarried (aOR: 1.87; 95% CI: 1.29–2.71) or unemployed/retired (aOR: 2.77; 95% CI: 1.73–4.45) were more likely to drink alcohol more than once per week. MSM who consumed alcohol more than once per week were more likely to use drug (P < 0.01), have sex with women (P < 0.01), have unprotected insertive (P = 0.04) or receptive (P = 0.03) anal sex with men, have more than 10 lifetime male sex partners (P < 0.01), predominantly practice insertive anal sex (P < 0.01), and trade sex for money (P < 0.01). Pooled overall alcohol use prevalence was 32%. Pooled prevalence for MSM who drank alcohol more than once per week and who drank alcohol before sex with male partners was 23%. Our findings provide the basis for further exploring the alcohol-HIV association and developing risk reduction interventions.
PMCID: PMC3966324
4.  Efficacy of Peer-Led Interventions to Reduce Unprotected Anal Intercourse among Men Who Have Sex with Men: A Meta-Analysis 
PLoS ONE  2014;9(3):e90788.
To conduct a systematic review and meta-analysis to evaluate the efficacy of peer-led interventions in reducing unprotected anal intercourse (UAI) among men who have sex with men (MSM).
Randomized clinical trials (RCTs), quasi-experimental studies, pre- and post-intervention studies without control groups, and serial cross-sectional assessments involving peers delivering interventions among MSM and published as of February 2012 were identified by systematically searching 13 electronic databases and cross-referencing. Effect sizes (ES) were calculated as the changes of standardized mean difference (SMD) in UAI between groups or pre-post intervention.
A total of 22 studies met the eligibility criteria, including five RCTs, six quasi-experimental studies, six pre-and-post intervention studies, and five serial cross-sectional intervention studies. We used 15 individual studies including 17 interventions for overall ES calculation; peer-led interventions reduced UAI with any sexual partners in meta-analysis (mean ES: -0.27; 95% confidence interval [CI]: −0.41, −0.13; P<0.01). Subgroup analyses demonstrated a statistically significant reduction on UAI in quasi-experimental studies (mean ES: −0.30; 95% CI: −0.50, −0.09; P = 0.01) and serial cross-sectional intervention studies (mean ES: −0.33; 95% CI: −0.57, −0.09; P = 0.01), but non-significant reduction in RCTs (mean ES: −0.15; 95% CI: −0.36, 0.07; P = 0.18) or pre- and post-intervention studies (mean ES: −0.29; 95% CI: −0.69, 0.11; P = 0.15). Heterogeneity was large across these 15 studies (I2 = 77.5%; P<0.01), largely due to pre-and-post intervention studies and serial cross-sectional intervention studies.
Peer-led HIV prevention interventions reduced the overall UAI among MSM, but the efficacy varied by study design. More RCTs are needed to evaluate the effect of peer-led interventions while minimizing potential bias.
PMCID: PMC3948720  PMID: 24614809
5.  The Functional Polymorphisms of miR-146a Are Associated with Susceptibility to Severe Sepsis in the Chinese Population 
Mediators of Inflammation  2014;2014:916202.
MicroRNA-146a (miR-146a) acts as a pivotal regulatory molecule in immune response and various diseases, such as carcinoma and autoimmune diseases. Growing evidences have demonstrated the association of miR-146a gene single-nucleotide polymorphisms (SNPs) with risk of several diseases, but no genetic relevance studies of miR-146a gene polymorphisms to sepsis have been reported by now. Our study has analyzed the association of sepsis with two functional miR-146a gene SNPs rs2910164 G/C and rs57095329 A/G in a Chinese Han population (226 sepsis cases; 206 healthy controls). Our results indicated a higher prevalence of the miR-146a gene SNP rs2910164 C allele and CC genotype in patients with severe sepsis (rs2910164G versus rs2910164C: P = 0.0029, odds ratio (OR) = 1.664; GG+GC versus CC: P = 0.0045, OR = 1.947). Neither the genotype nor the allele in rs57095329 showed significant differences between the septic cases and the controls (P = 0.5901 and 0.3580, resp.), and no significant difference was observed in the subgroups. In addition, we confirmed that the two SNPs rs2910164 and rs57095329 could functionally affect the miR-146a expression levels and the reduction of miR146a was accompanied with the upregulation of the expression levels of TRAF-6 and IRAK-1 in severe sepsis patients. This present study might provide valuable clinical evidence that miR-146a gene polymorphism rs2910164 is associated with the risk of severe sepsis.
