RESUMEN
Perivascular macrophages (PVMs) and, to a lesser degree, microglia are targets and reservoirs of HIV and simian immunodeficiency virus (SIV) in the brain. Previously, we demonstrated that colony-stimulating factor 1 receptor (CSF1R) in PVMs was upregulated and activated in chronically SIV-infected rhesus macaques with encephalitis, correlating with SIV infection of PVMs. Herein, we investigated the role of CSF1R in the brain during acute SIV infection using BLZ945, a brain-penetrant CSF1R kinase inhibitor. Apart from three uninfected historic controls, nine Indian rhesus macaques were infected acutely with SIVmac251 and divided into three groups (n = 3 each): an untreated control and two groups treated for 20-30â days with low- (10â mg/kg/day) or high- (30â mg/kg/day) dose BLZ945. With the high-dose BLZ945 treatment, there was a significant reduction in cells expressing CD163 and CD206 across all four brain areas examined, compared with the low-dose treatment and control groups. In 9 of 11 tested regions, tissue viral DNA (vDNA) loads were reduced by 95%-99% following at least one of the two doses, and even to undetectable levels in some instances. Decreased numbers of CD163+ and CD206+ cells correlated significantly with lower levels of vDNA in all four corresponding brain areas. In contrast, BLZ945 treatment did not significantly affect the number of microglia. Our results indicate that doses as low as 10â mg/kg/day of BLZ945 are sufficient to reduce the tissue vDNA loads in the brain with no apparent adverse effect. This study provides evidence that infected PVMs are highly sensitive to CSF1R inhibition, opening new possibilities to achieve viral clearance.
Asunto(s)
Encéfalo , Macaca mulatta , Macrófagos , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/virología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Carga Viral/efectos de los fármacos , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Antígenos CD/metabolismo , Masculino , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/virología , Antígenos de Diferenciación Mielomonocítica/metabolismo , Receptores de Superficie Celular/metabolismo , AnisolesRESUMEN
Effective antiretroviral therapy (ART) has transitioned HIV to a chronic disease, with more than 50% of people living with HIV (PLWH) being over the age of 50. HIV targets activated CD4+ T cells expressing HIV-specific co-receptors (CCR5 and CXCR4). Previously, we reported that chronic binge alcohol (CBA)-administered male rhesus macaques had a higher percentage of gut CD4+ T cells expressing simian immunodeficiency virus (SIV) co-receptor CXCR4. Evidence also suggests that gonadal hormone loss increased activated peripheral T cells. Further, mitochondrial function is critical for HIV replication and alcohol dysregulates mitochondrial homeostasis. Hence, we tested the hypothesis that CBA and ovariectomy (OVX) increase circulating activated CD4+ T cells expressing SIV co-receptors and dysregulate mitochondrial homeostasis in SIV-infected female rhesus macaques. Results showed that at the study end-point, CBA/SHAM animals had increased peripheral CD4+ T cell SIV co-receptor expression, and a lower CD4+ T cell count compared to CBA/OVX animals. CBA and OVX animals had altered peripheral immune cell gene expression important for maintaining mitochondrial homeostasis. These results provide insights into how at-risk alcohol use could potentially impact viral expression in cellular reservoirs, particularly in SIV-infected ovariectomized rhesus macaques.
