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1.  Macaque models of enhanced susceptibility to HIV 
Virology Journal  2015;12:90.
There are few nonhuman primate models of enhanced HIV susceptibility. Such models can improve comprehension of HIV acquisition risk factors and provide rigorous testing platforms for preclinical prevention strategies. This paper reviews past, current, and proposed research on macaque HIV acquisition risk models and identifies areas where modeling is significantly lacking. We compare different experimental approaches and provide practical considerations for designing macaque susceptibility studies. Modifiable (mucosal and systemic coinfections, hormonal contraception, and rectal lubricants) and non-modifiable (hormonal fluctuations) risk factors are highlighted. Risk acquisition models via vaginal, rectal, and penile challenge routes are discussed. There is no consensus on the best statistical model for evaluating increased susceptibility, and additional research is required. The use of enhanced susceptibility macaque models would benefit multiple facets of the HIV research field, including basic acquisition and pathogenesis studies as well as the vaccine and other biomedical preventions pipeline.
PMCID: PMC4479314  PMID: 26070461
SIV; SHIV; HIV; Susceptibility; Risk; Nonhuman primate model; Coinfection model
2.  Targeting α4β7 integrin reduces mucosal transmission of SIV and protects GALT from infection 
Nature medicine  2014;20(12):1397-1400.
α4β7 integrin expressing CD4+ T cells preferentially traffic to gut-associated lymphoid tissues (GALT) and play a key role in HIV/SIV pathogenesis. The administration of an anti-α4β7 monoclonal antibody during acute infection protects macaques from transmission following repeated low-dose intra-vaginal challenges with SIVmac251. In treated animals that became infected the GALT was significantly protected and CD4+ T–cell numbers were maintained. Thus, targeting α4β7 reduces mucosal transmission of SIV in macaques.
PMCID: PMC4257865  PMID: 25419708
SIV; α4β7 monoclonal antibody; GI pathology; Repeated Low Dose challenge model; and rhesus macaques; mucosal transmission
3.  Rectal Application of a Highly Osmolar Personal Lubricant in a Macaque Model Induces Acute Cytotoxicity but Does Not Increase Risk of SHIV Infection 
PLoS ONE  2015;10(4):e0120021.
Personal lubricant use is common during anal intercourse. Some water-based products with high osmolality and low pH can damage genital and rectal tissues, and the polymer polyquaternium 15 (PQ15) can enhance HIV replication in vitro. This has raised concerns that lubricants with such properties may increase STD/HIV infection risk, although in vivo evidence is scarce. We use a macaque model to evaluate rectal cytotoxicity and SHIV infection risk after use of a highly osmolar (>8,000 mOsm/kg) water-based lubricant with pH of 4.4, and containing PQ15.
Cytotoxicity was documented by measuring inflammatory cytokines and epithelial tissue sloughing during six weeks of repeated, non-traumatic lubricant or control buffer applications to rectum and anus. We measured susceptibility to SHIVSF162P3 infection by comparing virus doses needed for rectal infection in twenty-one macaques treated with lubricant or control buffer 30 minutes prior to virus exposure.
Lubricant increased pro-inflammatory cytokines and tissue sloughing while control buffer (phosphate buffered saline; PBS) did not. However, the estimated AID50 (50% animal infectious dose) was not different in lubricant- and control buffer-treated macaques (p = 0.4467; logistic regression models).
Although the test lubricant caused acute cytotoxicity in rectal tissues, it did not increase susceptibility to infection in this macaque model. Thus neither the lubricant-induced type/extent of inflammation nor the presence of PQ15 affected infection risk. This study constitutes a first step in the in vivo evaluation of lubricants with regards to HIV transmission.