PMCID: PMC3950573
6.  Virological Outcomes and Drug Resistance in Chinese Patients after 12 Months of 3TC-Based First-Line Antiretroviral Treatment, 2011–2012 
PLoS ONE  2014;9(2):e88305.
To determine the prevalence of virological failure and HIV drug resistance among Chinese patients one year after initiating lamivudine-based first-line antiretroviral treatment.
A prospective cohort study with follow-up at 12 months was conducted in four urban sentinel sites in China. Antiretroviral naive patients ≥18 years old were recruited. Blood samples were collected for testing CD4 cell count, viral load, and (for samples with HIV-1 RNA ≥1000 copies/ml) genotyping of drug resistance.
A total of 513 patients were enrolled in this cohort, of whom 448 (87.3%) were retained at 12 months. The median final CD4 cell count was 313 cells/mm3, which increased from 192 cells/mm3 at baseline (P<0.0001). Of the 448 remaining subjects, 394 (87.9%) had successful virological suppression (HIV RNA <1000 copies/ml). Among 54 samples with viral load ≥1000 copies/ml, 40 were successfully genotyped, and 11 were found with detectable HIV drug resistance mutations. Of these, the proportions of drug resistance to NNRTIs, NRTIs and PIs were 100%, 81.8% and 0%, respectively. Injecting drug use (AOR = 0.40, 95% CI: 0.19,0.84; P = 0.0154), CD4 count at baseline ≥350 cells/mm3 (AOR = 0.32, 95% CI: 0.14,0.72; P = 0.0056), and missed doses in the past month (AOR = 0.30, 95% CI: 0.15,0.60; P = 0.0006) were significantly negatively associated with HIV RNA <1000 copies/ml.
Our study demonstrates effective virological and immunological outcomes at 12 months among these who initiated first-line ART treatment. However, patients infected through drug injection, who missed doses, or with higher CD4 count at baseline are at increased risk for poor virological response.
PMCID: PMC3917868  PMID: 24516631
7.  Changing the Landscape of the HIV Epidemic among MSM in China: Results from Three Consecutive Respondent-Driven Sampling Surveys from 2009 to 2011 
BioMed Research International  2014;2014:563517.
This study assessed the changes of HIV incidence and its predictors among Beijing's men who have sex with men (MSM). Three consecutive cross-sectional surveys were carried out using a consistent respondent-driven sampling (RDS) approach in 2009, 2010, and 2011, respectively. Structured-questionnaire based interviews were completed with computer-assisted self-administration. Incident infection was examined with BED capture enzyme immunoassay (BED-CEIA). The overall rate of HIV prevalence was 8.0% in the three years (95% confidence interval [CI]: 4.9%–11.2%). The overall rate of BED-CEIA incidence was 7.8/100 person years (PY) (95% CI: 5.5–10.1) with 6.8/100PY (95% CI: 3.4–10.2) in 2009, 11.2/100PY (95% CI: 6.2–16.3) in 2010, and 5.8/100PY (95% CI: 2.4–9.3) in 2011, respectively. Multivariable logistic regression analysis revealed that, compared with HIV-negative MSM, recently infected MSM were more likely to be bisexual (adjusted odds ratio [AOR] = 2.1, 95% CI: 1.1–4.1), live in Beijing ≤3 years (AOR = 2.1, 95% CI: 1.2–4.0), and have a negative attitude towards safe sex (AOR = 1.1 per scale point, 95% CI: 1.0–1.1). This study demonstrated a disturbing rise of HIV infections among Beijing's MSM. These findings underscored the urgency of scaling up effective and better-targeted intervention services to stop the rapid spread of the virus.
PMCID: PMC3918367  PMID: 24575408
8.  HIV, Syphilis, and Behavioral Risk Factors among Female Sex Workers before and after Implementation of Harm Reduction Programs in a High Drug-Using Area of China 
PLoS ONE  2014;9(1):e84950.
To evaluate the impact of harm reduction programs on HIV and syphilis infection and related risk behaviors among female sex workers (FSWs) in a drug trafficking city in Southwest China.
Before and after harm reduction program study.
Two cross-sectional surveys were conducted among FSWs before and after harm reduction programs were launched in Xichang city, Sichuan province. The first and second cross-sectional surveys were conducted in 2004 and 2010, respectively. Temporal changes in odds of HIV, syphilis, and behavioral risk factors were assessed by multivariable logistic regression while controlling for socio-demographics.