Asunto(s)
Infecciones por VIH , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Etanol , Femenino , Expresión Génica , Homeostasis , Hormonas , Humanos , Macaca mulatta , Masculino , Mitocondrias/metabolismo , Virus de la Inmunodeficiencia de los Simios/genéticaRESUMEN
Aging people living with HIV (PLWH), especially postmenopausal women may be at higher risk of comorbidities associated with HIV, antiretroviral therapy (ART), hypogonadism, and at-risk alcohol use. Our studies in simian immunodeficiency virus (SIV)-infected male macaques demonstrated that chronic binge alcohol (CBA) reduced acute insulin response to glucose (AIRG), and at-risk alcohol use decreased HOMA-ß in PLWH. The objective of this study was to examine the impact of ovariectomy (OVX) on glucose-insulin dynamics and integrity of pancreatic endocrine function in CBA/SIV-infected female macaques. Female macaques were administered CBA (12-15 g/kg/wk) or isovolumetric water (VEH) intragastrically. Three months after initiation of CBA/VEH administration, all macaques were infected with SIVmac251, and initiated on antiretroviral therapy (ART) 2.5 mo postinfection. After 1 mo of ART, macaques were randomized to OVX or sham surgeries (n = 7 or 8/group), and euthanized 8 mo post-OVX (study endpoint). Frequently sampled intravenous glucose tolerance tests (FSIVGTT) were performed at selected time points. Pancreatic gene expression and islet morphology were determined at study endpoint. There was a main effect of CBA to decrease AIRG at Pre-SIV and study endpoint. There were no statistically significant OVX effects on AIRG (P = 0.06). CBA and OVX decreased the expression of pancreatic markers of insulin docking and release. OVX increased endoplasmic stress markers. CBA but not OVX impaired glucose-insulin expression dynamics in SIV-infected female macaques. Both CBA and OVX altered integrity of pancreatic endocrine function. These findings suggest increased vulnerability of PLWH to overt metabolic dysfunction that may be exacerbated by alcohol use and ovarian hormone loss.
Asunto(s)
Consumo Excesivo de Bebidas Alcohólicas/complicaciones , Glucemia/metabolismo , Trastornos del Metabolismo de la Glucosa/etiología , Resistencia a la Insulina , Insulina/sangre , Ovariectomía/efectos adversos , Páncreas/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/complicaciones , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Animales , Antirretrovirales/uso terapéutico , Consumo Excesivo de Bebidas Alcohólicas/sangre , Consumo Excesivo de Bebidas Alcohólicas/fisiopatología , Biomarcadores/sangre , Modelos Animales de Enfermedad , Femenino , Trastornos del Metabolismo de la Glucosa/sangre , Trastornos del Metabolismo de la Glucosa/fisiopatología , Macaca mulatta , Páncreas/fisiopatología , Factores de Riesgo , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Factores de TiempoRESUMEN
OBJECTIVE: The present study examined interactions between simian immunodeficiency virus (SIV), chronic binge alcohol (CBA), and antiretroviral therapy (ART) on growth factor signaling, neuroinflammatory markers, viral loads (VL), and CD4+ cell counts. DESIGN: Adult male rhesus macaques were administered CBA (13-14âg ethanol (EtOH)/kg per week) or sucrose (SUC) 3 months prior to SIVmac251 infection until the study endpoint. At viral setpoint, a subset of CBA/SIV+ and SUC/SIV+ macaques were randomized to receive daily ART (9-[2-Phosphonyl-methoxypropyly]adenine [PMPA] 20âmg/kg, 2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC), 30âmg/kg). Frontal cortex (FC) and basal ganglia (BG) were collected for gene and protein expression. METHODS: Relationships between brain and plasma VL or CD4+ cell counts were determined using linear regression. Effects of SIV, CBA, and ART on markers of neuroinflammation and brain-derived neurotrophic factor (BDNF) signaling were determined by ANOVA and linear regression. RESULTS: SIV increased FC and BG neuroinflammatory and glial cell gene expression (CX3CR1, B2M), and reduced FC protein kinase B phosphorylation. CBA decreased FC and BG tropomyosin receptor kinase B (TrkB) phosphorylation, and increased full-length TrkB (TrkB-FL) and SLC1A3 expression in FC and BG, respectively. ART suppressed plasma and brain VL, reduced neuroinflammatory gene expression in FC (IBA1, CX3CR1, and GFAP), and BG (CD74 and CD11ß), and did not restore FC or BG BDNF signaling deficits. CONCLUSIONS: Results show ART-mediated reduction in VL and neuroinflammatory gene expression, irrespective of CBA administration. ART did not attenuate SIV- and CBA-mediated BDNF signaling deficits, suggesting these deficits, despite effective neuroinflammation suppression, may explain CBA- and SIV-associated neurocognitive deficits. Therapeutics targeting growth factor signaling may be important adjuvants in treating HIV-associated neurocognitive decline.
