[Show abstract][Hide abstract] ABSTRACT: Activation of the kynurenine pathway (KP) of tryptophan catabolism likely contributes to HIV-associated neurological disorders. However, KP activation in brain tissue during HIV infection has been understudied, and the effect of combination antiretroviral therapy (cART) on KP induction in the brain is unknown. To examine these questions, tryptophan, kynurenine, 3-hydroxykynurenine, quinolinic acid, and serotonin levels were measured longitudinally during SIV infection in the striatum and CSF from untreated and cART-treated pigtailed macaques. Messenger RNA (mRNA) levels of KP enzymes also were measured in the striatum. In untreated macaques, elevations in KP metabolites coincided with transcriptional induction of upstream enzymes in the KP. Striatal KP induction was also temporally associated-but did not directly correlate-with serotonin losses in the brain. CSF quinolinic acid/tryptophan ratios were found to be the earliest predictor of neurological disease in untreated SIV-infected macaques, outperforming other KP metabolites as well as the putative biomarkers interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1). Finally, cART did not restore KP metabolites to control levels in the striatum despite the control of the virus, though CSF metabolite levels were normalized in most animals. Overall, these results demonstrate that cerebral KP activation is only partially resolved with cART and that CSF QUIN/TRP ratios are an early, predictive biomarker of CNS disease.
Journal of NeuroVirology 03/2015; 21(4). DOI:10.1007/s13365-015-0334-2 · 2.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Immune pressure exerted by MHC class I-restricted cytotoxic T cells drives the development of viral escape mutations, thereby regulating HIV disease progression. Nonetheless, the relationship between host immunity and HIV central nervous system (CNS) disease remains poorly understood. The simian immunodeficiency virus (SIV) macaque model recapitulates key features of HIV infection including development of AIDS and CNS disease. To investigate cell-mediated immunity regulating SIV CNS disease progression, we compared the incidence of SIV encephalitis and the influence of MHC class I allele expression on the development of CNS disease in rhesus macaques (Macaca mulatta) versus pigtailed macaques (Macaca nemestrina). After inoculation with the immunosuppressive swarm SIV/DeltaB670 and the neurovirulent molecular clone SIV/17E-Fr, pigtailed macaques progressed more rapidly to AIDS, had higher plasma and cerebrospinal fluid (CSF) viral loads, and were more likely to progress to SIV-associated encephalitis (SIVE) compared to rhesus macaques. In addition, MHC class I alleles were neuroprotective in both species (Mamu-A*001 in rhesus macaques and Mane-A1*084:01:01 in pigtailed macaques); animals expressing these alleles were less likely to develop SIV encephalitis and correspondingly had lower viral replication in the brain. Species-specific differences in susceptibility to SIV disease demonstrated that cell mediated immune responses are critical to SIV CNS disease progression.
Journal of NeuroVirology 02/2015; 21(2). DOI:10.1007/s13365-015-0313-7 · 2.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
This study examines factors related to general health and health behavior, including smoking, that may be associated with binge drinking, drinking "at risk," and potential for alcohol use disorder among young adults of Mexican ancestry.
A total of 2191 young adult emergency department (ED) patients (18-30 years) of Mexican ancestry in a public hospital proximate to the US-Mexico border completed health surveys while they were waiting to be treated, including questions on general health, drinking, smoking, and drug use.
Thirty-seven percent of the study participants reported binge drinking, 38% were "at-risk" alcohol users (above National Institute on Alcohol Abuse and Alcoholism guidelines), and 22% were Rapid Alcohol Problem Screen (RAPS) positive (indicating potential for alcohol use disorder). Smoking was reported by 31%, marijuana use by 16%, and other drug use by 9%. Multiple variable models revealed that smoking was the strongest factor associated with binge drinking. Those who smoked were 3.1 (P < .0001) times more likely to binge drink. Other factors independently associated with binge drinking were age 22-25 years (odds ratio [OR] = 1.5, P = .003), male gender (OR = 1.5, P = .0001), and ED visit for injury (OR = 1.4, P = .007).