The 2004 and 2010 cross-sectional surveys recruited 343 and 404 FSWs, respectively. From 2004 to 2010, the odds of syphilis infection decreased by 35% and was of borderline statistical significance (AOR: 0.65, 95% CI: 0.41–1.03), while odds of HIV infection rose, but not significantly (AOR: 4.12, 95% CI: 0.76–22.45). Although odds of unprotected sex with primary sex partners did not significantly change over time (AOR: 0.96; 95% CI: 0.61–1.50), odds of unprotected sex with clients declined significantly and remarkably (AOR: 0.14, 95% CI: 0.09–0.21). Notably, the odds of reporting ≥10 new sex partners in the previous month increased by 37% (AOR: 1.37; 95% CI: 0.98–1.90).
Harm reduction strategies may be an effective means of reducing unprotected sex with clients among FSWs. Future research is needed to better target both FSWs and IDUs and interrupt bridging networks for HIV transmission in high drug-using areas of China.
PMCID: PMC3885653  PMID: 24416319
9.  Correction: Willingness to Use the Oral Fluid HIV Rapid Test among Men Who Have Sex with Men in Beijing, China 
PLoS ONE  2014;9(1):10.1371/annotation/47ef6213-e854-4dca-b321-704c261c6167.
PMCID: PMC3883729
10.  Short Communication: Emerging Transmitted HIV Type 1 Drug Resistance Mutations Among Patients Prior to Start of First-Line Antiretroviral Therapy in Middle and Low Prevalence Sites in China 
AIDS Research and Human Retroviruses  2012;28(12):1637-1639.
It is known that transmitted drug resistance (TDR) will most likely emerge in regions where antiretroviral therapy (ART) has been widely available for years. However, after a decade of rapid scale-up of ART in China, there are few data regarding TDR among HIV-infected patients prior to initiating first-line ART in China. A prospective, observational cohort study was performed at sentinel sites in five provinces or municipalities. Study participants were recruited at the county- or city-level centers for disease control (CDCs), during routine monitoring visits following referral from diagnosing parties (e.g., hospitals). Each province or municipality recruited 140 patients through sequential sampling throughout the 2011 calendar year. A total of 627 eligible subjects were included in the analysis. the median CD4+ cell count was 206 cells/ml at the baseline survey. The majority of patients (93.5%) had plasma HIV viral load ≥1,000 copies/ml. Of the 627 patients, 17 (2.7%) had drug resistance mutations for any type of HIV drugs. The prevalence of drug resistance mutations to nonnucleoside reverse transcriptase inhibitor (NNRTI) drugs (8/627, 1.3%) was higher than to nucleoside reverse transcriptase inhibitor (NRTI) drugs (5/627, 0.8%) and protease inhibitor (PI) drugs (4/627, 0.6%). A logistic regression model showed that the only predictive factor was the route of infection through homosexual intercourse, i.e., men who have sex with men (MSM) status. As HIV prevalence is rising rapidly among Chinese MSM, it is essential to continue surveying this risk group and related high-risk populations with low awareness of HIV, and to develop new public health interventions that help to reduce the spread of drug-resistant HIV.
PMCID: PMC3505058  PMID: 22822770
11.  A Pilot Study Comparing the Development of EIAV Env-Specific Antibodies Induced by DNA/Recombinant Vaccinia-Vectored Vaccines and an Attenuated Chinese EIAV Vaccine 
Viral Immunology  2012;25(6):477-484.
Data from successful attenuated lentiviral vaccine studies indicate that fully mature Env-specific antibodies characterized by high titer, high avidity, and the predominant recognition of conformational epitopes are associated with protective efficacy. Although vaccination with a DNA prime/recombinant vaccinia-vectored vaccine boost strategy has been found to be effective in some trials with non-human primate/simian/human immunodeficiency virus (SHIV) models, it remains unclear whether this vaccination strategy could elicit mature equine infectious anemia virus (EIAV) Env-specific antibodies, thus protecting vaccinated horses against EIAV infection. Therefore, in this pilot study we vaccinated horses using a strategy based on DNA prime/recombinant Tiantan vaccinia (rTTV)-vectored vaccines encoding EIAV env and gag genes, and observed the development of Env-specific antibodies, neutralizing antibodies, and p26-specific antibodies. Vaccination with DNA induced low titer, low avidity, and the predominant recognition of linear epitopes by Env-specific antibodies, which was enhanced by boosting vaccinations with rTTV vaccines. However, the maturation levels of Env-specific antibodies induced by the DNA/rTTV vaccines were significantly lower than those induced by the attenuated vaccine EIAVFDDV. Additionally, DNA/rTTV vaccines did not elicit broadly neutralizing antibodies. After challenge with a virulent EIAV strain, all of the vaccinees and control horses died from EIAV disease. These data indicate that the regimen of DNA prime/rTTV vaccine boost did not induce mature Env-specific antibodies, which might have contributed to immune protection failure.
