Last data update: May 13, 2024. (Total: 46773 publications since 2009)
Records 1-8 (of 8 Records) |
Query Trace: Butera S[original query] |
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Lack of in vitro–in vivo correlation for a UC781-releasing vaginal ring in macaques
McConville C , Smith JM , McCoy CF , Srinivasan P , Mitchell J , Holder A , Otten RA , Butera S , Doncel GF , Friend DR , Malcolm RK . Drug Deliv Transl Res 2015 5 (1) 27-37 This study describes the preclinical development of a matrix-type silicone elastomer vaginal ring device designed to provide controlled release of UC781, a non-nucleoside reverse transcriptase inhibitor. Testing of both human- and macaque-sized rings in a sink condition in vitro release model demonstrated continuous UC781 release in quantities considered sufficient to maintain vaginal fluid concentrations at levels 82–860-fold higher than the in vitro IC50 (2.0 to 10.4 nM) and therefore potentially protect against mucosal transmission of HIV. The 100-mg UC781 rings were well tolerated in pig-tailed macaques, did not induce local inflammation as determined by cytokine analysis and maintained median concentrations in vaginal fluids of UC781 in the range of 0.27 to 5.18 mM during the course of the 28-day study. Analysis of residual UC781 content in rings after completion of both the in vitro release and macaque pharmacokinetic studies revealed that 57 and 5 mg of UC781 was released, respectively. The pharmacokinetic analysis of a 100-mg UC781 vaginal ring in pig-tailed macaques showed poor in vivo–in vitro correlation, attributed to the very poor solubility of UC781 in vaginal fluid and resulting in a dissolution-controlled drug release mechanism rather than the expected diffusion-controlled mechanism. |
Prevalence and correlates of GB virus C infection in HIV-infected and HIV-uninfected pregnant women in Bangkok, Thailand
Bhanich Supapol W , Remis RS , Raboud J , Millson M , Tappero J , Kaul R , Kulkarni P , McConnell MS , Mock PA , McNicholl JM , Roongpisuthipong A , Chotpitayasunondh T , Shaffer N , Butera S . J Med Virol 2011 83 (1) 33-44 GB virus C (GBV-C) is an apathogenic virus that has been shown to inhibit HIV replication. This study examined the prevalence and correlates of GBV-C infection and clearance in three cohorts of pregnant women in Thailand. The study population consisted of 1,719 (1,387 HIV-infected and 332 HIV-uninfected) women from three Bangkok perinatal HIV transmission studies. Stored blood was tested for GBV-C RNA, GBV-C antibody, and if RNA-positive, genotype. Risk factors associated with the prevalence of GBV-C infection (defined as presence of GBV-C RNA and/or antibody) and viral clearance (defined as presence of GBV-C antibody in the absence of RNA) among women with GBV-C infection were examined using multiple logistic regression. The prevalence of GBV-C infection was 33% among HIV-infected women and 15% among HIV-uninfected women. GBV-C infection was independently associated (AOR, 95% CI) with an increasing number of lifetime sexual partners (referent-1 partner, 2 partners [1.60, 1.22-2.08], 3-10 partners [1.92, 1.39-2.67], >10 partners [2.19, 1.33-3.62]); injection drug use (5.50, 2.12-14.2); and HIV infection (3.79, 2.58-5.59). Clearance of GBV-C RNA among women with evidence of GBV-C infection was independently associated with increasing age in years (referent <20, 20-29 [2.01, 1.06-3.79] and ≥30 [3.18, 1.53-6.60]), more than 10 lifetime sexual partners (3.05, 1.38-6.75), and HIV infection (0.29, 0.14-0.59). This study found that GBV-C infection is a common infection among Thai women and is associated with HIV infection and both sexual and parenteral risk behaviors. |
Preventing influenza coinfection among HIV-infected persons: a complex picture coming into focus
Reyes-Teran G , Butera ST . AIDS 2010 24 (14) 2283-5 The impact of seasonal influenza in patients with HIV infection has been debated in the medical literature and systematic clinical guidance on treatment and benefits of vaccination has yet to clearly emerge, in part owing to limited data. A significant excess mortality due to pneumonia or influenza has been found in this population [1], but a typical clinical presentation and a rate of secondary complications similar to those of non-HIV infected individuals have also been reported [2]. Without question, HAART has improved the clinical course of HIV-infected individuals and significantly decreased mortality [3], and hospitalization rates owing to cardiopulmonary disease [4]. Similar therapeutic benefit may be deduced from initial reports focused on HIV-infected persons with the pandemic influenza virus A (H1N1) during 2009. One such study involved 20 HIV patients on HAART (median CD4 cell count of 494 cells/μl; viral load of <400 copies/ml), the clinical presentation of influenza disease was not distinctive from that reported in HIV-negative individuals, and a favorable outcome was observed in the majority of individuals [5]. Another study included 56 individuals with controlled HIV infection (median CD4 cell count of 583 cells/μl; 95% had <50 copies/ml); HIV infection did not make influenza A (H1N1) more clinically severe and influenza A (H1N1) did not have a major effect on clinical measures of HIV infection [6]. In contrast, among patients with advanced HIV disease, H1N1 infection appeared more severe with clinical and radiographic symptoms masked by active opportunistic infections, thus delaying H1N1 antiviral treatment [7]. These initial studies clearly suggest that stage of HIV disease and accessibility of HAART must be considered when estimating the impact of influenza. |
