 |
|
|
| |
VLA-4 (Tysabri) Treatment Blocks Virus Traffic to the Gut and Brain Early, and Stabilizes CNS Injury Late in Infection
|
| |
| |
Reported by Jules Levin
CROI 2013
Tysabri has been used for several years in MS & Crohns disease due to its ability to prevent traffic of leukocytes to the brain & small intestine
Tysabri stabilizes neuronal injury
Tysabri prevents accumulation of SIV infected macrophages into the brain
Tysabri blocks traffic of T lymphocytes and monocyte/macrophage to gut
Tysabri reduces T cell but not monocyte/macrophage traffic to lymph nodes
AUTHOR SUMMARY & CONCLUSIONS
- In 28 PI Tysabri treated animals, suppression of macrophage traffic and viral entry into the brain and small intestine, stabilization of neuronal injury
Continuous traffic of monocyte/macrophage required for neuromal damage
- Cell associated virus undetectable in brain, significantly reduced in small intestine of cohort starting Tysabri on 0 PI
Cell associated virus comes from traffic of cells into tissue during infection
- Tysabri treatment prevented release of LPS into plasma
Initial blockade of traffic to gut may prevent breakdown of mucosal barriers
In combination with ART therapy, Tysabri treatment very early in HIV infection may stop seeding of the brain and gut with virus, thus preventing the establishment of latent resrvoirs
link to webcast
http://webcasts.retroconference.org/console/player/19408?mediaType=podiumVideo
program abstract
VLA-4 Treatment Blocks Virus Traffic to the Gut and Brain Early, and Stabilizes CNS Injury Late in Infection
Jennifer Campbell*1, P Autissier1, A MacLean2, T Burdo1, S Westmoreland3, G Gonzalez4,5, E-M Ratai4,5, and K Williams1
1Boston Coll, Chestnut Hill, MA, US; 2Tulane Natl Primate Res Ctr, Covington, LA, US; 3New England Regional Primate Res Ctr, Southborough, MA, US; 4Harvard Med Sch, Boston, MA, US; and 5Athinoula A Martinos Ctr for Biomed Imaging, Massachusetts Gen Hosp, Boston, US
Background: Whether active monocyte/macrophage traffic in AIDS is required for pathogenesis has not been directly demonstrated. Here we used a functional anti-VLA-4 blocking antibody, natalizumab, and treated SIV-infected monkeys with high viral load and central nervous system (CNS) injury to stop monocyte/macrophage traffic. Moreover, we treated animals at the time of infection to stop traffic of virus to the gut and CNS, but not to lymph nodes.
Methods: 10 rhesus macaques were infected with SIVmac251, CD8+ lymphocyte depleted, and natalizumab (30 mg/kg) was administered once a week for 3 weeks beginning at the time of infection (day 0, n = 6) or day 28 post-infection (n = 4). Upon sacrifice, gut, brain, and lymph node tissues were examined by immunohistochemistry and in situ hybridization for monocyte/macrophage traffic and accumulation, and viral infection. In animals treated 28 days post-infection, metabolite concentrations of n-acetylaspartate (NAA/Cr) for neuronal injury were assessed and analysis of variance with repeated measures (RM-analysis of variance [ANOVA]) was used. If significant by RM-ANOVA (p <0.05), Student-Newman-Keuls tests were used to isolate significant differences between time-points. All other p values were calculated using Students 2-tailed, paired t tests.
Results: With natalizumab treatment 28 days post-infection we found a stabilization of neuronal injury (NAA/Cr) by magnetic resonance spectroscopy (MRS) and no further macrophage traffic by immunohistochemistry. Natalizumab treatment blocked the accumulation of CD68+, MAC387+, BrdU+ monocyte/macrophage into the gut and CNS, but not lymph nodes. In parallel, peripheral blood mononuclear cells (PBMC) from treated macaques exhibited impaired adhesive and transmigratory capabilities ex vivo in response to proinflammatory stimulation. Tissue analysis revealed significantly lower numbers of inflammatory (CD68+), recently recruited macrophages (MAC387+, BrdU+), and virally infected cells (p28+) in the small intestine and brain of day 28 treated macaques when compared to animals that did not receive natalizumab (n = 6). Strikingly there was no cell-associated virus in the small intestine and brain of animals treated at the time of infection.
Conclusions: Our studies using natalizumab in macaques infected 28 days demonstrate conclusively that stopping monocyte traffic stabilizes CNS disease. Studies in animals treated at the time of infection underscore the possibility of natalizumab to stop seeding of the gut and brain with virus early in infection.
|
| |
|
|
|
|
|