PMCID: PMC3518545  PMID: 23171359
12.  Construction and Characterization of Highly Infectious Full-Length Molecular Clones of a HIV-1 CRF07_BC Isolate from Xinjiang, China 
PLoS ONE  2013;8(11):e79177.
Among the various subtypes of the M group of human immunodeficiency virus type 1 (HIV-1), clade CRF07_BC is the most prevalent in China. To date, no strong replicable CRF07_BC infectious clone has been constructed. Here we report on the construction and characterization of highly replicable infectious molecular clones from the isolate XJDC6291 of this HIV-1 subtype. Four full-length clones pXJDC2-7, pXJDC3-7, pXJDC2-6 and pXJDC3-6 were successfully produced, but only pXJDC2-7 presented detectable infectivity and replication capability. To improve the replication capability of pXJDC2-7, a 4.8 kb region spanning from the pol Integrase to nef gene of the clone was replaced by PCR products of the corresponding fragments from the original isolate XJDC6291, which produced two clones pXJDC13 and pXJDC17 that exhibited strong replication capability. The viral stocks obtained by pXJDC-13 and pXJDC-17 transfection into 293T cells replicated efficiently in human PBMCs, human primary CD4+ T cells and displayed CCR5 tropism. Sequence alignment between pXJDC13, pXJDC17 and pXJDC2-7 suggested that polymorphisms in the V1V2 region may influence infectivity, and reverse genetic experiment showed that V1V2 polymorphisms may influence the infectivity of the clones but did not affect the replication capability at a significant level. pXJDC13 and pXJDC17 displayed strong replication capability and are the first full-length infectious clones of HIV-1 CRF07_BC clade in the world. The availability of CRF07_BC infectious clones provides a useful tool for a wide range of studies, including antiretroviral drug and vaccine research as related to this HIV subtype.
PMCID: PMC3850540  PMID: 24324545
13.  Meta-Analysis of Interventions for Reducing Number of Sexual Partners and Drug and Alcohol Abuse among People Living with HIV/AIDS 
To perform a systematic review and meta-analysis of the efficacy of risk reduction interventions on HIV-related risk behaviors among people living with HIV/AIDS (PLWHA)
Studies included in the meta-analysis were randomized clinical trials (RCTs) of risk reduction interventions, which targeted PLWHA aged 18 year or older and assessed the changes of number of sexual partners, drug use, needle sharing, and/or alcohol abuse between pre- and post-intervention. The standardized mean differences (SMD) between study arms as well as between baseline and post-intervention, defined as the effect sizes (ES), were calculated in random effects models. Heterogeneity of studies was estimated by the I2 statistic.
Twelve RCTs involving 3993 PLWHA were included in our analysis: seven reported impacts on the number of sexual partners, and three reported impacts on drug use, needle sharing, and alcohol abuse, respectively. There were no statistically significant impacts of risk reduction interventions on the number of total sexual partners (mean ES, -0.10; 95% confidence interval [CI], -0.26, 0.06; P=0.22) or on the subset of HIV-negative or unknown-status sexual partners (mean ES, 0.003; 95% CI, -0.54, 0.54; P=0.99). Overall, risk reduction intervention studies documented a reduction of drug abuse (mean ES: -0.26; 95% CI: -0.51, -0.01; P=0.04) among HIV-infected drug users, but this impact was mainly attributable to one study. Risk reduction interventions did not show a reduction of needle sharing (mean ES, -0.15; 95% CI, -0.43, 0.13; P=0.29) or of alcohol abuse (mean ES, -0.10; 95% CI, -0.36, 0.17; P=0.47). No heterogeneity or publication bias was found across individual studies.
Our meta-analysis did not find a positive impacts of risk reduction interventions on number of sexual partners, drug use, needle sharing, or alcohol abuse among PLWHA, but the small number of studies meeting our review criteria limits these findings.
PMCID: PMC3819193  PMID: 24224118
People living with HIV/AIDS (PLWHA); Randomized clinical trial (RCT); Sexual partners; Positive prevention; Drug use; Alcohol abuse; Meta-analysis
14.  DNA prime-protein boost using subtype consensus Env was effective in eliciting neutralizing antibody responses against subtype BC HIV-1 viruses circulating in China 
Human Vaccines & Immunotherapeutics  2012;8(11):1630-1637.