There is a strong association of smoking and binge drinking. Study findings suggest that brief interventions designed to reduce preventable health risks for young Hispanics should include discussion of both binge drinking and smoking behaviors.
[Show abstract][Hide abstract] ABSTRACT: Objectives
As the U.S. economy began its downward trend in 2008, many citizens lost their jobs and, ultimately, their employer-sponsored health care insurance. The expectation was that many of the newly uninsured would turn to emergency departments (EDs) for their health care. This study was undertaken to determine, first, if changes in the insurance status of the general population were reflected in the ED insurance payer mix and, second, whether there was evidence of an increased reliance on the ED as a continuing source of health care for any payer group(s).Methods
This was a retrospective observational study using public data files from the National Hospital Ambulatory Medical Care Survey for Emergency Departments for years 2006 through 2010 (2008 ± 2 years). Changes in the relative proportions of ED visits funded annually by private insurance, Medicaid, Medicare, and self-pay (uninsured) were analyzed using a logistic model. Poisson regression was used to compare trends in the rates of ED visits for each payer type (i.e., number of ED visits per 100 persons with each insurance type). A linear spline term was used to determine if there was a change in each risk estimate after 2008 compared to the risk estimate before 2008.ResultsBefore 2008, the odds of an ED visit being funded by private insurance increased by 4% per year (odds ratio [OR] = 1.04, 95% confidence interval [CI] = 0.98 to 1.10; p = 0.15), but after 2008 the odds reversed, decreasing by nearly 10% per year (OR = 0.91, 95% CI = 0.85 to 0.97; p = 0.02). Medicaid-funded visits demonstrated opposite trends with a small decreasing trend of 2% per year before 2008 (OR = 0.98, 95% CI = 0.92 to 1.04; p = 0.52), followed by a significantly increasing trend of 20% per year after 2008 (OR = 1.20, 95% CI = 1.12 to 1.27; p = 0.001). The growth in Medicaid-funded ED visits was attributable to increased numbers of visits by both pediatric (<18 years old) and non-elderly adult (19 to 64 years old) patients. For both Medicaid and private insurance visits, the change in trend in 2008 was statistically significant (p < 0.001 and p = 0.004, respectively). Self-pay visits were fairly steady before 2008 and then increased by about 5% per year after 2008, but this was not statistically significant (OR = 1.05, 95% CI = 0.96 to 1.14; p = 0.46), nor was the change in trend (p = 0.29). The results for Medicare-funded visits were also small and not statistically significant. There was also evidence of increased reliance on the ED by Medicaid-funded patients based on the comparison of ED visit rates. After 2008, the incidence rate ratio (IRR) for Medicaid-funded visits increased by 10% per year (IRR = 1.10, 95% CI = 1.10 to 1.10; p < 0.001) while the IRR for the other three payer groups changed about 1% per year (IRR = 0.99, 95% CI = 0.99 to 0.099; p < 0.001), indicating an increasing utilization of the ED by patients with Medicaid-funded care.Conclusions
After 2008, Medicaid patients were more dependent on ED services than uninsured, Medicare, or privately insured patients. Medicaid patients made up an increasing proportion of ED patients, and the rate of usage of ED services by all ages of Medicaid patients was significantly greater than that of the other three payer groups.
Academic Emergency Medicine 12/2014; 22(1). DOI:10.1111/acem.12553 · 2.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Effective combined antiretroviral therapy (cART) in HIV-infected patients has made HIV a treatable infection; however, debilitating HIV-associated neurocognitive disorders (HAND) can still affect approximately 50 % of HIV-infected individuals even under cART. While cART has greatly reduced the prevalence of the most severe form of HAND, milder forms have increased in prevalence, leaving the total proportion of HIV-infected individuals suffering from HAND relatively unchanged. In this study, an in vitro drug screen identified fluconazole and paroxetine as protective compounds against HIV gp120 and Tat neurotoxicity. Using an accelerated, consistent SIV/macaque model of HIV-associated CNS disease, we tested the in vivo neuroprotective capabilities of combination fluconazole/paroxetine (FluPar) treatment. FluPar treatment protected macaques from SIV-induced neurodegeneration, as measured by neurofilament light chain in the CSF, APP accumulation in axons, and CaMKIIα in the frontal cortex, but did not significantly reduce markers of neuroinflammation or plasma or CNS viral loads. Since HIV and SIV neurodegeneration is often attributed to accompanying neuroinflammation, this study provides proof of concept that neuroprotection can be achieved even in the face of ongoing neuroinflammation and viral replication.
