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Peripheral and central immune cell reservoirs in tissues from asymptomatic cats chronically infected with feline immunodeficiency virus

View Article: PubMed Central - PubMed

ABSTRACT

Feline immunodeficiency virus (FIV) infection in cats results in life-long viral persistence and progressive immunopathology. We have previously described a cohort of experimentally infected cats demonstrating a progressive decline of peripheral blood CD4+ T-cell over six years in the face of apparent peripheral viral latency. More recently we reported findings from this same cohort that revealed popliteal lymph node tissue as sites for ongoing viral replication suggesting that tissue reservoirs are important in FIV immunopathogenesis during the late asymptomatic phase of infection. Results reported herein characterize important tissue reservoirs of active viral replication during the late asymptomatic phase by examining biopsied specimens of spleen, mesenteric lymph node (MLN), and intestine from FIV-infected and uninfected control cats. Peripheral blood collected coincident with harvest of tissues demonstrated severe CD4+ T-cell depletion, undetectable plasma viral gag RNA and rarely detectable peripheral blood mononuclear cell (PBMC)-associated viral RNA (vRNA) by real-time PCR. However, vRNA was detectable in all three tissue sites from three of four FIV-infected cats despite the absence of detectable vRNA in plasma. A novel in situ hybridization assay identified B cell lymphoid follicular domains as microanatomical foci of ongoing FIV replication. Additionally, we demonstrated that CD4+ leukocyte depletion in tissues, and CD4+ and CD21+ leukocytes as important cellular reservoirs of ongoing replication. These findings revealed that tissue reservoirs support foci of ongoing viral replication, in spite of highly restricted viral replication in blood. Lentiviral eradication strategies will need address tissue viral reservoirs.

No MeSH data available.


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Histologic examination of MLN, spleen and intestine from FIV-infected progressor cats in the late asymptomatic phase and uninfected cats.MLNs from FIV-infected progressor cats were smaller in size and characterized by paracortical atrophy relative to those from uninfected cats (a,b, 20x). MLN follicles from FIV-infected cats revealed active germinal centers with less densely populated dark (DZ) and light zones (LZ), a prominent mantle zone (MA) and a thin, sparsely populated paracortical rim (PC) relative to uninfected cats (c,d, 100x). Spleens of infected progressor cats showed less densely populated white pulp that exhibited indistinct periarteriolar lymphoid sheaths (PALS), prominent active germinal center follicles (F) with expanded mantle (MA) and marginal zones (MG), relative to uninfected cats (e,f 40x, g,h 100x). Notable differences in intestinal mucosal architecture and leukocyte density were not observed between uninfected and FIV-infected cats (200x, i,j). Intestinal Peyer’s patches (lymphoid follicles) of uninfected and infected cats both contained active germinal centers; however, interfollicular T-cell zones (IFT) were better demarcated in intestinal biopsies from uninfected cats relative to infected cats (k,l, 40x).
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pone.0175327.g005: Histologic examination of MLN, spleen and intestine from FIV-infected progressor cats in the late asymptomatic phase and uninfected cats.MLNs from FIV-infected progressor cats were smaller in size and characterized by paracortical atrophy relative to those from uninfected cats (a,b, 20x). MLN follicles from FIV-infected cats revealed active germinal centers with less densely populated dark (DZ) and light zones (LZ), a prominent mantle zone (MA) and a thin, sparsely populated paracortical rim (PC) relative to uninfected cats (c,d, 100x). Spleens of infected progressor cats showed less densely populated white pulp that exhibited indistinct periarteriolar lymphoid sheaths (PALS), prominent active germinal center follicles (F) with expanded mantle (MA) and marginal zones (MG), relative to uninfected cats (e,f 40x, g,h 100x). Notable differences in intestinal mucosal architecture and leukocyte density were not observed between uninfected and FIV-infected cats (200x, i,j). Intestinal Peyer’s patches (lymphoid follicles) of uninfected and infected cats both contained active germinal centers; however, interfollicular T-cell zones (IFT) were better demarcated in intestinal biopsies from uninfected cats relative to infected cats (k,l, 40x).

Mentions: Histologic examination of the MLNs from the two uninfected control cats revealed multiple active germinal centers with well-demarcated dark, light and mantle zones in the cortical regions of the MLNs (Fig 5a and 5c). The light zone of the germinal centers frequently contained a small amount of extracellular homogeneous/glassy/hyalinized eosinophilic material (presumed immunoglobulin). In both control animals, paracortical regions were densely and thickly populated by small mature lymphocytes. MLNs were analyzed from two FIV-progressor cats (184 and 186) and both demonstrated two striking histologic features (Fig 5b and 5d). The first feature was marked paracortical atrophy characterized by a thin paracortical rim with a scarcity of leukocytes, a decreased distance between the medullary sinuses and capsule, and decreased space between cortical follicles. A second histologic feature of MLNs from FIV-infected progressor cats related to MLN dark and light zones that were less densely populated with leukocytes and showed increased clear space between cells. These findings were consistent with mixed lymphoid hyperplasia and follicular involution.[19] Similar to the uninfected cats, the germinal centers of FIV-progressor cats contained acellular eosinophilic material (presumed to be immunoglobulin) within the germinal center light zone. MLN sampled from the LTNP cat revealed well-populated paracortical zones and follicular domains similar to those of the uninfected cats.