Asunto(s)
Consumo Excesivo de Bebidas Alcohólicas , Infecciones por VIH , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Factor Neurotrófico Derivado del Encéfalo , Etanol , Macaca mulatta , Masculino , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Carga ViralRESUMEN
On November 15, 2019, the 24th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held as a satellite conference during the annual Society for Leukocyte Biology meeting in Boston, Massachusetts. The 2019 meeting focused on alcohol, immunity, and organ damage, and included two plenary sessions. The first session highlighted new research exploring the mechanisms of alcohol-induced inflammation and liver disease, including effects on lipidomics and lipophagy, regulatory T cells, epigenetics, epithelial cells, and age-related changes in the gut. The second session covered alcohol-induced injury of other organs, encompassing diverse areas of research ranging from neurodegeneration, to lung barrier function, to colon carcinogenesis, to effects on viral infection. The discussions also highlighted current laboratory and clinical research used to identify biomarkers of alcohol use and disease.
Asunto(s)
Consumo de Bebidas Alcohólicas , Consumo de Bebidas Alcohólicas/efectos adversos , Alcoholismo/diagnóstico , Biomarcadores , Boston , Congresos como Asunto , Etanol/toxicidad , Humanos , InflamaciónRESUMEN
AIMS: Microarray analysis of hippocampal tissue from chronic binge alcohol (CBA)-administered, simian immunodeficiency virus (SIV)-infected male macaques identified altered immune response and neurogenesis as potential mechanisms underlying cognitive deficits in macaques. This study investigated the differential brain region associations between markers of neuroinflammation and growth factor signaling with microtubule-associated protein 2 (MAP2) expression. METHODS: Adult male rhesus macaques were administered CBA (13-14 g EtOH/kg/week, n = 8) or sucrose (SUC, n = 7) beginning 3 months prior to SIV infection and continued until animals reached end-stage disease criteria (3-24 months post infection). Expression of inflammatory cytokines, growth factors, and viral loads were determined in the prefrontal cortex (PFC), caudate (CD), and hippocampus (HP). Brain-derived neurotropic factor (BDNF) expression and phosphorylation of intracellular kinases downstream of BDNF were investigated in the PFC. RESULTS: Our results show reduced MAP2 expression in the PFC of longer-surviving, CBA/SIV macaques. BDNF expression was most closely associated with MAP2 expression in the PFC. In the caudate, significant positive associations were observed between MAP2 and BDNF, time to end-stage and set-point viral load and significant negative associations for CBA. In the hippocampus, positive associations were observed between MAP2 and inflammatory cytokines, and negative associations for brain viral load and CBA. CONCLUSIONS: CBA differentially affects growth factor and inflammatory cytokine expression and viral load across brain regions. In the PFC, suppression of growth factor signaling may be an important neuropathological mechanism, while inflammatory processes may play a more important role in the CD and HP.
Asunto(s)
Consumo Excesivo de Bebidas Alcohólicas/metabolismo , Encéfalo/metabolismo , Mediadores de Inflamación/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/metabolismo , Virus de la Inmunodeficiencia de los Simios , Animales , Consumo Excesivo de Bebidas Alcohólicas/complicaciones , Consumo Excesivo de Bebidas Alcohólicas/patología , Encéfalo/patología , Macaca mulatta , Masculino , Transducción de Señal/fisiología , Síndrome de Inmunodeficiencia Adquirida del Simio/complicaciones , Síndrome de Inmunodeficiencia Adquirida del Simio/patologíaRESUMEN
Despite combination antiretroviral therapies making HIV a chronic rather than terminal condition for many people, the prevalence of HIV-associated neurocognitive disorders (HAND) is increasing. This is especially problematic for children living with HIV. Children diagnosed HAND rarely display the hallmark pathology of HIV encephalitis in adults, namely infected macrophages and multinucleated giant cells in the brain. This finding has also been documented in rhesus macaques infected perinatally with simian immunodeficiency virus (SIV). However, the extent and mechanisms of lack of susceptibility to encephalitis in perinatally HIV-infected children remain unclear. In the current study, we compared brains of macaques infected with pathogenic strains of SIV at different ages to determine neuropathology, correlates of neuroinflammation, and potential underlying mechanisms. Encephalitis was not found in the macaques infected within 24 h of birth despite similar high plasma viral load and high monocyte turnover. Macaques developed encephalitis only when they were infected after 4 months of age. Lower numbers of CCR5-positive cells in the brain, combined with a less leaky blood-brain barrier, may be responsible for the decreased virus infection in the brain and consequently the absence of encephalitis in newborn macaques infected with SIV.
