RESUMEN
Penile acquisition of HIV accounts for most infections among men globally. Nevertheless, candidate HIV interventions for men advance to clinical trials without preclinical efficacy data, due primarily to a paucity of relevant animal models of penile HIV infection. Using our recently developed macaque model, we show that a single subcutaneous administration of broadly neutralizing antibody (bNAb) 10-1074 conferred durable protection against repeated penile exposures to simian-human immunodeficiency virus (SHIVSF162P3). Macaques co-administered bNAbs 10-1074 and 3BNC117, or 3BNC117 alone, also exhibited significant protection against repeated vaginal SHIVAD8-EO exposures. Regression modeling estimated that individual plasma bNAb concentrations of 5 µg ml-1 correlated with ≥99.9% relative reduction in SHIV infection probability via penile (10-1074) or vaginal (10-1074 or 3BNC117) challenge routes. These results demonstrate that comparably large reductions in penile and vaginal SHIV infection risk among macaques were achieved at clinically relevant plasma bNAb concentrations and inform dose selection for the development of bNAbs as long-acting pre-exposure prophylaxis candidates for use by men and women.
Asunto(s)
Vacunas contra el SIDA/administración & dosificación , Anticuerpos ampliamente neutralizantes/administración & dosificación , Anticuerpos Anti-VIH/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Síndrome de Inmunodeficiencia Adquirida del Simio/transmisión , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunas contra el SIDA/sangre , Animales , Anticuerpos ampliamente neutralizantes/sangre , Modelos Animales de Enfermedad , Femenino , Anticuerpos Anti-VIH/sangre , Infecciones por VIH/prevención & control , Infecciones por VIH/transmisión , Semivida , Inmunización Pasiva , Macaca mulatta , Masculino , Pene/inmunología , Pene/virología , Profilaxis Pre-Exposición , Vagina/inmunología , Vagina/virologíaRESUMEN
Penile acquisition of HIV infection contributes substantially to the global epidemic. Our goal was to establish a preclinical macaque model of penile HIV infection for evaluating the efficacy of new HIV prevention modalities. Rhesus macaques were challenged once or twice weekly with consistent doses of SHIVsf162P3 (a chimeric simian-human immunodeficiency virus containing HIV env) ranging from 4-600 TCID50 (50% tissue culture infective dose), via two penile routes, until systemic SHIV infection was confirmed. One route exposed the inner foreskin, glans and urethral os to virus following deposition into the prepuce (foreskin) pouch. The second route introduced the virus non-traumatically into the distal urethra only. Single-route challenges resulted in dose-dependent rates of SHIV acquisition informing selection of optimal SHIV dosing. Concurrent SHIV challenges via the prepuce pouch (200 TCID50) and urethra (16 TCID50) resulted in infection of 100% (10/10) animals following a median of 2.5 virus exposures (range, 1-12). We describe the first rhesus macaque repeat-exposure SHIV challenge model of penile HIV acquisition. Utilization of the model should further our understanding of penile HIV infection and facilitate the development of new HIV prevention strategies for men.
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Infecciones por VIH/prevención & control , Síndrome de Inmunodeficiencia Adquirida del Simio/diagnóstico , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Animales , Modelos Animales de Enfermedad , Prepucio/virología , Humanos , Macaca mulatta , Masculino , ARN Viral/análisis , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Uretra/virología , Carga ViralRESUMEN
BACKGROUND: In response to the ongoing infection prevention (IP) challenges in England, a 90-day quality improvement (QI) collaborative programme was developed. The paper discusses the approach, benefits, challenges and evaluation of the programme. OBJECTIVE: The objective of the collaborative was to develop new approaches to enable sustainable and effective IP. METHODOLOGY: Six trusts in the region participated in the collaborative. Each defined their bespoke IP focus. There was no expectation that statistically significant measurable improvements would be identified during the short time frame. The experiences of the participants were sought both during the programme to facilitate its constant review and at the end of the programme to evaluate its effectiveness. The feedback focused on achievements, barriers to change and benefits of participating in a QI collaborative. To measure the potential success of the projects, participants completed the Model for Understanding Success in Quality framework. (MUSIQ; Kaplan et al., 2012). RESULTS: Since each trusts IP focus was bespoke commonalities of success were not evaluated. Participants identified a positive outcome from their QI interventions. The MUSIQ score identified the projects had the potential for success. DISCUSSION: The feedback from the participants demonstrated that it is worthy of further development.
