CD8+ clonality is associated with prolonged acute plasma viremia and altered mRNA cytokine profiles during the course of Feline Immunodeficiency Virus infection

Abstract

Acute lentiviral infection is characterized by early CD8+ cytotoxic T cell (CTL) activity and a subsequent decline in plasma viremia. However, CD8+ lymphocytes fail to eliminate the virus and a progressive T cell immune dysfunction develops during the course of chronic lentiviral infection. To further define this CD8+ immune dysfunction we utilized PARR (PCR for Antigen Receptor Rearrangements), a technique which measures clonally expanded lymphocyte populations by comparison of highly conserved T cell receptor (TCR) regions to identify the prevalence of clonal CD8+ T cells following FIV infection. We then compared phenotype, mRNA profiles, CD8+ proliferation and plasma viremia during acute and chronic infection for PARR positive (PARR+) and PARR negative (PARR−) Feline Immunodeficiency virus (FIV) infected cats. We demonstrated that approximately forty percent of the FIV+ cats examined exhibit CD8+ clonality compared to none of the FIV− control cats. There were no phenotypic differences between PARR+ and PARR− CD8+ lymphocytes from FIV+ cats but retrospective analysis of plasma viremia over the course of infection revealed a delayed peak in plasma viremia and a decline in lymphocyte counts were observed in the PARR+ group during acute infection. CD8+ lymphocytes isolated from chronically infected PARR− cats exhibited significantly higher mRNA expression of IFN-γ and IL-2 following mitogenic stimulation when compared to PARR+ CD8+ lymphocytes. These data suggest that clonal CD8+ expansion may be related to impaired control of acute viremia and less effective CD8+ anti-viral function. Using PARR to assess changes in CD8+ clonality during the progression from acute to chronic FIV infection may help to better characterize the factors which contribute to CD8+ anergy and lentiviral persistence.

Modulating DNA Methylation in Activated CD8+ T Cells Inhibits Regulatory T Cell–Induced Binding of Foxp3 to the CD8+ T Cell IL-2 Promoter

“…We and others have previously established that CD8 + T cells exhibit an activated phenotype during the course of FIV infection (23, 62, 63). Therefore, the focus of this investigation was to demonstrate how Treg cells may utilize CD8 + T cell activation as a route for CD8 + T cell suppression.…”

ACVIMconsensus statement guidelines on diagnosing and distinguishing low‐grade neoplastic from inflammatory lymphocytic chronic enteropathies in cats

“… 17 , 187 Much data indicates that clonality is not synonymous with malignancy and it has been shown that any strong chronic antigenic stimulation can promote selective proliferation of lymphocyte clones. Benign clonal expansions have been documented in humans, 188 , 189 , 190 , 191 , 192 , 193 dogs, 194 , 195 , 196 and cats with infectious diseases 197 (e.g., ehrlichiosis, leishmaniasis, feline immunodeficiency virus), chronic inflammatory intestinal disorders, neoplasia, and drug administration. In addition, it has been reported that inflammatory and low‐grade neoplastic lymphoid lesions can coexist in the same cat.…”

Monocyte-Derived Dendritic Cells from Feline Immunodeficiency Virus Positive Cats are Productively Infected and Maintain CD8+ T Cell Stimulatory Capacity

“…FIV+ animals were infected with the NCSU 1 isolate of FIV. Each cat was administered 1X10 5 TCID 50 intravenously of cell-free virus as previously described [13,14]. At the time of these studies, all cats had been infected for 1-3 years and were in the chronic stage of infection.…”