Previously, we have shown that DNA prime-protein boost is effective in eliciting neutralizing antibodies (NAb) against randomly selected HIV-1 isolates. Given the genetic diversity of HIV-1 viruses and the unique predominant subtypes in different geographic regions, it is critical to test the DNA prime-protein boost approach against circulating viral isolates in key HIV endemic areas. In the current study, the same DNA prime-protein boost vaccine was used as in previous studies to investigate the induction of NAb responses against HIV-1 clade BC, a major subtype circulating in China. A codon optimized gp120-BC DNA vaccine, based on the consensus envelope (Env) antigen sequence of clade BC, was constructed and a stable CHO cell line expressing the same consensus BC gp120 protein was produced. The immunogenicity of this consensus gp120-BC was examined in New Zealand White rabbits by either DNA prime-protein boost or protein alone vaccination approaches. High levels of Env-specific antibody responses were elicited by both approaches. However, DNA prime-protein boost but not the protein alone immune sera contained significant levels of NAb against pseudotyped viruses expressing HIV-1 BC Env antigens. Furthermore, high frequencies of CD4 binding site-targeted antibodies were found in the DNA prime- protein boost rabbit sera indicating that the positive NAb may be the result of antibodies against conformationally sensitive epitopes on HIV-1 Env. The findings support that DNA prime-protein boost was effective in eliciting NAb against a key HIV-1 virus subtype in China. This result may lead to the development of regional HIV vaccines through this approach.
PMCID: PMC3601137  PMID: 23111170
DNA vaccine; prime-boost; HIV-1; subtype BC; neutralizing antibody
15.  Comparison of Three Intervention Models for Promoting Circumcision among Migrant Workers in Western China to Reduce Local Sexual Transmission of HIV 
PLoS ONE  2013;8(9):e76107.
Three models for promoting male circumcision (MC) as a preventative intervention against HIV infection were compared among migrant worker populations in western China.
A cohort study was performed after an initial cross-sectional survey among migrant workers in three provincial level districts with high HIV prevalence in western China. A total of 1,670 HIV seronegative male migrants were cluster-randomized into three intervention models, in which the dissemination of promotional materials and expert- and volunteer-led discussions are conducted in one, two, and three stage interventions. Changes in knowledge of MC, acceptability of MC, MC surgery uptake, and the costs of implementation were analyzed at 6-month and 9-month follow-up visits.
All three models significantly increased the participants’ knowledge about MC. The three-stage model significantly increased the acceptability of MC among participants and led to greatest increase in MC uptake. At the end of follow-up, 9.2% (153/1,670) of participants underwent MC surgery; uptake among the one-, two-, and three-stage models were 4.9%, 9.3%, and 14.6%, respectively. Multivariable Cox regression analysis showed that three-stage model was the most effective method to scale up MC, with RR = 2.0 (95% CI, 1.3-3.1, P=0.002) compared to the on-site session model. The two-stage intervention model showed no significant difference with either the on-site session model (RR=1.5, 95% CI, 0.92-2.4, P=0.12) or three-stage model (P=0.10).
A three-stage intervention with gradual introduction of knowledge led to the significantly increase in MC uptake among migrant workers in western China, and was also the most cost-effective method among the three models.
PMCID: PMC3786908  PMID: 24098770
16.  The effects of HIV Tat DNA on regulating the immune response of HIV DNA vaccine in mice 
Virology Journal  2013;10:297.
HIV trans-activator protein (Tat) is the crucial factor to control HIV transcription, and is usually considered as an important immunogen for the design of HIV vaccine. Recent studies reported some special bio-activities of Tat protein on immunoregulation. However, to date, few studies have focused on exploring the effects of Tat expression plasmid (pTat) on regulating the immune responses induced by HIV DNA vaccines. In this study, our main objective is to investigate the immunoregulation mediated by pTat in mice.
Four gene-coding plasmids (pTat, pGag, pEnv and pPol) were constructed, and the gene expression was detected by western blot method. The effects of pTat on regulating the immune responses to antigens Gag, Env, Pol were assessed by enzyme-linked immunospot and enzyme-linked immunosorbent assay. The data was analysed by one-way analysis of variance.