Asunto(s)
Barrera Hematoencefálica/inmunología , Tronco Encefálico/inmunología , Resistencia a la Enfermedad , Encefalitis Viral/inmunología , Lóbulo Frontal/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Factores de Edad , Animales , Animales Recién Nacidos , Barrera Hematoencefálica/patología , Barrera Hematoencefálica/virología , Tronco Encefálico/patología , Tronco Encefálico/virología , Permeabilidad Capilar/inmunología , Encefalitis Viral/genética , Encefalitis Viral/patología , Encefalitis Viral/virología , Lóbulo Frontal/patología , Lóbulo Frontal/virología , Expresión Génica , Macaca mulatta/virología , Macrófagos/inmunología , Macrófagos/patología , Macrófagos/virología , Monocitos/inmunología , Monocitos/patología , Monocitos/virología , ARN Viral/genética , ARN Viral/metabolismo , Receptores CCR5/genética , Receptores CCR5/inmunología , Receptores Virales/genética , Receptores Virales/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/fisiología , Carga ViralRESUMEN
Alcohol use in persons living with HIV (PLWH) worsens the severity of bacterial pneumonia. However, the exact mechanism(s) by which this occurs remain ill-defined. We hypothesized that alcohol in the setting of HIV infection decreases Streptococcus pneumoniae clearance from the lung through mechanisms mediated by the gut microbiota. Humanized BLT (bone marrow, liver, thymus) mice were infected with 1 × 104 TCID50 of HIV (BAL and JRCSF strains) via intraperitoneal (i.p.) injection. One week post-HIV infection, animals were switched to a Lieber-DeCarli 5% ethanol diet or an isocaloric control diet for 10 days. Alcohol-fed animals were also given two binges of 2 g/kg ethanol on days 5 and 10. Feces were also collected, banked, and the community structures were analyzed. Mice were then infected with 1 × 105 CFU (colony-forming units) of S. pneumoniae and were sacrificed 48 h later. HIV-infected mice had viral loads of â¼2 × 104 copies/mL of blood 1 week post-infection, and exhibited an â¼57% decrease in the number of circulating CD4+ T cells at the time of sacrifice. Fecal microbial community structure was significantly different in each of the feeding groups, as well as with HIV infection. Alcohol-fed mice had a significantly higher burden of S. pneumoniae 48 h post-infection, regardless of HIV status. In follow-up experiments, female C57BL/6 mice were treated with a cocktail of antibiotics daily for 2 weeks and recolonized by gavage with intestinal microbiota from HIV+ ethanol-fed, HIV+ pair-fed, HIV- ethanol-fed, or HIV- pair-fed mice. Recolonized mice were then infected with S. pneumoniae and were sacrificed 48 h later. The intestinal microbiota from alcohol-fed mice (regardless of HIV status) significantly impaired clearance of S. pneumoniae. Collectively, these data indicate that alcohol feeding, as well as alcohol-associated intestinal dysbiosis, compromise pulmonary host defenses against pneumococcal pneumonia. Determining whether HIV infection acts synergistically with alcohol use in impairing pulmonary host defenses will require additional study.
Asunto(s)
Susceptibilidad a Enfermedades/inducido químicamente , Disbiosis/microbiología , Etanol/efectos adversos , Microbioma Gastrointestinal/efectos de los fármacos , Infecciones por VIH/complicaciones , Neumonía Neumocócica/etiología , Animales , Trasplante de Médula Ósea , Recuento de Linfocito CD4 , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/microbiología , Susceptibilidad a Enfermedades/virología , Disbiosis/virología , Femenino , Microbioma Gastrointestinal/genética , Trasplante de Células Madre Hematopoyéticas , Humanos , Trasplante de Hígado , Ratones , ARN Ribosómico 16S/genética , Timo/trasplante , Trasplante Heterólogo , Carga Viral/efectos de los fármacosRESUMEN
SHORT SUMMARY: : Effective combined antiretroviral therapy regimens have extended survival of persons living with HIV (PLWH). Heavy alcohol consumption is common in PLWH. This overview integrates evidence from clinical and preclinical research to identify salient alcohol-related mechanisms and comorbidities contributing to disease pathogenesis and accelerated aging and senescence in PLWH.