PMCID: PMC4390343  PMID: 25853710
4.  Pharmacokinetic and Safety Analyses of Tenofovir and Tenofovir-Emtricitabine Vaginal Tablets in Pigtailed Macaques 
Vaginal rapidly disintegrating tablets (RDTs) containing tenofovir (TFV) or TFV and emtricitabine (FTC) were evaluated for safety and pharmacokinetics in pigtailed macaques. Two separate animal groups (n = 4) received TFV (10 mg) or TFV-FTC (10 mg each) RDTs, administered near the cervix. A third group (n = 4) received 1 ml TFV gel. Blood plasma, vaginal tissue biopsy specimens, and vaginal fluids were collected before and after product application at 0, 0.5, 1, 4, and 24 h. A disintegration time of <30 min following vaginal application of the RDTs was noted, with negligible effects on local inflammatory cytokines, vaginal pH, and microflora. TFV pharmacokinetics were generally similar for both RDTs and gel, with peak median concentrations in vaginal tissues and vaginal secretions being on the order of 104 to 105 ng/g (147 to 571 μM) and 106 ng/g (12 to 34 mM), respectively, at 1 to 4 h postdose. At 24 h, however, TFV vaginal tissue levels were more sustained after RDT dosing, with median TFV concentrations being approximately 1 log higher than those with gel dosing. FTC pharmacokinetics after combination RDT dosing were similar to those of TFV, with peak median vaginal tissue and fluid levels being on the order of 104 ng/g (374 μM) and 106 ng/g (32 mM), respectively, at 1 h postdose with levels in fluid remaining high at 24 h. RDTs are a promising alternative vaginal dosage form, delivering TFV and/or FTC at levels that would be considered inhibitory to simian-human immunodeficiency virus in the macaque vaginal microenvironment over a 24-h period.
PMCID: PMC3993262  PMID: 24566178
5.  Risk Behaviors and Risk Factors for HIV Infection among Participants in the Bangkok Tenofovir Study, an HIV Pre-Exposure Prophylaxis Trial among People Who Inject Drugs 
PLoS ONE  2014;9(3):e92809.
HIV spread rapidly among people who inject drugs in Bangkok in the late 1980s. In recent years, changes in drug use and HIV-associated risk behaviors have been reported. We examined data from the Bangkok Tenofovir Study, an HIV pre-exposure prophylaxis trial conducted among people who inject drugs, to assess participant risk behavior and drug use, and to identify risk factors for HIV infection.
The Bangkok Tenofovir Study was a randomized, double-blind, placebo-controlled trial. HIV status was assessed monthly and risk behavior every 3 months. We used generalized estimating equations logistic regression to model trends of injecting, needle sharing, drugs injected, incarceration, and sexual activity reported at follow-up visits; and proportional hazards models to evaluate demographic characteristics, sexual activities, incarceration, drug injection practices, and drugs injected during follow-up as predictors of HIV infection.
The proportion of participants injecting drugs, sharing needles, and reporting sex with more than one partner declined during follow-up (p<0.001). Among participants who reported injecting at enrollment, 801 (53.2%) injected methamphetamine, 559 (37.1%) midazolam, and 527 (35.0%) heroin. In multivariable analysis, young age (i.e., 20–29 years) (p = 0.02), sharing needles (p<0.001), and incarceration in prison (p = 0.002) were associated with incident HIV infection. Participants reporting sex with an opposite sex partner, live-in partner, casual partner, or men reporting sex with male partners were not at a significantly higher risk of HIV infection compared to those who did not report these behaviors.
Reports of HIV-associated risk behavior declined significantly during the trial. Young age, needle sharing, and incarceration were independently associated with HIV infection. Sexual activity was not associated with HIV infection, suggesting that the reduction in HIV incidence among participants taking daily oral tenofovir compared to those taking placebo was due to a decrease in parenteral HIV transmission.
PMCID: PMC3965466  PMID: 24667938
Human immunology  2011;72(4):312-318.
Populations of African ancestry continue to account for a disproportionate burden of human immunodeficiency virus type 1 (HIV-1) epidemic in the US. We investigated the effects of human leukocyte antigen (HLA) class I markers in association with virologic and immunologic control of HIV-1 infection among 338 HIV-1 subtype B-infected African Americans in two cohorts: REACH (Reaching for Excellence in Adolescent Care and Health) and HERS (HIV Epidemiology Research Study). One-year treatment-free interval measurements of HIV-1 RNA viral loads and CD4+ T-cells were examined both separately and combined to represent three categories of HIV-1 disease control (76 “controllers,” 169 “intermediates,” and 93 “non-controllers”). Certain previously or newly implicated HLA class I alleles (A*32, A*36, A*74, B*14, B*1510, B*3501, B*45, B*53, B*57, Cw*04, Cw*08, Cw*12, and Cw*18) were associated with one or more of the endpoints in univariate analyses. After multivariable adjustments for other genetic and non-genetic risk factors of HIV-1 progression, the subset of alleles more strongly or consistently associated with HIV-1 disease control included A*32, A*74, B*14, B*45, B*53, B*57, and Cw*08. Carriage of infrequent HLA-B but not HLA-A alleles was associated with more favorable disease outcomes. Certain HLA class I associations with control of HIV-1 infection span the boundaries of race and viral subtype; while others appear confined within one or the other of those boundaries.