RESUMEN
BACKGROUND: Hormonal changes during menstrual cycling may affect susceptibility to HIV. METHODS: We determined the simian human immunodeficiency virus (SHIV) acquisition time point in 43 cycling pigtail macaques infected by repeated vaginal virus exposures initiated randomly in the cycle. RESULTS: SHIV infection was first detected in the follicular phase in 38 macaques (88%), and in the luteal phase in five macaques (12%), indicating a statistically significant timing difference. Assuming a 7-day eclipse phase, most infections occurred during or following a high-progesterone period associated with menstruation, vaginal epithelium thinning, and suppressed mucosal immunity. CONCLUSIONS: This raises questions whether other high-progesterone conditions (pregnancy, hormonal contraception) similarly affect HIV risk.
Asunto(s)
Susceptibilidad a Enfermedades/inmunología , Macaca nemestrina , Ciclo Menstrual/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/fisiología , Animales , Susceptibilidad a Enfermedades/virología , Femenino , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Factores de Tiempo , Vagina/virologíaRESUMEN
Sharps injuries pose a serious threat to health professionals, patients, and downstream workers. FIT4Safety is an initiative that seeks to promote safety and best practice in the diabetes setting. An Introduction to FIT4Safety and its Recommendations for the Safety of Sharps in the Diabetes Care Setting explains how and why the FIT4Safety initiative was formed, what it aims to achieve, and the importance of ensuring safety in the diabetes care setting. Outputs from FIT4Safety include Injection Safety in UK and Ireland: Safety of Sharps in Diabetes Recommendations. These recommendations were developed to provide a resource for all those directly involved in, or overseeing, diabetes care. The main topics and guidance detailed within the recommendations are discussed, as well as EU Directive 2010/32 on sharps injury prevention and the UK's Health and Safety (Sharp Instruments in Healthcare) Regulations 2013.
Asunto(s)
Accidentes de Trabajo/prevención & control , Diabetes Mellitus/enfermería , Lesiones por Pinchazo de Aguja/prevención & control , Administración de la Seguridad , Europa (Continente) , Humanos , Medición de RiesgoRESUMEN
Infections following repeated, low-dose (RLD), mucal S(H)IV exposures of macaques are used to model sexual HIV exposures for biomedical prevention testing. Different susceptibilities among animals can complicate study designs. In rhesus macaques, TRIM5 alleles Q, CypA, and TFP are resistance factors for infection with some S(H)IV strains, but not for SIVmac239 due to its capsid properties. SIVmac239-derived SHIVSF162P3 has been demonstrated to reproducibly infect mucosally in vaginal and rectal RLD models. To further test the suitability of SHIVSF162P3 for RLD models, we studied the influence of the TRIM5 genotype on susceptibility to rectal RLD infection and on plasma viremia by analyzing 43 male Indian rhesus macaques from control arms of completed studies. The median number of exposures required for infection was three (Q/Q, n=4) (TRIM5 alleles, number of macaques, respectively), four (Q/CypA, n=7), three (TFP/Q, n=15), three (TFP/TFP, n=15), and two (TFP/CypA, n=2); TRIM5(CypA/CypA) was not represented in our study. Median peak viremia (log10 viral copies/ml) in infected animals was 7.4 (Q/Q, n=4), 7.2 (Q/CypA, n=6), 7.3 (TFP/Q, n=13), 7.1 (TFP/TFP, n=15), and 6.5 (TFP/CypA; n=2). Neither susceptibility nor peak viremia was significantly different (log rank test, Kruskal-Wallis test, respectively). Rhesus macaques' susceptibility to RLD SHIVSF162P3 is independent of the TRIM5 TFP, CypA, and Q alleles, with the limitation that the power to detect any impact of CypA/CypA and TFP/CypA genotypes was nonexistent or low, due to absence or infrequency, respectively. The finding that TRIM5 alleles do not restrict mucosal infection or ensuing replication rates suggests that SHIVSF162P3 is indeed suitable for RLD experimentation.