Asunto(s)
Envejecimiento/efectos de los fármacos , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , Infecciones por VIH/epidemiología , Infecciones por VIH/psicología , Comorbilidad , Infecciones por VIH/patología , HumanosRESUMEN
Despite optimization of preventative measures for vertical HIV-1 transmission, daily, roughly 400 infants become HIV infected, most of them through breastfeeding. Viral entry has been presumed to occur in the gastrointestinal tract; however, the exact entry site(s) have not been defined. Therefore, we quantified simian immunodeficiency virus (SIV) RNA and DNA in oral, intestinal, and systemic tissues of 15 infant macaques within 48-96 h after oral SIVmac251 exposure. SIV DNA was detected as early as 48 h, whereas SIV RNA was typically detected at later time points (72-96 h). Transmitted founder viruses were identical or very similar to a single genotype in the SIVmac251 challenge stock. SIV RNA and DNA were most frequently found in lymph nodes (LNs) draining the oral cavity and in the ileum. Using in situ hybridization, SIV-infected cells in LNs were exclusively represented by CD3+ T cells. SIV RNA and DNA were also detected in the lungs of 20% of the animals, and 60% of the animals had detectable SIV DNA in the cerebrum. The early detection of viral RNA or DNA in lung and brain tissues emphasizes the need for early treatment of pediatric HIV infection to prevent damage not only to the immune system but also to the respiratory tract and central nervous system.
Asunto(s)
Encéfalo/virología , Tracto Gastrointestinal/virología , Pulmón/virología , Mucosa Bucal/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/transmisión , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Replicación Viral/fisiología , Animales , Animales Recién Nacidos , Encéfalo/patología , Modelos Animales de Enfermedad , Tracto Gastrointestinal/patología , Transmisión Vertical de Enfermedad Infecciosa , Pulmón/patología , Macaca mulatta , Mucosa Bucal/patología , ARN Viral , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Carga ViralRESUMEN
Persistent HIV reservoirs and the absolute quantification of viral RNA copies in tissues have become a prominent focus of multiple areas ofHIV/SIV research. Absolute quantification of viral RNA via reverse transcription, quantitative PCR (RT-qPCR) necessitates the use of an appropriate RNA reference gene whose expression is unaffected by both experimental and confounding conditions. In this study, we demonstrate the utility of ribosomal protein S13 mRNA (RPS13) as a stable, medium abundance reference gene for RT-qPCR normalization of HIV/SIV RNA copy number. We developed a RPS13 RNA standard assay utilizing an in vitro RNA transcript for normalization of absolute SIV RNA quantities in tissues reservoirs. The RT-qPCR assay showed a high degree of repeatability and reproducibility across RNA levels appropriate for absolute SIV quantification. In assessing the utility of RPS13 as a reference gene, limited variation in the absolute, inter-tissue quantities of RPS13 mRNA was observed within multiple tissue samples obtained from rhesus macaques (average CV=2.86%). We demonstrate rhesus macaque RPS13 mRNA expression is not affected by alcohol administration, SIV infection, or antiviral therapy (PMPA/FTC). Additionally, assay functionality was validated for normalization of SIV copy number using cellular RNA prepared from samples of variable RNA integrity. RPS13 is a suitable reference gene for normalization of absolute SIV RNA quantities in tissues and is most appropriate for intra-tissue or similar tissue type comparisons of SIV copy number.
