Peripheral immunophenotype and viral promoter variants during the asymptomatic phase of feline immunodeficiency virus infection

Murphy, Brian G; Hillman, C.; McDonnel, Samantha J.

doi:10.1016/j.virusres.2013.11.017

Cited by 13 publications

(21 citation statements)

References 31 publications

(51 reference statements)

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“…This animal has been characterized as a FIV-infected long-term non-progressor (LTNP) cat. [9,11] Additionally, we have demonstrated methylation and deacetylation of histone proteins physically associated with the FIV-promoter in peripheral blood CD4+ T cells isolated during the asymptomatic phase, which is consistent with a condensed chromatin pattern and viral latency. [12] Recently, we demonstrated evidence of active FIV replication in the popliteal lymph nodes in the face of an apparent absence of active viral replication in peripheral blood.…”

Section: Introductionsupporting

confidence: 71%

“…Severe peripheral blood CD4+ depletion, as observed for the FIV-infected progressor cats, is a hallmark of FIV infection in cats. [9,11] Due to low animal numbers, statistical comparisons could not be performed. Subjectively, differences in the frequencies of CD8+ and CD21+ leukocytes were not observed in the peripheral blood; however all FIV-infected cats (including the LTNP cat) showed a higher frequency of peripheral CD11b+ cells, which is part of a heterodimeric leukocyte adhesion protein present on feline monocytes, dendritic cells, and neutrophils.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Introductionsupporting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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“…Importantly, relatively few studies have monitored the frequency of CD4+ and CD8+ T cell subsets into the late stages of infection. However, findings from these few studies, including experimental and natural infections, show that CD4+ T cell counts continue to progressively decline to very low levels in blood and lymphoid tissues and may be associated with declining peripheral CD8+ T cell frequencies and clinical signs of immunodeficiencies [7,19,83]. Interestingly, significant declines in CD4+ T cells counts are not always associated with clinical signs of acquired immunodeficiencies and other factors such as environmental stresses may determine disease onset [7,24,79].…”

Section: Cell Reservoirs Of Fivmentioning

confidence: 99%

Central and peripheral reservoirs of feline immunodeficiency virus in cats: a review

Eckstrand

Sparger

Murphy

2017

Journal of General Virology

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Infection with feline immunodeficiency virus (FIV), a lentivirus similar to human immunodeficiency virus (HIV), results in lifelong viral persistence and progressive immunopathology in the cat. FIV has the ability to infect and produce infectious virus in a number of different cell types. FIV provirus can also be maintained in a replication-competent but transcriptionally quiescent state, facilitating viral persistence over time. Immediately after the initial infection, FIV infection quickly disseminates to many anatomical compartments within the host including lymphoid organs, gastrointestinal tract and brain. Collectively, the anatomic and cellular compartments that harbour FIV provirus constitute the viral reservoir and contain foci of both ongoing viral replication and transcriptionally restricted virus that may persist over time. The relative importance of the different phenotypes observed for infected cells, anatomic compartment, replication status and size of the reservoir represent crucial areas of investigation for developing effective viral suppression and eradication therapies. In this review, we discuss what is currently known about FIV reservoirs, and emphasize the utility of the FIV-infected cat as a model for the HIV-infected human.

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“…Our group has demonstrated that within this FIV-infected experimental cohort, viral latency in peripheral blood-derived CD4+ T cells is associated with epigenetic modification of histone proteins physically associated with the FIV 5’ LTR (viral promoter) [ 11 , 12 ]. Despite an inactive viral transcription status and a condensed chromatin pattern of the FIV LTR, circulating CD4+ T cell numbers have progressively declined over time in this cohort of cats [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Viral Reservoirs in Lymph Nodes of FIV-Infected Progressor and Long-Term Non-Progressor Cats during the Asymptomatic Phase

et al. 2016

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BackgroundExamination of a cohort of cats experimentally infected with feline immunodeficiency virus (FIV) for 5.75 years revealed detectable proviral DNA in peripheral blood mononuclear cells (PBMCs) harvested during the asymptomatic phase, undetectable plasma viral RNA (FIV gag), and rarely detectable cell-associated viral RNA. Despite apparent viral latency in peripheral CD4+ T cells, circulating CD4+ T cell numbers progressively declined in progressor animals. The aim of this study was to explore this dichotomy of peripheral blood viral latency in the face of progressive immunopathology. The viral replication status, cellular immunophenotypes, and histopathologic features were compared between popliteal lymph nodes (PLNs) and peripheral blood. Also, we identified and further characterized one of the FIV-infected cats identified as a long-term non-progressor (LTNP).ResultsPLN-derived leukocytes from FIV-infected cats during the chronic asymptomatic phase demonstrated active viral gag transcription and FIV protein translation as determined by real-time RT-PCR, Western blot and in situ immunohistochemistry, whereas viral RNA in blood leukocytes was either undetectable or intermittently detectable and viral protein was not detected. Active transcription of viral RNA was detectable in PLN-derived CD4+ and CD21+ leukocytes. Replication competent provirus was reactivated ex vivo from PLN-derived leukocytes from three of four FIV-infected cats. Progressor cats showed a persistent and dramatically decreased proportion and absolute count of CD4+ T cells in blood, and a decreased proportion of CD4+ T cells in PLNs. A single long-term non-progressor (LTNP) cat persistently demonstrated an absolute peripheral blood CD4+ T cell count indistinguishable from uninfected animals, a lower proviral load in unfractionated blood and PLN leukocytes, and very low amounts of viral RNA in the PLN.ConclusionCollectively our data indicates that PLNs harbor important reservoirs of ongoing viral replication during the asymptomatic phase of infection, in spite of undetectable viral activity in peripheral blood. A thorough understanding of tissue-based lentiviral reservoirs is fundamental to medical interventions to eliminate virus or prolong the asymptomatic phase of FIV infection.

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Peripheral immunophenotype and viral promoter variants during the asymptomatic phase of feline immunodeficiency virus infection

Cited by 13 publications

References 31 publications

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

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

Central and peripheral reservoirs of feline immunodeficiency virus in cats: a review

Viral Reservoirs in Lymph Nodes of FIV-Infected Progressor and Long-Term Non-Progressor Cats during the Asymptomatic Phase

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