Journal of NeuroVirology 09/2014; 20(6). DOI:10.1007/s13365-014-0283-1 · 2.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diastolic dysfunction is a highly prevalent cardiac abnormality in asymptomatic as well as ART-treated human immunodeficiency virus (HIV) patients. Although the mechanisms underlying depressed cardiac function remain obscure, diastolic dysfunction in SIV-infected rhesus macaques is highly correlated with myocardial viral load. As cardiomyocytes are not productively infected, damage may be an indirect process attributable to a combination of pro-inflammatory mediators and viral proteins.
Given the diverse roles of CCR5 in mediating recruitment of leukocytes to inflammatory sites and serving as a receptor for HIV entry into cells, we investigated the role of CCR5 in the SIV/macaque model of diastolic dysfunction. We found that in SIV-infected macaques, CCR5 inhibition dramatically impacted myocardial viral load measured by qRT-PCR and prevented diastolic dysfunction measured by echocardiography. Complementary in vitro experiments using fluorescence microscopy showed that CCR5 ligands impaired contractile function of isolated cardiomyocytes, thus identifying CCR5 signaling as a novel mediator of impaired cardiac mechanical function.
Together, these findings incriminate SIV/HIV gp120-CCR5 as well as chemokine-CCR5 interactions in HIV-associated cardiac dysfunction. These findings also have important implications for the treatment of HIV-infected individuals: in addition to antiviral properties and reduced chemokine-mediated recruitment and activation of inflammatory cells, CCR5 inhibition may provide a cardioprotective benefit by preventing cardiomyocyte CCR5 signaling.
Journal of the American Heart Association 04/2014; 3(2):e000874. DOI:10.1161/JAHA.114.000874 · 4.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The American College of Cardiology/American Society of Nuclear Cardiology published revised appropriate use criteria (AUC) for SPECT MPI in 2009. We assessed adherence to these guidelines and factors associated with inappropriate utilization at the University Medical Center.
The AUC was applied retrospectively to 420 SPECT MPI studies. Two-sample t test, Fisher's exact test, and multivariable logistic regression models were used for analysis.
There were 322 appropriate (86%) and 54 (14%) inappropriate studies. The odds of having an inappropriate test increased with younger age (P < .001) and female gender (P < .001). Subjects with diabetes (P = .007) and chest pain (P < .001) were less likely to have an inappropriate test. Academic outpatients were three times more likely to have an inappropriate study (P = .123), while community PCPs were 5.6 times (P = .011) and community cardiologists eight times more likely to order inappropriate tests (P = .031).
Inappropriate SPECT MPI in low risk younger women is an important issue on the USA-Mexico border. Initiatives to reduce inappropriate SPECT MPI should focus on a few indications and evaluation of cardiovascular symptoms in younger age women in outpatient/community practices.
[Show abstract][Hide abstract] ABSTRACT: HIV-associated neurocognitive deficits remain a challenge despite suppressive combined anti-retroviral therapy. Given the association between HIV-induced CNS disease and replication of HIV in immune-activated macrophages, CCR5 antagonists may attenuate CNS disease by modulating inflammatory signaling and by limiting viral replication.
To establish whether initiating CCR5 inhibition during early infection altered CNS disease progression, outcomes were compared between SIV-infected macaques treated with maraviroc versus untreated SIV-infected macaques.