Asunto(s)
Macaca mulatta , Reacción en Cadena en Tiempo Real de la Polimerasa/normas , Estándares de Referencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/normas , Proteínas Ribosómicas/genética , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Carga Viral/normas , Animales , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Virus de la Inmunodeficiencia de los Simios/genética , Carga Viral/métodosRESUMEN
UNLABELLED: Despite significant progress in reducing peripartum mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) with antiretroviral therapy (ART), continued access to ART throughout the breastfeeding period is still a limiting factor, and breast milk exposure to HIV accounts for up to 44% of MTCT. As abstinence from breastfeeding is not recommended, alternative means are needed to prevent MTCT of HIV. We have previously shown that oral vaccination at birth with live attenuated Mycobacterium tuberculosis strains expressing simian immunodeficiency virus (SIV) genes safely induces persistent SIV-specific cellular and humoral immune responses both systemically and at the oral and intestinal mucosa. Here, we tested the ability of oral M. tuberculosis vaccine strains expressing SIV Env and Gag proteins, followed by systemic heterologous (MVA-SIV Env/Gag/Pol) boosting, to protect neonatal macaques against oral SIV challenge. While vaccination did not protect infant macaques against oral SIV acquisition, a subset of immunized animals had significantly lower peak viremia which inversely correlated with prechallenge SIV Env-specific salivary and intestinal IgA responses and higher-avidity SIV Env-specific IgG in plasma. These controller animals also maintained CD4(+) T cell populations better and showed reduced tissue pathology compared to noncontroller animals. We show that infants vaccinated at birth can develop vaccine-induced SIV-specific IgA and IgG antibodies and cellular immune responses within weeks of life. Our data further suggest that affinity maturation of vaccine-induced plasma antibodies and induction of mucosal IgA responses at potential SIV entry sites are associated with better control of viral replication, thereby likely reducing SIV morbidity. IMPORTANCE: Despite significant progress in reducing peripartum MTCT of HIV with ART, continued access to ART throughout the breastfeeding period is still a limiting factor. Breast milk exposure to HIV accounts for up to 44% of MTCT. Alternative measures, in addition to ART, are needed to achieve the goal of an AIDS-free generation. Pediatric HIV vaccines constitute a core component of such efforts. The results of our pediatric vaccine study highlight the potential importance of vaccine-elicited mucosal Env-specific IgA responses in combination with high-avidity systemic Env-specific IgG in protection against oral SIV transmission and control of viral replication in infant macaques. The induction of potent mucosal IgA antibodies by our vaccine is remarkable considering the age-dependent development of mucosal IgA responses postbirth. A deeper understanding of postnatal immune development may inform the design of improved vaccine strategies to enhance systemic and mucosal SIV/HIV antibody responses.
Asunto(s)
Anticuerpos Antivirales/análisis , Anticuerpos Antivirales/sangre , Formación de Anticuerpos , Inmunidad Mucosa , Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Viremia/prevención & control , Administración Oral , Animales , Animales Recién Nacidos , Portadores de Fármacos/administración & dosificación , Inmunoglobulina A/análisis , Inmunoglobulina G/sangre , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Macaca mulatta , Mycobacterium tuberculosis/genética , Vacunas contra el SIDAS/administración & dosificación , Vacunas contra el SIDAS/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunologíaRESUMEN
Chlamydia trachomatis causes a predominantly asymptomatic, but generally inflammatory, genital infection that is associated with an increased risk for HIV acquisition. Endocervical epithelial cells provide the major niche for this obligate intracellular bacterium in women, and the endocervix is also a tissue in which HIV transmission can occur. The mechanism by which CT infection enhances HIV susceptibility at this site, however, is not well understood. Utilizing the A2EN immortalized endocervical epithelial cell line grown on cell culture inserts, we evaluated the direct role that CT-infected epithelial cells play in facilitating HIV transmission events. We determined that CT infection significantly enhanced the apical-to-basolateral migration of cell-associated, but not cell-free, HIVBaL, a CCR5-tropic strain of virus, across the endocervical epithelial barrier. We also established that basolateral supernatants from CT-infected A2EN cells significantly enhanced HIV replication in peripheral mononuclear cells and a CCR5+ T cell line. These results suggest that CT infection of endocervical epithelial cells could facilitate both HIV crossing the mucosal barrier and subsequent infection or replication in underlying target cells. Our studies provide a mechanism by which this common STI could potentially promote the establishment of founder virus populations and the maintenance of local HIV reservoirs in the endocervix. Development of an HIV/STI co-infection model also provides a tool to further explore the role of other sexually transmitted infections in enhancing HIV acquisition.
