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Southborough, MA, United States

Singh I.,Tufts University | Singh I.,Sanofi S.A. | Carville A.,New England Regional Primate Research Center | Tzipori S.,Tufts University
AIDS Research and Human Retroviruses | Year: 2011

The intestinal immune dysfunction due to loss of mucosal and peripheral CD4 + T cells in individuals with HIV/AIDS is presumably responsible for the establishment of persistent cryptosporidiosis. Simian immunodeficiency virus (SIV)-infected macaques were used to investigate the phase/timing in SIV infection, which permits a self-limiting Cryptosporidium parvum infection to become persistent in immunodeficient hosts because of significant mucosal immune defects. Two groups of SIV-infected macaques were challenged with C. parvum; one was challenged during the acute SIV infection phase (2 weeks post-SIV infection) and the second was challenged during the chronic SIV phase (CD4 counts 200-500 cells/μl of blood). Samples (fecal, blood, biopsy, and necropsy) were collected at different time points after infection to correlate the progression of disease with the immune status of the animals. All seven SIV-infected macaques challenged during the acute phase of SIV infection became persistently infected and excreted oocysts for 1-4 months. However, four of the six in the chronic SIV phase became infected with cryptosporidiosis, of which one survived 2 weeks and one became naturally infected. Sequential analysis of CD4 + in blood and intestines of coinfected macaques exhibited pronounced losses of CD4 T cells during the first 2 weeks after SIV infection, followed by transient rebound of CD4 T cells in the gut after C. parvum infection, and then a gradual loss over subsequent months. Persistent cryptosporidiosis was more consistently induced during the acute SIV phase indicating that profound viral damage to gut lymphoid tissue during the acute phase was more conducive, compared with the chronic phase, to establishing persistent cryptosporidiosis than low circulating CD4 T cells. © Copyright 2011, Mary Ann Liebert, Inc. Source


Campbell J.H.,Boston College | Burdo T.H.,Boston College | Autissier P.,Boston College | Bombardier J.P.,New England Regional Primate Research Center | And 7 more authors.
PLoS ONE | Year: 2011

Background: Minocycline is a tetracycline antibiotic that has been proposed as a potential conjunctive therapy for HIV-1 associated cognitive disorders. Precise mechanism(s) of minocycline's functions are not well defined. Methods: Fourteen rhesus macaques were SIV infected and neuronal metabolites measured by proton magnetic resonance spectroscopy (1H MRS). Seven received minocycline (4 mg/kg) daily starting at day 28 post-infection (pi). Monocyte expansion and activation were assessed by flow cytometry, cell traffic to lymph nodes, CD16 regulation, viral replication, and cytokine production were studied. Results: Minocycline treatment decreased plasma virus and pro-inflammatory CD14+CD16+ and CD14loCD16+ monocytes, and reduced their expression of CD11b, CD163, CD64, CCR2 and HLA-DR. There was reduced recruitment of monocyte/macrophages and productively infected cells in axillary lymph nodes. There was an inverse correlation between brain NAA/Cr (neuronal injury) and circulating CD14+CD16+ and CD14loCD16+ monocytes. Minocycline treatment in vitro reduced SIV replication CD16 expression on activated CD14+CD16+ monocytes, and IL-6 production by monocytes following LPS stimulation. Conclusion: Neuroprotective effects of minocycline are due in part to reduction of activated monocytes, monocyte traffic. Mechanisms for these effects include CD16 regulation, reduced viral replication, and inhibited immune activation. © 2011 Campbell et al. Source


Sampson S.L.,Harvard University | Sampson S.L.,Imperial College London | Mansfield K.G.,New England Regional Primate Research Center | Carville A.,New England Regional Primate Research Center | And 8 more authors.
Vaccine | Year: 2011

We have previously described the development of a live, fully attenuated Mycobacterium tuberculosis (Mtb) vaccine candidate strain with two independent attenuating auxotrophic mutations in leucine and pantothenate biosynthesis. In the present work, those studies have been extended to include testing for protective efficacy in a long-term guinea pig survival model and safety testing in the highly tuberculosis susceptible Rhesus macaque. To model the safety of the ΔleuD ΔpanCD strain in HIVinfected human populations, a Simian immunodeficiency virus (SIV)-infected Rhesus macaque group was included. Immunization with the non-replicating ΔleuD ΔpanCD conferred long-term protection against challenge with virulent M. tuberculosis equivalent to that afforded by BCG as measured by guinea pig survival. In safety studies, clinical, hematological and bacteriological monitoring of both SIV-positive and SIV-negative Rhesus macaques immunized with ΔleuD ΔpanCD, revealed no vaccine-associated adverse effects. The results support the further development of the ΔleuD ΔpanCD strain as a viable tuberculosis (TB) vaccine candidate. © 2011 Elsevier Ltd. All rights reserved. Source


Ratai E.-M.,Massachusetts General Hospital | Ratai E.-M.,Harvard University | Bombardier J.P.,Massachusetts General Hospital | Bombardier J.P.,Brandeis University | And 22 more authors.
PLoS ONE | Year: 2010

Background: Despite the advent of highly active anti-retroviral therapy (HAART), HIV-associated neurocognitive disorders continue to be a significant problem. In efforts to understand and alleviate neurocognitive deficits associated with HIV, we used an accelerated simian immunodeficiency virus (SIV) macaque model of NeuroAIDS to test whether minocycline is neuroprotective against lentiviral-induced neuronal injury. Methodology/Principal Findings: Eleven rhesus macaques were infected with SIV, depleted of CD8+ lymphocytes, and studied until eight weeks post inoculation (wpi). Seven animals received daily minocycline orally beginning at 4 wpi. Neuronal integrity was monitored in vivo by proton magnetic resonance spectroscopy and post-mortem by immunohistochemistry for synaptophysin (SYN), microtubule-associated protein 2 (MAP2), and neuronal counts. Astrogliosis and microglial activation were quantified by measuring glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (IBA-1), respectively. SIV infection followed by CD8+ cell depletion induced a progressive decline in neuronal integrity evidenced by declining N-acetylaspartate/creatine (NAA/Cr), which was arrested with minocycline treatment. The recovery of this ratio was due to increases in NAA, indicating neuronal recovery, and decreases in Cr, likely reflecting downregulation of glial cell activation. SYN, MAP2, and neuronal counts were found to be higher in minocyclinetreated animals compared to untreated animals while GFAP and IBA-1 expression were decreased compared to controls. CSF and plasma viral loads were lower in MN-treated animals. Conclusions/Significance: In conclusion, oral minocycline alleviates neuronal damage induced by the AIDS virus. © 2010 Ratai et al. Source

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