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PROGRESSIVE LYMPH NODE DYSFUNCTION DURING SIV INFECTION IS NOT REVERSED WITH ART
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PROGRESSIVE LYMPH NODE DYSFUNCTION DURING SIV INFECTION IS NOT REVERSED WITH ART
Author(s):
Claire Deleage1, Ismail B. Turkbey2, Peter L. Choyke2, Yanling Liu3, Gregory Q. Del Prete3, Brandon Keele3, Jeffrey D. Lifson3, Jacob D. Estes3
1AIDS and Cancer Virus Program, Frederick, MD, USA,2National Cancer Institute, Bethesda, MD, USA,3Frederick National Laboratory for Cancer Research, Frederick, MD, USA
WEBCAST: http://www.croiwebcasts.org/console/player/37053?mediaType=slideVideo&&crd_fl=1&ssmsrq=1521912612637&ctms=5000&csmsrq=920
Abstract Body:
Initiation and maintenance of effective immune responses depends on the structural and functional integrity of secondary lymphoid tissues, particularly lymph nodes (LN). Among the fundamental biological functions of LN is the filtration of lymph and the capture of particulate antigens. To evaluate the functional consequences of progressive fibrotic damage to lymphoid tissue seen in HIV/SIV infection, we used longitudinal magnetic resonance imaging (MRI) to study uptake of a simulated particulate antigen by draining lymph nodes in SIV infected rhesus macaques (RM), and correlated these findings with histopathological analysis. We also evaluated the impact of combination antiretroviral therapy (cART) and adjunctive anti-fibrotic intervention.
Four RM were infected (IV) with SIVmac239M, placed on cART (TDF/FTC/DTG) starting at 36 weeks post infection (wpi), and then treated with the anti-fibrotic drug pirfenidone started at 50 wpi continuing through 82 wpi. Longitudinal dynamic MRI scans were used to monitor and quantify lymphatic drainage and inguinal lymph node uptake of gadolinium G5-DOTA dendrimer (∼8 nm diameter simulated particulate antigen) after intradermal injection into the anterior portion of the feet. MRI was performed prior to SIV infection and at multiple time points following infection. Correlative analysis of axillary LN fibrotic damage and inflammation were performed using immunohistochemistry and quantitative image analysis.
We observed the rapid onset (beginning 2 weeks post infection) of LN dysfunction manifested by restricted uptake of dendrimer by inguinal LN. Persistent impaired inguinal LN dendrimer uptake correlated with histopathologic evidence of fibrotic damage in axillary LN. cART for 46 weeks, combined with 28 weeks of pirfenidone did not restore dendrimer uptake into the draining lymph nodes, and suggests that fibrotic impairment of LN function may persist for long periods of time.
SIV, and likely HIV, infection is associated with a profound impairment of LN function due to collagen deposition, which may affect the ability to mount effective immune responses. Fibrosis may also impact tissue bioavailability of anti-viral drugs in affected sites.
PROGRESSIVE LYMPH NODE DYSFUNCTION DURING SIV INFECTION IS NOT REVERSED WITH ART
Author(s):
Claire Deleage1, Ismail B. Turkbey2, Peter L. Choyke2, Yanling Liu3, Gregory Q. Del Prete3, Brandon Keele3, Jeffrey D. Lifson3, Jacob D. Estes3
1AIDS and Cancer Virus Program, Frederick, MD, USA,2National Cancer Institute, Bethesda, MD, USA,3Frederick National Laboratory for Cancer Research, Frederick, MD, USA
WEBCAST: http://www.croiwebcasts.org/console/player/37053?mediaType=slideVideo&&crd_fl=1&ssmsrq=1521912612637&ctms=5000&csmsrq=920
Abstract Body:
Initiation and maintenance of effective immune responses depends on the structural and functional integrity of secondary lymphoid tissues, particularly lymph nodes (LN). Among the fundamental biological functions of LN is the filtration of lymph and the capture of particulate antigens. To evaluate the functional consequences of progressive fibrotic damage to lymphoid tissue seen in HIV/SIV infection, we used longitudinal magnetic resonance imaging (MRI) to study uptake of a simulated particulate antigen by draining lymph nodes in SIV infected rhesus macaques (RM), and correlated these findings with histopathological analysis. We also evaluated the impact of combination antiretroviral therapy (cART) and adjunctive anti-fibrotic intervention.
Four RM were infected (IV) with SIVmac239M, placed on cART (TDF/FTC/DTG) starting at 36 weeks post infection (wpi), and then treated with the anti-fibrotic drug pirfenidone started at 50 wpi continuing through 82 wpi. Longitudinal dynamic MRI scans were used to monitor and quantify lymphatic drainage and inguinal lymph node uptake of gadolinium G5-DOTA dendrimer (∼8 nm diameter simulated particulate antigen) after intradermal injection into the anterior portion of the feet. MRI was performed prior to SIV infection and at multiple time points following infection. Correlative analysis of axillary LN fibrotic damage and inflammation were performed using immunohistochemistry and quantitative image analysis.
We observed the rapid onset (beginning 2 weeks post infection) of LN dysfunction manifested by restricted uptake of dendrimer by inguinal LN. Persistent impaired inguinal LN dendrimer uptake correlated with histopathologic evidence of fibrotic damage in axillary LN. cART for 46 weeks, combined with 28 weeks of pirfenidone did not restore dendrimer uptake into the draining lymph nodes, and suggests that fibrotic impairment of LN function may persist for long periods of time.
SIV, and likely HIV, infection is associated with a profound impairment of LN function due to collagen deposition, which may affect the ability to mount effective immune responses. Fibrosis may also impact tissue bioavailability of anti-viral drugs in affected sites.
Excerpts see full webcast
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