Asunto(s)
Chlamydia trachomatis/fisiología , Células Epiteliales/microbiología , Células Epiteliales/virología , VIH/fisiología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/microbiología , Linfocitos T CD4-Positivos/virología , Línea Celular , Células Cultivadas , Cuello del Útero/citología , Coinfección/microbiología , Coinfección/virología , Medios de Cultivo Condicionados/farmacología , Femenino , Interacciones Huésped-Patógeno , Humanos , Leucocitos Mononucleares/microbiología , Leucocitos Mononucleares/virología , Interacciones Microbianas , Modelos Biológicos , Receptores CCR5/metabolismo , Replicación Viral/efectos de los fármacos , Replicación Viral/fisiologíaRESUMEN
HIV disease and alcohol independently influence the human immune system, so it stands to reason that, together, their influence may be additive. Here, we review the evidence that alcohol can exacerbate HIV's influence on the immune system, thereby affecting disease progression and transmission. We focus particularly on alcohol's effect on the mucosal immune system in the tissues of the gastrointestinal tract, the genital tract and the lungs, all of which play a role in transmission and progression of HIV disease.
Asunto(s)
Consumo de Bebidas Alcohólicas/inmunología , Alcoholismo/inmunología , Tracto Gastrointestinal/inmunología , Infecciones por VIH/inmunología , Inmunidad Mucosa/inmunología , Alcoholismo/complicaciones , Progresión de la Enfermedad , Infecciones por VIH/complicaciones , Infecciones por VIH/transmisión , HumanosRESUMEN
PROBLEM: HIV infection among women is frequently modeled in female rhesus macaques. Longitudinal studies on genital compartment and hormonal factors that can influence susceptibility to SIV infection are lacking in this animal model. METHOD OF STUDY: Genital specimens and menstruation of indoor-housed female rhesus macaques were analyzed prior to and after SIV infection. RESULTS: Median menstrual cycle length averaged 27 days, although highly variable cycle lengths and frequent periods of amenorrhea were observed during summer months. The vaginal microbiota, characterized by adapted Nugent scoring, showed predominance of small Gram-variable rods and Gram-positive cocci. Highly variable vaginal cytokine levels were observed pre- and post-SIV infection. Vaginal viral loads correlated with plasma viral loads, but were not associated with progesterone levels. CONCLUSION: These results provide an integrated characterization of important factors in the vaginal microenvironment that are relevant to the experimental design of HIV prevention and transmission studies in female rhesus macaques.
Asunto(s)
Genitales Femeninos/metabolismo , Infecciones por VIH/inmunología , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/fisiología , Animales , Microambiente Celular , Citocinas/sangre , Modelos Animales de Enfermedad , Femenino , Genitales Femeninos/microbiología , Genitales Femeninos/virología , Humanos , Ciclo Menstrual , Microbiota , Progesterona/sangre , Carga ViralRESUMEN
HIV-associated mortality has been significantly reduced with antiretroviral therapy (ART), and HIV infection has become a chronic disease that frequently coexists with many disorders, including substance abuse (Azar et al. Drug Alcohol Depend 112:178-193, 2010; Phillips et al. J Gen Int Med 16:165, 2001). Alcohol and drugs of abuse may modify host-pathogen interactions at various levels including behavioral, metabolic, and immune consequences of HIV infection, as well as the ability of the virus to integrate into the genome and replicate in host cells. Identifying mechanisms responsible for these interactions is complicated by many factors, such as the tissue specific responses to viral infection, multiple cellular mechanisms involved in inflammatory responses, neuroendocrine and localized responses to infection, and kinetics of viral replication. An integrated physiological analysis of the biomedical consequences of chronic alcohol and drug use or abuse on disease progression is possible using rhesus macaques infected with simian immunodeficiency virus (SIV), a relevant model of HIV infection. This review will provide an overview of the data gathered using this model to show that chronic administration of two of the most commonly abused substances, alcohol and cannabinoids (Δ(9)-Tetrahydrocannabinol; THC), affect host-pathogen interactions.