PMCID: PMC3778654  PMID: 21262311
HLA class I; Allele frequency; HIV-1 control; African American
7.  Reduced Inflammation and CD4 Loss in Acute SHIV Infection During Oral Pre-Exposure Prophylaxis  
The Journal of Infectious Diseases  2012;206(5):770-779.
Background.The impact of pre-exposure prophylaxis (PrEP) with antiretrovirals on breakthrough HIV or SHIV infection is not fully documented. We addressed the hypothesis that SHIVSF162P3 infection despite active PrEP results in altered early immune parameters, compared with untreated infection.
Methods.Eleven rhesus macaques were infected during repeated, rectal, low-dose SHIVSF162P3 exposures while receiving concurrent oral PrEP (Truvada [n = 2] or GS7340 [n = 4]) or as untreated controls (n = 5). We measured SHIV RNA, inflammatory cytokines, CD4 cells, and SHIV-specific and memory T cells until 20 weeks after peak viremia.
Results.SHIV infection during PrEP resulted in 100-fold lower peak viremia and lower IL-15, IL-18, and IL-1Ra levels, compared with controls (P < .05; Wilcoxon rank-sum test). Unlike controls, PrEP-treated macaques showed no significant CD4 cell count reduction during acute infection and developed more SHIV-specific central memory T cells, relative to controls. After in vivo CD8 cell depletion, viral load increased to similar levels, indicating that CD8 cells were critical for viral control in both groups.
Conclusions.PrEP with antiretrovirals has beneficial effects on early SHIV infection even when infection is not prevented. Although long-term immune control could not be examined in this SHIV infection model, our results suggest that PrEP results in improved early disease parameters in breakthrough infections.
PMCID: PMC3491742  PMID: 22740713
8.  UC781 Microbicide Gel Retains Anti-HIV Activity in Cervicovaginal Lavage Fluids Collected following Twice-Daily Vaginal Application 
The potent nonnucleoside reverse transcriptase inhibitor UC781 has been safety tested as a vaginal microbicide gel formulation for prevention of HIV-1 sexual transmission. To investigate whether UC781 retained anti-infective activity following exposure to the female genital tract, we conducted an ex vivo analysis of the UC781 levels and antiviral activity in cervicovaginal lavage (CVL) fluids from 25 Thai women enrolled in a 14-day safety trial of twice-daily vaginal application of two concentrations of the UC781 microbicide gel. CVL samples were collected from women in the 0.1% (n = 5), 0.25% (n = 15), and placebo (n = 5) gel arms following the first application of gel (T15 min) and 8 to 24 h after the final application (T8-24 h) and separated into cell-free (CVL-s) and pelletable (CVL-p) fractions. As UC781 is highly hydrophobic, there were significantly higher levels of UC781 in the CVL-p samples than in the CVL-s samples for the UC781 gel arms. In T8-24 h CVL-p samples, 2/5 and 13/15 samples collected from the 0.1% and 0.25% UC781 gel arms, respectively, efficiently blocked infection with ≥4 log10 50% tissue culture infective dose (TCID50) of a CCR5-tropic CRF01_AE HIV-1 virus stock. Independent of the arm, the 11 CVL-p samples with UC781 levels of ≥5 μg/CVL sample reduced infectious HIV by ≥4 log10 TCID50. Our results suggest that the levels and anti-infective activities of UC781 gel formulations are likely to be associated with a cellular or pelletable component in CVL samples. Therefore, cellular and pelletable fractions should be assayed for drug levels and anti-infective activity in preclinical studies of candidate microbicides.