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Proteínas Portadoras/genética , Macaca mulatta/genética , Macaca mulatta/virología , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Alelos , Animales , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Genotipo , VIH/patogenicidad , Infecciones por VIH/transmisión , Interacciones Huésped-Patógeno/genética , Mucosa Intestinal/virología , Masculino , Recto/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/etiología , Síndrome de Inmunodeficiencia Adquirida del Simio/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/transmisión , Viremia/etiología , Viremia/genéticaRESUMEN
BACKGROUND: FTY720 is an immunomodulatory agent that reduces lymphocytes in peripheral tissues and circulation. Such agents may be effective as vaginal microbicides for HIV prevention. Systemic or vaginal application of FTY720 may reduce lymphocyte concentrations in genital tissues, reducing HIV target cell numbers. METHODS: Five female pigtail macaques received topical vaginal gel FTY720 (n = 2), intravenous (i.v.) FTY720 (n = 2), or placebo gel (n = 1) in this pilot study. Circulating and mucosal lymphocytes and genital mucosa, cytokines, and tissue histology were analyzed to document topical and i.v. FTY720 effects. RESULTS: Topical and i.v. FTY720 appeared to decrease the levels of cervicovaginal IL-8, IL-1ra, and genital inflammatory cells. Small sample size precluded statistical analysis. Topical administration had no overt adverse effects. CONCLUSIONS: This study introduces FTY720 as an immunomodulatory agent for the vaginal mucosa, compares topical effects to those of i.v. administration, and provides the basis for future studies involving FTY720 for HIV prevention.
Asunto(s)
Recuento de Linfocitos , Macaca nemestrina , Glicoles de Propileno/administración & dosificación , Esfingosina/análogos & derivados , Vagina/efectos de los fármacos , Vagina/inmunología , Administración Intravaginal , Administración Intravenosa , Animales , Antiinfecciosos , Cuello del Útero/química , Cuello del Útero/efectos de los fármacos , Cuello del Útero/inmunología , Evaluación Preclínica de Medicamentos , Femenino , Clorhidrato de Fingolimod , Infecciones por VIH/prevención & control , Inmunosupresores , Proteína Antagonista del Receptor de Interleucina 1/análisis , Interleucina-8/análisis , Membrana Mucosa/química , Membrana Mucosa/efectos de los fármacos , Membrana Mucosa/inmunología , Proyectos Piloto , Placebos , Glicoles de Propileno/efectos adversos , Esfingosina/administración & dosificación , Esfingosina/efectos adversos , Vagina/química , Cremas, Espumas y Geles VaginalesRESUMEN
Member states of the European Union have until May 112013 to implement the Council Directive 2010/32/EU Implementing the Framework Agreement on Prevention from Sharps Injuries in the Hospital and Healthcare Sector. The aim of this legislation is to achieve a safe working environment and prevent injuries to healthcare professionals caused by all medical sharps, including needlesticks. This article examines the issues surrounding needlestick and sharps injuries, including risk assessment and prevention, information provision, raising awareness, use of safety devices, training and reporting procedures.
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Lesiones por Pinchazo de Aguja/prevención & control , Educación Continua en Enfermería , Humanos , Lesiones por Pinchazo de Aguja/epidemiología , Lesiones por Pinchazo de Aguja/psicología , Medición de RiesgoRESUMEN
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 SHIV(SF162P3) 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 SHIV(SF162P3) 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.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/farmacología , Linfocitos T CD4-Positivos/inmunología , Desoxicitidina/análogos & derivados , Compuestos Organofosforados/farmacología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Adenina/farmacología , Alanina , Animales , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/virología , Citocinas/sangre , Citocinas/inmunología , Desoxicitidina/farmacología , Combinación de Medicamentos , Combinación Emtricitabina y Fumarato de Tenofovir Disoproxil , Estudios Longitudinales , Macaca mulatta , Masculino , ARN Viral/química , ARN Viral/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Estadísticas no Paramétricas , Tenofovir/análogos & derivados , Viremia/inmunología , Viremia/virologíaRESUMEN
Member states of the European Union have until May 11 2013 to implement the Council Directive 2010/32/EU Implementing the Framework Agreement on Prevention from Sharps Injuries in the Hospital and Healthcare Sector. The aim of this legislation is to achieve a safe working environment and prevent injuries to healthcare professionals caused by all medical sharps, including needlesticks. This article examines the issues surrounding needlestick and sharps injuries, including risk assessment and prevention, information provision, raising awareness, use of safety devices, training and reporting procedures.