After two immunizations, mice vaccinated with antigen expressing plasmid (pGag, pEnv or pPol) plus pTat exhibited significantly stronger IFN-gamma response than that vaccinated with the corresponding antigen alone. Moreover, mice receiving two injections of antigen plus pTat exhibited the same strong IFN-gamma response as those receiving three injections of antigen alone did. Furthermore, addition of pTat not only induced a more balanced Th1 and Th2 response, but also broadened IgG subclass responses to antigens Gag and Pol.
pTat exhibited the appreciable effects on modulating immune responses to HIV antigens Gag, Env and Pol, providing us interesting clues on how to optimize HIV DNA vaccine.
PMCID: PMC3851266  PMID: 24073803
HIV DNA vaccine; Tat expression plasmid; T cell response; IgG subclass; Th polarization
17.  Anal human papillomavirus infection among HIV-infected and uninfected men who have sex with men in Beijing, China 
To determine prevalence, genotypes and predictors of anal human papillomavirus (HPV) among HIV-infected and uninfected men who have sex with men (MSM) in Beijing, China. In 2010–2011, we recruited MSM (age range 18–61; median 28 years) through peer volunteers, and collected demographic/behavioral information via interviewer-administrated questionnaires. Trained health workers collected anal swabs for HPV genotyping by PCR and blood samples for HIV/syphilis serologies . We obtained anal specimens from 212 HIV-infected and 459 HIV-uninfected participants. Among HIV-infected MSM, 82.1% were HPV-infected vs. 57.5% in HIV-uninfected (p<0.01). HIV-infected men had the greatest likelihood of multiple types: 17.9% uninfected; 36.3% with one type; 36.8% with 2–3; 9.0% with >4. Oncogenic HPV prevalence was higher among HIV- infected (61.3%) than uninfected participants (39.7%; p<0.01). HIV-uninfected MSM reporting always using condoms during insertive anal intercourse (past 6 months) were less likely to be HPV-infected (OR=0.49, 95%CI: 0.31–0.77). Among HIV-uninfected MSM, HPV infection was associated with unprotected receptive anal intercourse (past 6 months; OR=1.92, 95%CI: 1.19–3.11) and being forced to have sex (previous year; OR=3.32, 95%CI: 1.10–10.0). Multivariable logistic analysis among HIV infected MSM suggested that unprotected oral intercourse (past 6 months) was associated with HPV (adjusted OR=2.12, 95%CI: 1.00–4.48). Syphilis occurred in 55.8% of HIV-infected/HPV-infected, 50.0% of HIV-infected/HPV-uninfected, 19.6% of HIV-uninfected/HPV-infected, and 13.0% of HIV-uninfected/HPV-uninfected MSM. HPV anal infections were more common among HIV-infected than uninfected MSM in China, including oncogenic and multiple types. Unprotected oral and receptive anal sex were significant HPV risk factors. Promotion of safer sex and HPV vaccination is strongly recommended among MSM.
PMCID: PMC3780393  PMID: 23732908
Human papillomavirus; HIV; syphilis; genotype; men who have sex with men; China
18.  Predictors of HIV testing among men who have sex with men in a large Chinese city 
Sexually transmitted diseases  2013;40(3):235-240.
HIV testing is the gateway for prevention and care. We explored factors associated with HIV testing among Chinese men who have sex with men (MSM).
In Chongqing City, we recruited 492 MSM in 2010 using respondent driven sampling in a cross-sectional study. Computer-assisted self-interviews were conducted to collect information on history of HIV testing.
Only 58% of participants reported ever having taken an HIV test. MSM who had a college degree [adjusted odds ratio (AOR): 1.7; 95% confidence interval (CI): 1.2-2.6; P=0.008] were more likely to take a test; those who preferred a receptive role in anal sex were less likely to do so than those with insertive sex preference (AOR: 0.6; 95% CI: 0.35-0.94; P=0.03); those who used condoms with the recent male partner during the past 6 months were more likely to get tested (AOR: 2.87; 95%CI: 1.25-6.62; P=0.01). Principal perceived barriers to testing included: fear of knowing a positive result, fear of discrimination if tested positive, low perceived risk of HIV infection, and not knowing where to take a test. Factors reported to facilitate testing were sympathetic attitudes from health staff and guaranteed confidentiality. Prevalence was high: 11.7% HIV-positive and 4.7% syphilis positive.
The HIV testing rate among MSM in Chongqing is still low, though MSM prevalence is high compared to other Chinese cities. MSM preferring receptive anal sex are less likely to get testing and perceive having lower HIV risk. Along with expanded education and social marketing, a welcoming and non-judgmental environment for HIV testing is needed.
