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.
Highlights
Feline immunodeficiency virus (FIV) is a lentivirus present in feral and domestic cat populations worldwide
One of the FIVinfected cats has proven atypical in disease progression based on an absolute CD4+ T cell count and CD4/CD8 ratio that remain indistinguishable from two uninfected control cats. This animal has been characterized as a FIV-infected long-term non-progressor (LTNP) cat. [9,11] 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]
In this study we showed that this cohort of FIV-infected cats in the late asymptomatic phase demonstrate active viral replication in multiple central tissue sites with a relatively quiescent viral replication status in the peripheral blood and concurrent CD4+ leukocyte depletion in peripheral blood and tissue sites
Summary
Feline immunodeficiency virus (FIV) is a lentivirus present in feral and domestic cat populations worldwide. As is true for all lentiviruses, infection is life-long due to irreversible integration of the provirus into genomes of leukocytes including lymphocytes and macrophages, and may be associated with progressive dysfunction of the immune system.[1] Classically, there are three sequential clinical phases of FIV-infection in cats including the acute, asymptomatic, and terminal acquired immunodeficiency phase. In the acute phase there is infection of multiple leukocyte subsets, prolific viral replication and dissemination to many tissue sites including brain, intestinal tract, and primary and secondary lymphoid organs such as the bone marrow, spleen, and lymph nodes.[2,3,4] The acute stage of infection is followed by an asymptomatic phase lasting months to years where the FIV-infected cat may demonstrate no outward signs of clinical disease despite the presence of a progressive immunopathology. Perhaps due to the high costs of keeping experimental animals for protracted time periods, the acute and early asymptomatic phases of infection have received the greatest investigative attention, while less is understood about viral and immunopathogenesis during the late asymptomatic period and the transition into the terminal stage of infection
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