RESUMEN
A clinical study was undertaken to compare the surface microbial contamination associated with pens constructed of either a copper alloy or stainless steel used by nurses on intensive care units. A significantly lower level of microbial contamination was found on the copper alloy pens.
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Cobre/química , Contaminación de Equipos , Equipos y Suministros de Hospitales/microbiología , Escritura Manual , Unidades de Cuidados Intensivos/provisión & distribución , Acero Inoxidable , Aleaciones , Recuento de Colonia Microbiana , Bacterias Gramnegativas/aislamiento & purificación , Cocos Grampositivos/aislamiento & purificación , Humanos , Enfermeras y Enfermeros , Propiedades de SuperficieRESUMEN
Pre-exposure prophylaxis (PrEP) with anti-viral drugs is currently in clinical trials for the prevention of HIV infection. Induction of adaptive immune responses to virus exposures during anti-viral drug administration, i.e., a "chemo-vaccination" effect, could contribute to PrEP efficacy. To study possible chemo-vaccination, we monitored humoral and cellular immune responses in nine rhesus macaques undergoing up to 14 weekly, low-dose SHIV(SF162P3) rectal exposures. Six macaques concurrently received PrEP with intermittent, oral Truvada; three were no-PrEP controls. PrEP protected 4 macaques from infection. Two of the four showed evidence of chemo-vaccination, because they developed anti-SHIV CD4(+) and CD8(+) T cells; SHIV-specific antibodies were not detected. Control macaques showed no anti-SHIV immune responses before infection. Chemo-vaccination-induced T cell responses were robust (up to 3,940 SFU/10(6) PBMCs), predominantly central memory cells, short-lived (≤22 weeks), and appeared intermittently and with changing specificities. The two chemo-vaccinated macaques were virus-challenged again after 28 weeks of rest, after T cell responses had waned. One macaque was not protected from infection. The other macaque concurrently received additional PrEP. It remained uninfected and T cell responses were boosted during the additional virus exposures. In summary, we document and characterize PrEP-induced T cell chemo-vaccination. Although not protective after subsiding in one macaque, chemo-vaccination-induced T cells warrant more comprehensive analysis during peak responses for their ability to prevent or to control infections after additional exposures. Our findings highlight the importance of monitoring these responses in clinical PrEP trials and suggest that a combination of vaccines and PrEP potentially might enhance efficacy.
Asunto(s)
Desoxicitidina/análogos & derivados , Membrana Mucosa/virología , Compuestos Organofosforados/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunación , Administración Oral , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/virología , Diferenciación Celular/efectos de los fármacos , Citocinas/biosíntesis , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Combinación de Medicamentos , Combinación Emtricitabina y Fumarato de Tenofovir Disoproxil , Epítopos/inmunología , Macaca mulatta/inmunología , Macaca mulatta/virología , Masculino , Membrana Mucosa/efectos de los fármacos , Membrana Mucosa/inmunología , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/farmacología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacosRESUMEN
Fluctuations in susceptibility to HIV or SHIV during the menstrual cycle are currently not fully documented. To address this, the time point of infection was determined in 19 adult female pigtail macaques vaginally challenged during their undisturbed menstrual cycles with repeated, low-dose SHIV(SF162P3) exposures. Eighteen macaques (95%) first displayed viremia in the follicular phase, as compared with 1 macaque (5%) in the luteal phase (P < 0.0001). Due to a viral eclipse phase, we estimated a window of most frequent virus transmission between days 24 and 31 of the menstrual cycle, in the late luteal phase. Thus, susceptibility to vaginal SHIV infection is significantly elevated in the second half of the menstrual cycle when progesterone levels are high and when local immunity may be low. Such susceptibility windows have been postulated before but not definitively documented. Our data support the findings of higher susceptibility to HIV in women during progesterone-dominated periods including pregnancy and contraceptive use.