PMCID: PMC3393398  PMID: 22508307
9.  Controlling HIV Epidemics among Injection Drug Users: Eight Years of Cross-Border HIV Prevention Interventions in Vietnam and China 
PLoS ONE  2012;7(8):e43141.
HIV in Vietnam and Southern China is driven by injection drug use. We have implemented HIV prevention interventions for IDUs since 2002–2003 in Lang Son and Ha Giang Provinces, Vietnam and Ning Ming County (Guangxi), China.
Interventions provide peer education and needle/syringe distribution. Evaluation employed serial cross-sectional surveys of IDUs 26 waves from 2002 to 2011, including interviews and HIV testing. Outcomes were HIV risk behaviors, HIV prevalence and incidence. HIV incidence estimation used two methods: 1) among new injectors from prevalence data; and 2) a capture enzyme immunoassay (BED testing) on all HIV+ samples.
We found significant declines in drug-related risk behaviors and sharp reductions in HIV prevalence among IDUs (Lang Son from 46% to 23% [p<0.001], Ning Ming: from 17% to 11% [p = 0.003], and Ha Giang: from 51% to 18% [p<0.001]), reductions not experienced in other provinces without such interventions. There were significant declines in HIV incidence to low levels among new injectors through 36–48 months, then some rebound, particularly in Ning Ming, but BED-based estimates revealed significant reductions in incidence through 96 months.
This is one of the longest studies of HIV prevention among IDUs in Asia. The rebound in incidence among new injectors may reflect sexual transmission. BED-based estimates may overstate incidence (because of false-recent results in patients with long-term infection or on ARV treatment) but adjustment for false-recent results and survey responses on duration of infection generally confirm BED-based incidence trends. Combined trends from the two estimation methods show sharp declines in incidence to low levels. The significant downward trends in all primary outcome measures indicate that the Cross-Border interventions played an important role in bringing HIV epidemics among IDUs under control. The Cross-Border project offers a model of HIV prevention for IDUs that should be considered for large-scale replication.
PMCID: PMC3428343  PMID: 22952640
10.  HIV Prevalence, Risk Behavior, Hormone Use and Surgical History Among Transgender Persons in Thailand 
AIDS and behavior  2011;15(3):650-658.
While Male-to-female transgender persons (TG) are believed to often engage in sex work and have high HIV infection risk, little is known about demographics, surgical and hormone use history, risk behaviors and HIV prevalence. Between March and October 2005, 474 TG from Bangkok, Chiangmai, and Phuket were surveyed using venue-day-time sampling. Of 474 participants, overall HIV prevalence was 13.5%. Most participants had completed at least secondary or vocational education (79.2%), gender self-identified as female (89.0%), had received money, gifts or valuables for sex (60.8%), and reported hormone use (88.6%). Surgical history was taken from 325 participants. Of these, 68.6% reported some form of surgery and 11.1% had undergone penile-vaginal reconstructive surgery. In multivariate analysis, being recruited from a park/street; older age, anal sex role identification as “versatile” and anal sex debut before age 13 were independently associated with HIV prevalence. The development, implementation and evaluation of culturally appropriate sexual health interventions for Thai TG is urgently needed.
PMCID: PMC3103223  PMID: 21104008
Men who have sex with men; Transgender; HIV/AIDS; Hormone use; Silicone injection; Thailand
11.  Enrollment Characteristics and Risk Behaviors of Injection Drug Users Participating in the Bangkok Tenofovir Study, Thailand 
PLoS ONE  2011;6(9):e25127.
The Bangkok Tenofovir Study was launched in 2005 to determine if pre-exposure prophylaxis with tenofovir will reduce the risk of HIV infection among injecting drug users (IDUs). We describe recruitment, screening, enrollment, and baseline characteristics of study participants and contrast risk behavior of Tenofovir Study participants with participants in the 1999–2003 AIDSVAX B/E Vaccine Trial.
The Bangkok Tenofovir Study is an ongoing, phase-3, randomized, double-blind, placebo-controlled, HIV pre-exposure prophylaxis trial of daily oral tenofovir. The Tenofovir Study and the Vaccine Trial were conducted among IDUs at 17 drug-treatment clinics in Bangkok. Tenofovir Study sample size was based on HIV incidence in the Vaccine Trial. Standardized questionnaires were used to collect demographic, risk behavior, and incarceration data. The Tenofovir Study is registered with, number-NCT00119106.