Asunto(s)
Cannabinoides/administración & dosificación , Progresión de la Enfermedad , Etanol/administración & dosificación , Infecciones por VIH/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Animales , Cannabinoides/toxicidad , Etanol/toxicidad , Infecciones por VIH/etiología , Humanos , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio/etiología , Virus de la Inmunodeficiencia de los SimiosRESUMEN
BACKGROUND: Alcohol use disorders (AUDs) are a frequent comorbidity in a large percentage of people living with HIV/AIDS (PLWHA). PLWHA with comorbid AUDs are consistently found to perform poorly at most levels of the HIV treatment cascade, resulting in a higher likelihood of virologic nonsuppression. This has been partly attributed to lower rates of persistence with and adherence to antiretroviral therapies (ART). Focus groups of in-care PLWHA identify the need to suspend ART on drinking days because of the potential for toxicity and/or lack of therapeutic effectiveness. The aim of this study was to examine whether chronic binge alcohol (CBA) consumption decreases the effectiveness of uninterrupted ART, specifically that of nucleoside reverse-transcriptase inhibitors (NRTI) tenofovir and emtricitabine in suppressing viral replication, or results in drug toxicity in simian immunodeficiency virus (SIV)-infected rhesus macaques. METHODS: Daily CBA or isocaloric sucrose (SUC) administration was initiated 3 months prior to intrarectal SIVmac251 inoculation and continued throughout the study period. ART was initiated 2.5 months after SIV infection and continued through the study period. RESULTS: CBA administration did not prevent or delay the ART-mediated reduction in viral load. Following ART, circulating levels of total protein and creatinine were significantly higher than baseline values in both SUC- and CBA-treated animals, but still within a normal range. No evidence of ART toxicity was observed in either CBA- or SUC-administered macaques. CONCLUSIONS: These findings indicate that CBA does not attenuate effectiveness of NRTI suppression of viral load, nor does it appear to interact with NRTI to produce toxicity during the initial 2 months of treatment. We conclude that while efforts to reduce AUD in PLWHA should be a priority, counseling on the importance of adherence to ART even on drinking days should also be promoted.
Asunto(s)
Antirretrovirales/uso terapéutico , Consumo Excesivo de Bebidas Alcohólicas/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Carga Viral/inmunología , Animales , Antirretrovirales/farmacología , Consumo Excesivo de Bebidas Alcohólicas/complicaciones , Enfermedad Crónica , Macaca mulatta , Masculino , Síndrome de Inmunodeficiencia Adquirida del Simio/complicaciones , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Carga Viral/efectos de los fármacosRESUMEN
Persons living with HIV/AIDS (PLWHA) frequently use cannabinoids, either recreationally by smoking marijuana or therapeutically (delta-9-tetrahydrocannabinol; Δ(9)-THC dronabinol). Previously, we demonstrated that chronic Δ(9)-THC administration decreases early mortality in male simian immunodeficiency virus (SIV)-infected macaques. In this study, we sought to examine whether similar protective effects resulted from chronic cannabinoid administration in SIV-infected female rhesus macaques. Clinical and viral parameters were evaluated in eight female rhesus macaques that received either Δ(9)-THC (0.18-0.32 mg/kg, intramuscularly, twice daily) or vehicle (VEH) starting 28 days prior to intravenous inoculation with SIVmac251. SIV disease progression was assessed by changes in body weight, mortality, viral levels in plasma and mucosal sites, and lymphocyte subsets. In contrast to our results in male animals, chronic Δ(9)-THC did not protect SIV-infected female rhesus macaques from early mortality. Markers of SIV disease, including viral load and CD4(+)/CD8(+) ratio, were not altered by Δ(9)-THC compared to control females; however, females that received chronic Δ(9)-THC did not gain as much weight as control animals. In addition, Δ(9)-THC administration increased total CXCR4 expression in both peripheral and duodenal CD4(+) and CD8(+) T lymphocytes prior to SIV inoculation. Although protection from early mortality was not evident, chronic Δ(9)-THC did not affect clinical markers of SIV disease progression. The contrasting effects of chronic Δ(9)-THC in males versus females remain to be explained, but highlight the need for further studies to explore the sex-dependent effects of Δ(9)-THC and other cannabinoids on the HIV disease course and their implications for virus transmission.