Asunto(s)
Fase Luteínica/fisiología , Síndrome de Inmunodeficiencia Adquirida del Simio/transmisión , Vagina/virología , Animales , Susceptibilidad a Enfermedades , Femenino , VIH-1 , Macaca nemestrina , Embarazo , Virus de la Inmunodeficiencia de los Simios , Carga Viral , ViremiaRESUMEN
Acinetobacter baumannii infection is responsible for a wide range of infections, including pneumonia, bacteraemia, meningitis, wound infections, and urinary tract infections. During June 2010, two patients on an intensive care unit in an acute hospital in the UK had multi-resistant A. baumannii identified in samples obtained from a variety of specimens. A further case was identified 31 days following confirmation of the first outbreak. The investigation and management of this outbreak included the introduction of enhanced infection prevention and control precautions; the establishment of an Outbreak Control Team; epidemiological investigations; and the decontamination of equipment and the environment. Isolate typing by the Health Protection Agency Centre for Infections laboratory confirmed the three cases had identical A. baumannii strains: European clone II lineage encoded with an OXA-51-type carbapenemase. This suggests that there was a patient-to-patient spread of multi-resistant A. baumannii.
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Infecciones por Acinetobacter/prevención & control , Acinetobacter baumannii , Infección Hospitalaria/prevención & control , Brotes de Enfermedades/prevención & control , Unidades de Cuidados Intensivos , Infecciones por Acinetobacter/diagnóstico , Infecciones por Acinetobacter/epidemiología , Infecciones por Acinetobacter/etiología , Acinetobacter baumannii/genética , Adulto , Auditoría Clínica , Infección Hospitalaria/diagnóstico , Infección Hospitalaria/epidemiología , Infección Hospitalaria/etiología , ADN Bacteriano/genética , Brotes de Enfermedades/estadística & datos numéricos , Farmacorresistencia Bacteriana Múltiple , Monitoreo del Ambiente , Estudios Epidemiológicos , Monitoreo Epidemiológico , Humanos , Control de Infecciones/organización & administración , Unidades de Cuidados Intensivos/organización & administración , Masculino , Persona de Mediana Edad , Grupo de Atención al Paciente , Factores de Riesgo , Estaciones del Año , Reino Unido/epidemiologíaRESUMEN
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.
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Quimiocina CCL11/inmunología , Quimiocina CCL5/inmunología , Interleucina-8/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Quimiocina CCL11/sangre , Quimiocina CCL5/sangre , Modelos Animales de Enfermedad , Femenino , Interleucina-8/sangre , Estimación de Kaplan-Meier , Macaca mulatta , Macaca nemestrina , Masculino , ARN Viral/sangre , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Viremia/inmunologíaRESUMEN
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.