From June 2005 through July 2010, 4094 IDUs were screened and 2413 enrolled in the Bangkok Tenofovir Study. The median age of enrolled participants was 31 years (range, 20–59), 80% were male, and 63% reported they injected drugs during the 3 months before enrollment. Among those who injected, 53% injected methamphetamine, 37% midazolam, and 35% heroin. Tenofovir Study participants were less likely to inject drugs, inject daily, or share needles (all, p<0.001) than Vaccine Trial participants.
The Bangkok Tenofovir Study has been successfully launched and is fully enrolled. Study participants are significantly less likely to report injecting drugs and sharing needles than participants in the 1999–2003 AIDSVAX B/E Vaccine Trial suggesting HIV incidence will be lower than expected. In response, the Bangkok Tenofovir Study enrollment was increased from 1600 to 2400 and the study design was changed from a defined 1-year follow-up period to an endpoint-driven design. Trial results demonstrating whether or not daily oral tenofovir reduces the risk of HIV infection among IDUs are expected in 2012.
PMCID: PMC3182181  PMID: 21969870
12.  Identifying Host Genetic Risk Factors in the Context of Public Health Surveillance for Invasive Pneumococcal Disease 
PLoS ONE  2011;6(8):e23413.
Host genetic factors that modify risk of pneumococcal disease may help target future public health interventions to individuals at highest risk of disease. We linked data from population-based surveillance for invasive pneumococcal disease (IPD) with state-based newborn dried bloodspot repositories to identify biological samples from individuals who developed invasive pneumococcal disease. Genomic DNA was extracted from 366 case and 732 anonymous control samples. TagSNPs were selected in 34 candidate genes thought to be associated with host response to invasive pneumococcal disease, and a total of 326 variants were successfully genotyped. Among 543 European Americans (EA) (182 cases and 361 controls), and 166 African Americans (AA) (53 cases and 113 controls), common variants in surfactant protein D (SFTPD) are consistently underrepresented in IPD. SFTPD variants with the strongest association for IPD are intronic rs17886286 (allelic OR 0.45, 95% confidence interval (CI) [0.25, 0.82], with p = 0.007) in EA and 5′ flanking rs12219080 (allelic OR 0.32, 95%CI [0.13, 0.78], with p = 0.009) in AA. Variants in CD46 and IL1R1 are also associated with IPD in both EA and AA, but with effects in different directions; FAS, IL1B, IL4, IL10, IL12B, SFTPA1, SFTPB, and PTAFR variants are associated (p≤0.05) with IPD in EA or AA. We conclude that variants in SFTPD may protect against IPD in EA and AA and genetic variation in other host response pathways may also contribute to risk of IPD. While our associations are not corrected for multiple comparisons and therefore must be replicated in additional cohorts, this pilot study underscores the feasibility of integrating public health surveillance with existing, prospectively collected, newborn dried blood spot repositories to identify host genetic factors associated with infectious diseases.
PMCID: PMC3156135  PMID: 21858107
13.  Assessment of BED HIV-1 Incidence Assay in Seroconverter Cohorts: Effect of Individuals with Long-Term Infection and Importance of Stable Incidence 
PLoS ONE  2011;6(3):e14748.
Performance of the BED assay in estimating HIV-1 incidence has previously been evaluated by using longitudinal specimens from persons with incident HIV infections, but questions remain about its accuracy. We sought to assess its performance in three longitudinal cohorts from Thailand where HIV-1 CRF01_AE and subtype B′ dominate the epidemic.
BED testing was conducted in two longitudinal cohorts with only incident infections (a military conscript cohort and an injection drug user cohort) and in one longitudinal cohort (an HIV-1 vaccine efficacy trial cohort) that also included long-term infections.
Incidence estimates were generated conventionally (based on the number of annual serocoversions) and by using BED test results in the three cohorts. Adjusted incidence was calculated where appropriate.
For each longitudinal cohort the BED incidence estimates and the conventional incidence estimates were similar when only newly infected persons were tested, whether infected with CRF01_AE or subtype B′. When the analysis included persons with long-term infections (to mimic a true cross-sectional cohort), BED incidence estimates were higher, although not significantly, than the conventional incidence estimates. After adjustment, the BED incidence estimates were closer to the conventional incidence estimates. When the conventional incidence varied over time, as in the early phase of the injection drug user cohort, the difference between the two estimates increased, but not significantly.