Six SIV-infected rhesus macaques were treated with maraviroc monotherapy for 5 months beginning 24 days post-inoculation; 22 SIV-infected animals served as untreated controls. SIV RNA levels in plasma, CSF, and brain, and CNS expression of TNFα and CCL2 were measured by qRT-PCR. Immunostaining for CD68 and amyloid precursor protein in the brain was measured by image analysis. Plasma sCD163 was measured by ELISA.
SIV RNA and proviral DNA levels in brain were markedly lower with maraviroc-treatment, demonstrating CCR5 inhibition reduces CNS replication of SIV and may reduce the CNS latent viral reservoir. Maraviroc-treatment also lowered monocyte and macrophage activation, represented by CNS CD68 immunostaining and plasma sCD163 levels, and reduced both TNFα and CCL2 RNA expression in brain. Treatment also reduced axonal amyloid precursor protein immunostaining to levels present in uninfected animals, consistent with neuroprotection.
CCR5 inhibitors may prevent neurologic disorders in HIV-infected individuals by reducing inflammation and by limiting viral replication in the brain. Furthermore, CCR5 inhibitors may reduce the latent viral reservoir in the CNS. Adding CCR5 inhibitors to combined anti-retroviral regimens may offer multiple neuroprotective benefits.
AIDS (London, England) 09/2013; 27(18). DOI:10.1097/QAD.0000000000000074 · 5.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Host cell microRNAs (miRNAs) have been shown to regulate the expression of both cellular and viral RNAs, in particular impacting both Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV). To investigate the role of miRNAs in regulating replication of the simian immunodeficiency virus (SIV) in macrophage lineage cells, we used primary macrophages to study targeting of SIV RNA by miRNAs. We examined whether specific host miRNAs directly target SIV RNA early in infection and might be induced via type I interferon pathways.
miRNA target prediction programs identified miRNA binding sites within SIV RNA. Predicted binding sites for miRs-29a, -29b, -9 and -146a were identified in the SIV Nef/U3 and R regions, and all four miRNAs decreased virus production and viral RNA expression in primary macrophages. To determine whether levels of these miRNAs were affected by SIV infection, IFNbeta or TNFalpha treatments, miRNA RT-qPCR assays measured miRNA levels after infection or treatment of macrophages. SIV RNA levels as well as virus production was downregulated by direct targeting of the SIV Nef/U3 and R regions by four miRNAs. miRs-29a, -29b, -9 and -146a were induced in primary macrophages after SIV infection. Each of these miRNAs was regulated by innate immune signaling through TNFalpha and/or the type I IFN, IFNbeta.
The effects on miRNAs caused by HIV/SIV infection are illustrated by changes in their cellular expression throughout the course of disease, and in different patient populations. Our data demonstrate that levels of primary transcripts and mature miRs-29a, -29b, -9 and -146a are modulated by SIV infection. We show that the SIV 3[prime] UTR contains functional miRNA response elements (MREs) for all four miRNAs. Notably, these miRNAs regulate virus production and viral RNA levels in macrophages, the primary cells infected in the CNS that drive inflammation leading to HIV-associated neurocognitive disorders. This report may aid in identification miRNAs that target viral RNAs and HIV/SIV specifically, as well as in identification of miRNAs that may be targets of new therapies to treat HIV.
[Show abstract][Hide abstract] ABSTRACT: The main objective of the present study was to assess culturable airborne fungal concentrations, and types in different seasons. Two-stage viable impactor samplers were used with malt extract agar medium as the collection media. Culturable airborne fungal concentrations were collected indoors and outdoors of 43 homes in urban and rural environments from November 2008 to October 2009 in Egypt. Fungal concentrations were significantly higher in the rural environment than the urban environment. The median indoor and outdoor total fungal concentrations were 608 and 675 CFU/m3 in the urban environment and 1,932 and 1,872 CFU/m3 in the rural environment, respectively. The greatest concentrations were found in the autumn and spring season. Indoor and outdoor concentrations were significantly correlated (P < 0.001). The highest concentrations were observed in the fungal size range of <8 µm (fine fraction). The indoor/outdoor (I/O) ratios were not statistically different between seasons. Alternaria, Aspergillus, Cladosporium, Penicillium and yeasts were the predominant genera indoors and outdoors, and the abundance of genera varied by season and region. This study is of a potential interest as little reported research on the indoor fungal air quality from Egypt.