PMCID: PMC3725775  PMID: 23403605
Human immunodeficiency virus; syphilis; men who have sex with men; HIV testing; respondent driven sampling; China
19.  Effectiveness of HIV Risk Reduction Interventions among Men who have Sex with Men in China: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(8):e72747.
To evaluate the effect of risk reduction interventions on HIV knowledge, attitudes and behaviors among men who have sex with men (MSM) in China.
We performed a systematic review and meta-analysis of HIV risk reduction intervention studies among Chinese MSM. The summary difference of standardized mean differences (SMD) between both study arms or between pre- and post-intervention assessments were defined as the effect size (ES); ES was calculated using standard meta-analysis in random effects models.
Thirty-four eligible studies were included in the analysis, including two randomized clinical trials (RCT), six quasi-experimental studies, six pre-and-post intervention studies, and twenty serial cross-sectional intervention studies. These studies showed an increase in consistent condom use with any male sexual partners (mean ES, 0.46; 95% confidence interval [CI], 0.35–0.56), with regular sexual partners (mean ES, 0.41; 95% CI, 0.18–0.63), and casual sexual partners (mean ES, 0.52; 95% CI, 0.24–0.79). The analysis of ten studies that measured the impact on uptake of HIV testing also showed a positive result (mean ES, 0.55; 95% CI, 0.38–0.71). The risk reduction interventions also improved HIV/AIDS-related knowledge (mean ES, 0.77; 95% CI, 0.60–0.94) and attitudes (mean ES, 1.35; 95% CI, 0.91–1.79), but did not reduce prevalence of HIV (mean ES, 0.23; 95% CI, 0.02–0.45) and syphilis infections (mean ES, −0.01; 95% CI, −0.19–0.17). There was significant heterogeneity among these studies.
On aggregate, HIV risk reduction interventions were effective in reducing risky behaviors and improving knowledge and attitudes among Chinese MSM, but were not associated with a change in the prevalence of HIV and syphilis. Future studies should use incidence as definitive study outcome.
PMCID: PMC3796948  PMID: 24137497
21.  Deletion of C7L and K1L Genes Leads to Significantly Decreased Virulence of Recombinant Vaccinia Virus TianTan 
PLoS ONE  2013;8(7):e68115.
The vaccinia virus TianTan (VTT) has been modified as an HIV vaccine vector in China and has shown excellent performance in immunogenicity and safety. However, its adverse effects in immunosuppressed individuals warrant the search for a safer vector in the following clinic trails. In this study, we deleted the C7L and K1L genes of VTT and constructed six recombinant vaccinia strains VTT△C7L, VTT△K1L, VTT△C7LK1L, VTKgpe△C7L, VTKgpe△K1L and VTT△C7LK1L-gag. The pathogenicity and immunogenicity of these recombinants were evaluated in mouse and rabbit models. Comparing to parental VTT, VTT△C7L and VTT△K1L showed significantly decreased replication capability in CEF, Vero, BHK-21 and HeLa cell lines. In particular, replication of VTT△C7LK1L decreased more than 10-fold in all four cell lines. The virulence of all these mutants were decreased in BALB/c mouse and rabbit models; VTT△C7LK1L once again showed the greatest attenuation, having resulted in no evident damage in mice and erythema of only 0.4 cm diameter in rabbits, compared to 1.48 cm for VTT. VTKgpe△C7L, VTKgpe△K1L and VTT△C7LK1L-gag elicited as strong cellular and humoral responses against HIV genes as did VTKgpe, while humoral immune response against the vaccinia itself was reduced by 4-8-fold. These data show that deletion of C7L and K1L genes leads to significantly decreased virulence without compromising animal host immunogenicity, and may thus be key to creating a more safe and effective HIV vaccine vector.
PMCID: PMC3698190  PMID: 23840887
22.  Genome Sequences of a Novel HIV-1 Circulating Recombinant Form (CRF61_BC) Identified among Heterosexuals in China 
Genome Announcements  2013;1(3):e00326-13.
We report here the first novel HIV-1 second-generation intercirculating recombinant form 61_BC (inter-CRF61_BC), composed of two established CRFs (CRF07_BC and CRF08_BC), in China. CRF61_BC is the first CRF found among the heterosexual population in two different regions in China, suggesting the increasing significance of heterosexual transmission of HIV in China.
PMCID: PMC3695425  PMID: 23814029
23.  Impact of HIV drug resistance on virologic and immunologic failure and mortality in a cohort of patients on antiretroviral therapy in China 
AIDS (London, England)  2013;27(11):1815-1824.