Peripheral and central immune cell reservoirs in tissues from asymptomatic cats chronically infected with feline immunodeficiency virus
Histologic examination of MLN, spleen and intestine from FIV-infected progressor cats in the late asymptomatic phase and uninfected cats.MLNs from FIV-infected progressor cats were smaller in size and characterized by paracortical atrophy relative to those from uninfected cats (a,b, 20x). MLN follicles from FIV-infected cats revealed active germinal centers with less densely populated dark (DZ) and light zones (LZ), a prominent mantle zone (MA) and a thin, sparsely populated paracortical rim (PC) relative to uninfected cats (c,d, 100x). Spleens of infected progressor cats showed less densely populated white pulp that exhibited indistinct periarteriolar lymphoid sheaths (PALS), prominent active germinal center follicles (F) with expanded mantle (MA) and marginal zones (MG), relative to uninfected cats (e,f 40x, g,h 100x). Notable differences in intestinal mucosal architecture and leukocyte density were not observed between uninfected and FIV-infected cats (200x, i,j). Intestinal Peyer’s patches (lymphoid follicles) of uninfected and infected cats both contained active germinal centers; however, interfollicular T-cell zones (IFT) were better demarcated in intestinal biopsies from uninfected cats relative to infected cats (k,l, 40x).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5383277&req=5

pone.0175327.g005: Histologic examination of MLN, spleen and intestine from FIV-infected progressor cats in the late asymptomatic phase and uninfected cats.MLNs from FIV-infected progressor cats were smaller in size and characterized by paracortical atrophy relative to those from uninfected cats (a,b, 20x). MLN follicles from FIV-infected cats revealed active germinal centers with less densely populated dark (DZ) and light zones (LZ), a prominent mantle zone (MA) and a thin, sparsely populated paracortical rim (PC) relative to uninfected cats (c,d, 100x). Spleens of infected progressor cats showed less densely populated white pulp that exhibited indistinct periarteriolar lymphoid sheaths (PALS), prominent active germinal center follicles (F) with expanded mantle (MA) and marginal zones (MG), relative to uninfected cats (e,f 40x, g,h 100x). Notable differences in intestinal mucosal architecture and leukocyte density were not observed between uninfected and FIV-infected cats (200x, i,j). Intestinal Peyer’s patches (lymphoid follicles) of uninfected and infected cats both contained active germinal centers; however, interfollicular T-cell zones (IFT) were better demarcated in intestinal biopsies from uninfected cats relative to infected cats (k,l, 40x).
Mentions: Histologic examination of the MLNs from the two uninfected control cats revealed multiple active germinal centers with well-demarcated dark, light and mantle zones in the cortical regions of the MLNs (Fig 5a and 5c). The light zone of the germinal centers frequently contained a small amount of extracellular homogeneous/glassy/hyalinized eosinophilic material (presumed immunoglobulin). In both control animals, paracortical regions were densely and thickly populated by small mature lymphocytes. MLNs were analyzed from two FIV-progressor cats (184 and 186) and both demonstrated two striking histologic features (Fig 5b and 5d). The first feature was marked paracortical atrophy characterized by a thin paracortical rim with a scarcity of leukocytes, a decreased distance between the medullary sinuses and capsule, and decreased space between cortical follicles. A second histologic feature of MLNs from FIV-infected progressor cats related to MLN dark and light zones that were less densely populated with leukocytes and showed increased clear space between cells. These findings were consistent with mixed lymphoid hyperplasia and follicular involution.[19] Similar to the uninfected cats, the germinal centers of FIV-progressor cats contained acellular eosinophilic material (presumed to be immunoglobulin) within the germinal center light zone. MLN sampled from the LTNP cat revealed well-populated paracortical zones and follicular domains similar to those of the uninfected cats.

View Article: PubMed Central - PubMed

ABSTRACT

Feline immunodeficiency virus (FIV) infection in cats results in life-long viral persistence and progressive immunopathology. We have previously described a cohort of experimentally infected cats demonstrating a progressive decline of peripheral blood CD4+ T-cell over six years in the face of apparent peripheral viral latency. More recently we reported findings from this same cohort that revealed popliteal lymph node tissue as sites for ongoing viral replication suggesting that tissue reservoirs are important in FIV immunopathogenesis during the late asymptomatic phase of infection. Results reported herein characterize important tissue reservoirs of active viral replication during the late asymptomatic phase by examining biopsied specimens of spleen, mesenteric lymph node (MLN), and intestine from FIV-infected and uninfected control cats. Peripheral blood collected coincident with harvest of tissues demonstrated severe CD4+ T-cell depletion, undetectable plasma viral gag RNA and rarely detectable peripheral blood mononuclear cell (PBMC)-associated viral RNA (vRNA) by real-time PCR. However, vRNA was detectable in all three tissue sites from three of four FIV-infected cats despite the absence of detectable vRNA in plasma. A novel in situ hybridization assay identified B cell lymphoid follicular domains as microanatomical foci of ongoing FIV replication. Additionally, we demonstrated that CD4+ leukocyte depletion in tissues, and CD4+ and CD21+ leukocytes as important cellular reservoirs of ongoing replication. These findings revealed that tissue reservoirs support foci of ongoing viral replication, in spite of highly restricted viral replication in blood. Lentiviral eradication strategies will need address tissue viral reservoirs.

No MeSH data available.


Related in: MedlinePlus