International Journal of Environmental Research and Public Health 03/2013; 10(3):936-949. DOI:10.3390/ijerph10030936 · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Chemokines provide critical immune cell homing and activation signals that if altered could affect the inflammatory milieu and cellular composition of lymphoid tissues. During HIV-1 and simian immunodeficiency virus (SIV)-infection, the virus triggers an increase in inflammation or activation, leading to immunodeficiency and development of opportunistic infections, such as in the lungs-a massive interface between the host and the environment.
Chemokine, cytokine, and chemokine receptor expression profiles were determined using real-time reverse transcriptase-polymerase chain reaction and in situ hybridization in hilar lymph nodes (HiLNs) from cynomolgus macaques at different stages after infection with SIV/DeltaB670. Immunostaining of tissue sections and flow cytometric analysis of cryopreserved cells were used to examine cellular compositions of lymph nodes.
Interferon-gamma, type 1 chemokine, and cognate chemokine receptor mRNAs were upregulated, whereas type 2 and homeostatic chemokine and chemokine receptor mRNAs were down-regulated in HiLNs after SIV infection. Local SIV and interferon-gamma levels were positively correlated with type 1 chemokine levels but negatively correlated with type 2 and homeostatic chemokine levels. Using in situ hybridization, Pneumocystis carinii rRNA was detected in lung-draining lymph nodes from animals with P. carinii pneumonia. Changes in the cellular composition of HiLNs included decreased proportions of CD4 cells and dendritic cells and increased proportions of CD8, CXCR3, and CCR5 cells.
SIV infection of cynomolgus macaques dramatically alters the cellular homing signals of lung-draining lymph nodes, which correlated with changes in the immune cellular composition. These changes could contribute to the loss of immune function that defines AIDS.
[Show abstract][Hide abstract] ABSTRACT: Fusion inhibitors are a class of antiretroviral drugs used to prevent entry of HIV into host cells. Many of the fusion inhibitors being developed, including the drug enfuvirtide, are peptides designed to competitively inhibit the viral fusion protein gp41. With the emergence of drug resistance, there is an increased need for effective and unique alternatives within this class of antivirals. One such alternative is a class of cyclic, cationic, antimicrobial peptides known as θ-defensins, which are produced by many non-human primates and exhibit broad-spectrum antiviral and antibacterial activity. Currently, the θ-defensin analog RC-101 is being developed as a microbicide due to its specific antiviral activity, lack of toxicity to cells and tissues, and safety in animals. Understanding potential RC-101 resistance, and how resistance to other fusion inhibitors affects RC-101 susceptibility, is critical for future development. In previous studies, we identified a mutant, R5-tropic virus that had evolved partial resistance to RC-101 during in vitro selection. Here, we report that a secondary mutation in gp41 was found to restore replicative fitness, membrane fusion, and the rate of viral entry, which were compromised by an initial mutation providing partial RC-101 resistance. Interestingly, we show that RC-101 is effective against two enfuvirtide-resistant mutants, demonstrating the clinical importance of RC-101 as a unique fusion inhibitor. These findings both expand our understanding of HIV drug-resistance to diverse peptide fusion inhibitors and emphasize the significance of compensatory gp41 mutations.
PLoS ONE 02/2013; 8(2):e55478. DOI:10.1371/journal.pone.0055478 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Problem:
Vaginal microbicides represent a promising approach for preventing heterosexual HIV transmission. However, preclinical evaluation should be conducted to ensure that microbicides will be safe for human cells and healthy microflora of the female reproductive tract. One microbicide candidate, RC-101, has been effective and well tolerated in preliminary cell culture and macaque models. However, the effect of RC-101 on primary vaginal tissues and resident vaginal microflora requires further evaluation.