Generation of a dual RT Env SHIV that is infectious in rhesus macaques
Smith JM , Dauner A , Li B , Srinivasan P , Mitchell J , Hendry M , Ellenberger D , Butera S , Otten RA . J Med Primatol 2010 39 (4) 213-23 BACKGROUND: The best current animal model for HIV infection and evaluation of antiviral compounds is the Simian-human immunodeficiency virus (SHIV)/macaque system. There are multiple recombinant SHIVs available, but these viruses have limitations in evaluating combination drug strategies for prevention. Drug combinations that target reverse transcriptase (RT, either nRTI or nnRTI) and envelope (entry or fusion inhibitors) have to be tested separately, which does not permit the assessment of additive, synergistic, or antagonistic effects of ARV combinations. We describe construction of a dual SHIV containing both HIV RT and a CCR5-specific HIV envelope gene in a simian immunodeficiency virus backbone. METHODS: The RT Env SHIV molecular clone was constructed using RT SHIV and SHIV162p3 sequences as templates to generate RT Env SHIV. RT Env SHIV was expanded in vitro in CD8-depleted macaque peripheral blood mononuclear cells (PBMC). Recombinant virus was used to infect a rhesus macaque (4.3 x 10(4) tissue culture infectious dose [TCID(50)], intravenously [IV]). A second passage in a macaque by IV transfer of 10 ml of blood obtained from the first infection was also done. The in vivo adapted virus stock from these macaques was used to produce high titer stocks in vitro and used to rectally infect an additional macaque. RESULTS: Peak viral load reached 6 x 10(5) vRNA copies/ml in plasma in both IV-exposed macaques and remained detectable in the one animal for 16 weeks after infection. A viral stock (1.68 x 10(4) TCID(50)) derived from the second macaque passage has been produced in CD8-depleted rhesus PBMC and was successfully used to demonstrate mucosal transmission. The resulting RT Env SHIV retained the sensitivity to HIV RT and entry inhibitors of its parental viruses. CONCLUSIONS: The objective of this study was to develop and characterize a SHIV recombinant virus for evaluating the efficacy of ART and microbicide products that target both HIV RT and/or Env-mediated entry. RT Env SHIV can productively infect macaques by both the IV and mucosal route, making it a valuable tool for transmission studies. |
Resistance to simian HIV infection is associated with high plasma interleukin-8, RANTES and Eotaxin in a macaque model of repeated virus challenges
Promadej-Lanier N , Hanson DL , Srinivasan P , Luo W , Adams DR , Guenthner PC , Butera S , Otten RA , Kersh EN . J Acquir Immune Defic Syndr 2010 53 (5) 574-81 Animal models for research on susceptibility to HIV are currently not available. Here we explore whether a macaque model of repeated low-dose rectal or vaginal virus challenges could be employed. We tested the hypothesis that susceptibility to Simian HIV is not merely stochastic in this model but rather is associated with identifiable host factors. Forty macaques required a median of 3.5 SHIVSF162P3 challenges for infection. We studied the association of their susceptibility with 13 predisposing plasma cytokines/chemokines (RANTES, Eotaxin, monocyte chemoattractant protein (MCP)-1, IL-7, MIP-1beta, TNF-alpha, MIP-1alpha, granulocyte colony-stimulating factor, IL-8, interferon-gamma, IL-17, IL-1beta, IL-6). Higher plasma RANTES, IL-8, and Eotaxin were associated with lower susceptibility, that is, higher resistance to infection. In a group of macaques with low IL-8 and RANTES, a median 3 exposures were required to infect; whereas, when either IL-8 or RANTES were high, a median 12 exposures were required. Thus, susceptibility was associated with identifiable discrete host factors and was not stochastic. In addition, the macaque model identified key human resistance factors (RANTES, Eotaxin), but also revealed a novel association with resistance (IL-8). Future direct evaluation of these or other factors in the animal model may be beneficial for developing new immunomodulation strategies for HIV prevention. |
Mother-to-child transmission of GB virus C in a cohort of women coinfected with GB virus C and HIV in Bangkok, Thailand