Evaluation of the performance of incidence assays requires the inclusion of a substantial number of cohort-derived specimens from individuals with long-term HIV infection and, ideally, the use of cohorts in which incidence remained stable. Appropriate adjustments of the BED incidence estimates generate estimates similar to those generated conventionally.
PMCID: PMC3048863  PMID: 21408214
14.  Human Leukocyte Antigen Class I Supertypes and HIV-1 Control in African Americans▿  
Journal of Virology  2009;84(5):2610-2617.
The role of human leukocyte antigen (HLA) class I supertypes in controlling human immunodeficiency virus type 1 (HIV-1) infection in African Americans has not been established. We examined the effects of the HLA-A and HLA-B alleles and supertypes on the outcomes of HIV-1 clade B infection among 338 African American women and adolescents. HLA-B58 and -B62 supertypes (B58s and B62s) were associated with favorable HIV-1 disease control (proportional odds ratio [POR] of 0.33 and 95% confidence interval [95% CI] of 0.21 to 0.52 for the former and POR of 0.26 and 95% CI of 0.09 to 0.73 for the latter); B7s and B44s were associated with unfavorable disease control (POR of 2.39 and 95% CI of 1.54 to 3.73 for the former and POR of 1.63 and 95% CI of 1.08 to 2.47 for the latter). In general, individual alleles within specific B supertypes exerted relatively homogeneous effects. A notable exception was B27s, whose protective influence (POR, 0.58; 95% CI, 0.35 to 0.94) was masked by the opposing effect of its member allele B*1510. The associations of most B supertypes (e.g., B58s and B7s) were largely explained either by well-known effects of constituent B alleles or by effects of previously unimplicated B alleles aggregated into a particular supertype (e.g., B44s and B62s). A higher frequency of HLA-B genotypic supertypes correlated with a higher mean viral load (VL) and lower mean CD4 count (Pearson's r = 0.63 and 0.62, respectively; P = 0.03). Among the genotypic supertypes, B58s and its member allele B*57 contributed disproportionately to the explainable VL variation. The study demonstrated the dominant role of HLA-B supertypes in HIV-1 clade B-infected African Americans and further dissected the contributions of individual class I alleles and their population frequencies to the supertype effects.
PMCID: PMC2820922  PMID: 20032191
15.  Critical Role for Env as well as Gag-Pol in Control of a Simian-Human Immunodeficiency Virus 89.6P Challenge by a DNA Prime/Recombinant Modified Vaccinia Virus Ankara Vaccine 
Journal of Virology  2002;76(12):6138-6146.
Cellular immune responses against epitopes in conserved Gag and Pol sequences of human immunodeficiency virus type 1 have become popular targets for candidate AIDS vaccines. Recently, we used a simian-human immunodeficiency virus model (SHIV 89.6P) with macaques to demonstrate the control of a pathogenic mucosal challenge by priming with Gag-Pol-Env-expressing DNA and boosting with Gag-Pol-Env-expressing recombinant modified vaccinia virus Ankara (rMVA). Here we tested Gag-Pol DNA priming and Gag-Pol rMVA boosting to evaluate the contribution of anti-Env immune responses to viral control. The Gag-Pol vaccine raised frequencies of Gag-specific T cells similar to those raised by the Gag-Pol-Env vaccine. Following challenge, these rapidly expanded to counter the challenge infection. Despite this, the control of the SHIV 89.6P challenge was delayed and inconsistent in the Gag-Pol-vaccinated group and all of the animals underwent severe and, in most cases, sustained loss of CD4+ cells. Interestingly, most of the CD4+ cells that were lost in the Gag-Pol-vaccinated group were uninfected cells. We suggest that the rapid appearance of binding antibody for Env in Gag-Pol-Env-vaccinated animals helped protect uninfected CD4+ cells from Env-induced apoptosis. Our results highlight the importance of immune responses to Env, as well as to Gag-Pol, in the control of immunodeficiency virus challenges and the protection of CD4+ cells.
PMCID: PMC136190  PMID: 12021347

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