Method of study:
We treated primary vaginal tissues and vaginal bacteria, both pathogenic and commensal, with RC-101 to investigate effects of this microbicide.
RC-101 was well tolerated by host tissues, and also by commensal vaginal bacteria. Simultaneously, pathogenic vaginal bacteria, which are known to increase susceptibility to HIV acquisition, were inhibited by RC-101.
By establishing vaginal microflora, the specific antibacterial activity of RC-101 may provide a dual mechanism of HIV protection. These findings support advancement of RC-101 to clinical trials.
American Journal Of Reproductive Immunology 11/2012; 69(2). DOI:10.1111/aji.12036 · 2.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Non-complaint Egyptian homes were examined to determine the residential culturable airborne bacterial concentrations so that these could be used as comparisons in indoor air quality investigations. Concentrations of airborne bacteria were investigated in 26 urban flats across Cairo and 17 rural flats in the Dakahlia governorate. Air samples were collected using a two-stage viable cascade impactor sampler, dividing particles into coarse (>8 μm) and fine (<8 μm) sizes. For urban flats, the year's median indoor and comparison site concentrations were 9133 CFU/m(3) and 9423 CFU/m(3), respectively. For rural flats, the year's median indoor and comparison site concentrations were 15,915 CFU/m(3) and 10,859 CFU/m(3), respectively. The median indoor bacterial concentrations increased in winter and spring compared to autumn and summer. Winter months had the greatest median concentration for coarse indoor organisms, whereas spring had the largest for the fine indoor organisms. Fine bacterial concentration composed more than 60% of the indoor bacterial fraction.
International Journal of Environmental Health Research 10/2012; 23(4). DOI:10.1080/09603123.2012.733932 · 1.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To establish the relationship between HIV-induced cardiac diastolic dysfunction, immune responses, and virus replication in the heart using the simian immunodeficiency virus (SIV)/macaque model.
Cardiac diastolic dysfunction is common in HIV-infected individuals including asymptomatic patients and those treated with combination antiretroviral therapy. SIV-infected macaques develop cardiac dysfunction, serving as a useful model to establish mechanisms underlying HIV-induced cardiac dysfunction. To understand the relationship between functional cardiac impairment, viral replication in the heart, and associated host inflammatory responses, cardiac function was evaluated in SIV-infected macaques and functional decline was correlated with features of the host immune response and the extent of viral replication in both the myocardium and plasma.
Cardiac function was evaluated longitudinally in 22 SIV-infected and eight uninfected macaques using mitral inflow and tissue Doppler echocardiography. Myocardial macrophage populations were evaluated by CD68 and CD163 immunostaining. SIV RNA levels in both myocardium and plasma were measured by qRT-PCR.
Echocardiographic abnormalities developed in SIV-infected macaques that closely resembled diastolic dysfunction reported in asymptomatic HIV-infected individuals. Although CD68 and CD163 were upregulated in the myocardium of SIV-infected animals, neither macrophage marker correlated with functional decline. SIV-induced diastolic dysfunction was strongly correlated with extent of SIV replication in the myocardium, implicating virus or viral proteins in the initiation and progression of cardiac dysfunction.
This study demonstrated a strong correlation between cardiac functional impairment and extent of SIV replication in the myocardium, suggesting that persistent viral replication in myocardial macrophages induces cardiomyocyte damage manifest as diastolic dysfunction.
AIDS (London, England) 02/2012; 26(7):815-23. DOI:10.1097/QAD.0b013e3283518f01 · 5.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The lower gastrointestinal tract is a major mucosal site of HIV entry and initial infection. Thus, the induction of strong cellular immune responses at this mucosal site will be an important feature of an effective HIV vaccine. We have used a novel prime-boost vaccination approach to induce immune responses at mucosal sites. Orally delivered recombinant Clostridium perfringens expressing HIV-1 gag (Cp-Gag) was evaluated for induction of HIV-1 Gag specific T cell responses in a prime-boost model with intranasal inoculation of HIV-1 virus like particles (VLP). HIV-1 specific cellular immune responses in both the effector (Lamina propria) and inductive sites (Peyer's patches) of the gastrointestinal (GI) tract were significantly higher in mice immunized using Cp-Gag and VLPs in a prime-boost approach compared to mice immunized with either Cp-Gag or VLPs alone. Such cellular immune response was found to be mediated by both CD8(+) and CD4(+) T cells. Such a strong mucosal immune response could be very useful in developing a mucosal vaccine against HIV-1.