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Infecciones por VIH/inmunología , VIH/inmunología , Recto/virología , Virus de la Inmunodeficiencia de los Simios/inmunología , Linfocitos T/inmunología , Animales , Proliferación Celular , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Granzimas/biosíntesis , Activación de Linfocitos , Macaca mulatta , MasculinoRESUMEN
OBJECTIVES: FTY720 causes retention of lymphocytes in lymphatic tissues. Previous studies revealed that FTY720 can decrease or eliminate chronic viral infections of mice. We address here whether therapeutic use of FTY720 in simian human immunodeficiency virus (SHIV)-infected rhesus macaques could also decrease viraemia. METHODS: FTY720 was administered intravenously to three SHIV(SF162P3)-infected macaques at 39, 7 or 6 weeks of infection; three control macaques (47, 48 or 6 weeks of infection) did not receive drug. FTY720 was given at 0.004 mg/kg on days 0, 1, 2, 14, 15 and 16, followed by 0.1 mg/kg on days 28, 29, 30, 42, 43 and 44. Blood was collected seven times throughout and four times during 47 days of follow-up. RESULTS: Only the 0.1 mg/kg dose resulted in a reduction in mean blood CD4+ T cells and B cells (to 33% and 27% of pre-drug levels, P=0.0024 and 0.003, respectively). FTY720 treatment did not lead to significant deviations from the natural pattern of viral control. Plasma viraemia progressed from a range of 10(4)-10(2) copies/mL before treatment to 10(4)-temporarily undetectable levels on the last day of treatment. SHIV(SF162P3) was not eliminated, however, as plasma viraemia and proviral DNA persisted during the follow-up. No significant alterations in T cell activity were noted throughout the drug course. CONCLUSIONS: FTY720 administration had no detectable therapeutic effect at the doses and schedules outlined here, although blood CD4+ T cells and B cells were effectively reduced. Future work might reveal whether FTY720 could be beneficial in more pathogenic SHIV, simian immunodeficiency virus or HIV infections.
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Factores Inmunológicos/uso terapéutico , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Glicoles de Propileno/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Esfingosina/análogos & derivados , Animales , ADN Viral/sangre , Clorhidrato de Fingolimod , Factores Inmunológicos/administración & dosificación , Inyecciones Intraventriculares , Recuento de Linfocitos , Macaca mulatta , Masculino , Glicoles de Propileno/administración & dosificación , ARN Viral/sangre , Esfingosina/administración & dosificación , Esfingosina/uso terapéutico , Carga ViralRESUMEN
We undertook a clinical trial to compare the efficacy of 2% (w/v) chlorhexidine gluconate in 70% (v/v) isopropyl alcohol with the efficacy of 70% (v/v) isopropyl alcohol alone for skin disinfection to prevent peripheral venous catheter colonization and contamination. We found that the addition of 2% chlorhexidine gluconate reduced the number of peripheral venous catheters that were colonized or contaminated.
Asunto(s)
2-Propanol/farmacología , Antiinfecciosos Locales/farmacología , Cateterismo Periférico , Clorhexidina/análogos & derivados , Desinfección/métodos , Piel/microbiología , Adulto , Anciano , Anciano de 80 o más Años , Bacterias/clasificación , Bacterias/aislamiento & purificación , Cateterismo Periférico/métodos , Catéteres de Permanencia/microbiología , Clorhexidina/farmacología , Contaminación de Equipos/prevención & control , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Preexposure prophylaxis (PrEP) with antiretroviral drugs constitutes a promising strategy for HIV prevention. Potent PrEP regimens with reverse transcriptase inhibitors can prevent detectable SHIV infection in a repeated low-dose macaque model that resembles human transmission, supporting plans to quickly move this approach into human trials. However, the possibility remains that extremely low levels of virus replication could nonetheless occur during PrEP and seed viral reservoirs in tissues. Therefore, seemingly protected macaques may harbor occult virus that may be initially contained by cytotoxic T cells, but could emerge later. To explore this possibility, we studied whether CD8(+) cells suppress viremia in four rhesus macaques apparently protected by daily or intermittent Truvada (FTC and tenofovir) during 14 low-dose, rectal SHIV(SF162P3) challenges and during a subsequent drug washout period. CD8(+) cells were efficiently ablated with antibodies in these and two additional control macaques that were previously infected but had reached undetectable virus set points. During 4 weeks of follow-up, all four macaques remained free of plasma viremia and provirus in blood lymphocytes. In contrast, plasma viremia resurged to 10(6) to 10(7) copies per milliliter within 2 weeks in both control macaques. Thus, these results indicate that the undetectable viremia in the PrEP-protected macaques was not due to CD8(+) cells that were containing a low-level infection. Rather, the PrEP treatment created conditions in which infection was prevented, eliminated, or controlled by unknown mechanisms. These data provide important information for PrEP usage to prevent HIV transmission, and fully support the continued pursuit of PrEP prevention measures in humans.