Bhanich Supapol W , Remis RS , Raboud J , Millson M , Tappero J , Kaul R , Kulkarni P , McConnell MS , Mock PA , McNicholl JM , Vanprapar N , Asavapiriyanont S , Shaffer N , Butera S . J Infect Dis 2009 200 (2) 227-35 BACKGROUND: GB virus C (GBV-C) is an apathogenic virus that inhibits human immunodeficiency virus (HIV) replication in vitro. Mother-to-child transmission (MTCT) of GBV-C has been observed in multiple small studies. Our study examined the rate and correlates of MTCT of GBV-C in a large cohort of GBV-C-HIV-coinfected pregnant women in Thailand. METHODS: Maternal delivery plasma specimens from 245 GBV-C-HIV-infected women and specimens from their infants at 4 or 6 months of age were tested for GBV-C RNA. Associations with MTCT of GBV-C were examined using logistic regression. RESULTS: One hundred one (41%) of 245 infants acquired GBV-C infection. MTCT of GBV-C was independently associated with maternal antiretroviral therapy (adjusted odds ratio [AOR], 5.21 [95% confidence interval {CI}, 2.12-12.81]), infant HIV infection (AOR, 0.05 [95% CI, 0.01-0.26]), maternal GBV-C load (8.0 log(10) copies/mL: AOR, 86.77 [95% CI, 15.27-481.70]; 7.0-7.9 log(10) copies/mL: AOR, 45.62 [95% CI, 8.41-247.51]; 5.0-6.9 log(10) copies/mL: AOR, 9.07 [95% CI, 1.85-44.33]: reference, <5 log(10) viral copies/mL), and caesarean delivery (AOR, 0.26 [95% CI, 0.12-0.59]). CONCLUSIONS: Associations with maternal GBV-C load and mode of delivery suggest transmission during pregnancy and delivery. Despite mode of delivery being a common risk factor for virus transmission, GBV-C and HIV were rarely cotransmitted. The mechanisms by which maternal receipt of antiretroviral therapy might increase MTCT of GBV-C are unknown. |
Repeated rectal SHIVSF162P3 exposures do not consistently induce sustained T cell responses prior to systemic Infection in the repeat-low dose preclinical macaque model
Kersh EN , Luo W , Adams DR , Srinivasan P , Smith JM , Promadej-Lanier N , Ellenberger D , Garcia-Lerma JG , Butera S , Otten R . AIDS Res Hum Retroviruses 2009 25 (9) 905-17 The macaque model of repeated SHIV exposures is increasingly used as a preclinical tool to evaluate biomedical HIV intervention strategies. It is unclear whether multiple virus exposures induce immune responses in macaques, as documented in uninfected individuals repeatedly exposed to HIV. We here address whether repeated, rectal SHIV(SF162P3) exposures lead to systemic T cell activation in 12 rhesus macaques, and whether this is associated with increased infection resistance. Eight macaques became systemically infected after 2-7 exposures, three macaques were less susceptible (infection after 10-12 exposures), and one macaque remained uninfected after 14 exposures. PBMCs were retrospectively monitored for increases in T cell activation by analyzing the proportion of CD8(+) T cells, recently activated or proliferated T cells (markers CD38, Ki67), a marker for cytotoxicity (granzyme B), or T cell-produced plasma cytokines (IFN-gamma, RANTES, IL-2). Repeated virus exposures did not induce sustained, potent, or diverse T cell responses prior to systemic infection. Some changes occurred in the analyzed parameters during repeated virus exposures, but similar T cell activities were also observed in five SHIV-unexposed control macaques. Thus, we found no evidence that delayed infection or resistance to infection was associated with systemic, long-lasting, protective T cell responses to repeated rectal virus exposures. Our results provide further insights into the repeat exposure macaque model. We find that this model can be used for testing biomedical prevention strategies without concern of eliciting a systemic vaccination effect. |
Development and evaluation of a vaginal ring device for sustained delivery of HIV microbicides to non-human primates
Promadej-Lanier Nattawan , Smith James M , Srinivasan Priya , McCoy Clare F , Butera Sal , Woolfson ADavid , Malcolm RKarl , Otten Ron A . J Med Primatol 2009 38 (4) 263-271 BACKGROUND: There is considerable interest in developing coitally independent, sustained release formulations for long-term administration of HIV microbicides. Vaginal ring devices are at the forefront of this formulation strategy. METHODS: Non-medicated silicone elastomer vaginal rings were prepared having a range of appropriate dimensions for testing vaginal fit in pig-tailed and Chinese rhesus macaques. Cervicovaginal proinflammatory markers were evaluated. Compression testing was performed to compare the relative flexibility of various macaque and commercial human rings. RESULTS: All rings remaine d in place during the study period and no tissue irritation or significant induction of cervicovaginal proinflammatory markers or signs of physical discomfort were observed during the 8-week study period. CONCLUSIONS: Qualitative evaluation suggests that the 25 x 5-mm ring provided optimal fit in both macaque species. Based on the results presented here, low-consistency silicone elastomers do not cause irritation in macaques and are proposed as suitable materials for the manufacture of microbicide-loaded vaginal rings. |
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