Current HIV research 12/2011; 9(8):613-22. DOI:10.2174/157016211798998808 · 1.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: HIV-infected individuals, even with antiretroviral therapy, often display cognitive, behavioral and motor abnormalities and have decreased dopamine (DA) levels. Minocycline prevents encephalitis and neurodegeneration in SIV models, suggesting that it might also protect against nigrostriatal dopaminergic system dysfunction. Using an SIV/macaque model of HIV-associated CNS disease, we demonstrated that striatal levels of DA were significantly lower in macaques late in infection and that levels of the metabolite DOPAC also tended to be lower. DA levels declined more than its metabolites, indicating a dysregulation of DA production or catabolism. Minocycline treatment beginning at 12 but not 21 days postinoculation prevented striatal DA loss. DA decline was not due to direct loss of dopaminergic projections to the basal ganglia as there was no difference in tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter 2 or synaptophysin between minocycline-treated and untreated macaques. SIV-infected macaques had significantly higher monoamine oxidase (MAO) activity than uninfected macaques, although MAO activity was not affected by minocycline. Oxidative/nitrosative stress was examined by nitrotyrosine staining in the deep white matter and was lower in SIV-infected, minocycline-treated macaques compared with untreated macaques. These data suggest that minocycline, which has antioxidant activity, has a protective effect on DA homeostasis when administered at an appropriate time in SIV neuropathogenesis.
[Show abstract][Hide abstract] ABSTRACT: An urgent need exists for HIV-1 microbicides. Here, we describe the in vivo testing of lactic acid bacteria bioengineered to secrete cyanovirin-N. We fed pigtail macaques a yogurt formulation that used bioengineered strains as a starter culture. Cyanovirin-N expression could be detected in the rectal vault during and immediately after feeding. Ex vivo viral challenge of rectal tissue biopsies revealed that peak viral burden was significantly lower in tissue obtained from experimental animals compared with control animals. Formulation of candidate compounds in lactic acid bacteria and their oral administration seems to be a feasible strategy for mucosal delivery of microbicides.
[Show abstract][Hide abstract] ABSTRACT: Peripheral neuropathy is the most common neurological complication of HIV-1 infection, affecting over one-third of infected individuals, including those treated with antiretroviral therapy. To study the pathogenesis of HIV-induced peripheral nervous system disease, we established a model in which SIV-infected macaques developed changes closely resembling alterations reported in components of the sensory pathway in HIV-infected individuals. Significant declines in epidermal nerve fiber density developed in SIV-infected macaques, similar to that of HIV-infected individuals with neuropathy. Changes in dorsal root ganglia (DRG) included macrophage infiltration, SIV replication in macrophages, immune activation of satellite cells, and neuronal loss. To determine whether dorsal root ganglion damage was associated with altered nerve function, we measured unmyelinated C-fiber conduction velocities (CV) in nerves of SIV-infected macaques and compared CV changes with DRG alterations. Twelve weeks postinoculation, SIV-infected macaques had significantly lower C-fiber conduction velocity in sural nerves than uninfected animals and the magnitude of conduction velocity decline correlated strongly with extent of DRG macrophage infiltration. Thus, injury to neurons in the DRG-mediated by activated macrophages-preceded altered conduction of unmyelinated nerve fibers in SIV-infected macaques, suggesting that macrophage-mediated DRG damage may be the initiating event in HIV-induced sensory neuropathy.
American Journal Of Pathology 09/2011; 179(5):2337-45. DOI:10.1016/j.ajpath.2011.07.047 · 4.59 Impact Factor