To study the dynamics of HIV drug resistance (HIVDR) and its association with virologic and immunologic failure as well as mortality among patients on combination antiretroviral therapy (cART) in China.
We recruited 365 patients on cART in two rural Chinese counties in 2003–2004 and followed them every 6 months until May 2010.
Virologic failure, HIVDR, immunologic failure and death were documented. We used Kaplan–Meier and the proportional hazards models to identify the timing of the events, and risk factors for mortality.
At the end of study, patients had been followed for 1974.3 person-years, a median of 6.1 years. HIVDR mutations were found in 235 (64.4%) patients and 75 died (20.5%, 3.8/100 person-years). Median time from cART to detection of virologic failure was 17.5 months, to HIVDR 36.6 months and to immunologic failure 55.2 months (≈18-month median interval between each adverse milestone). Being male, having a baseline CD4+ cell count of less than 50 cells/μl and HIVDR were associated with higher mortality. Patients who developed HIVDR in the first year of treatment had higher mortality than those developing HIVDR later (adjusted hazard ratio 1.90, 95% confidence interval 1.01–3.48).
HIVDR was common and was associated with higher mortality among Chinese patients on cART, particular when HIVDR was detected early in therapy. Our study reinforces the importance of improving patient adherence to cART in order to delay the emergence of HIVDR and obviate the need to switch to costly second-line drug regimens too early.
PMCID: PMC3694318  PMID: 23803794
antiretroviral therapy; China; cohort; drug resistance; immunologic failure; mortality; virologic failure
24.  Association of Serum Myeloid Cells of Soluble Triggering Receptor-1 Level with Myocardial Dysfunction in Patients with Severe Sepsis 
Mediators of Inflammation  2013;2013:819246.
Objective. To investigate the association of serum sTREM-1 with myocardial dysfunction in patients with severe sepsis. Methods. A total of 85 patients with severe sepsis were divided into severe sepsis group (n = 40) and septic shock group (n = 45). Serum levels of sTREM-1, NT-proBNP, APACHE II score, SOFA score, cardiac index, cardiac function index, global ejection fraction, and left ventricular contractility index were measured on days 1, 3, and 7 after admission to ICU. Results. Serum sTREM-1 levels of patients with septic shock were significantly higher than those with severe sepsis on days 1, 3, and 7. Serum sTREM-1 was positively correlated with APACHE II scores, SOFA scores, and NT-proBNP. However, The sTREM-1 level was markedly negatively correlated with CI, CFI, GEF, and dP/dt max, respectively. Multiple logistic regression analysis showed that sTREM-1 was independent risk factor to NT-proBNP increasing. The optimal cut-off point of sTREM-1 for detecting patients with myocardial dysfunction was 468.05 ng/mL with sensitivity (80.6%) and specificity (75.7%). There is no difference in TREM-1-mRNA expression between the two groups. Conclusions. Serum sTREM-1 is significantly associated with myocardial dysfunction and may be a valuable tool for determining the presence of myocardial dysfunction in patients with severe sepsis.
PMCID: PMC3703897  PMID: 23861562
25.  Broad HIV-1 Neutralizing Antibody Response Induced by Heterologous Gp140/Gp145 DNA Prime-Vaccinia Boost Immunization 
Vaccine  2012;30(28):4135-4143.
To develop an effective HIV vaccine strategy that can induce cross-reactive neutralizing antibody.
Codon-optimized gp140 and gp145 env genes derived from HIV-1cn54, a CRF07 B′/C recombinant strain, were constructed as DNA and recombinant Tiantan vaccinia (rTV) vaccines. The effect of heterologous immunization with gp140 and gp145 was tested in mice and guinea pigs. T cell responses were detected using the IFN-γ ELISPOT assay. A panel of primary isolates of clade B′ and B′/C HIV-1 and TZM-bl cells was used to determine the neutralizing activity of immunized sera.
The neutralizing antibodies (NAbs) induced by the heterologous immunogen immunization neutralized all HIV-1 B′ and B′/C primary isolates in the guinea pig model. Gp145 and gp140 heterologous prime-boost induced the best neutralizing antibody response with a broad neutralizing spectrum and the highest titer of 1:270 at 6 weeks after the last inoculation. However, the T cell response to HIV-1 peptides was significantly weaker than the gp145+gp145 homologous prime-boost.
This heterologous prime-boost immunization strategy could be used to design immunogen-generating broad neutralizing antibodies against genetic variance pathogens.
PMCID: PMC3422682  PMID: 22561314
HIV; vaccine; neutralizing antibody; heterologous prime-boost immunization

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