Lymphocyte subset alterations and viral determinants of immunodeficiency disease induction by the feline leukemia virus FeLV-FAIDS

Abstract

The FeLV-FAIDS strain of feline leukemia virus consistently induces fatal immunodeficiency. To investigate the immunopathogenesis and viral genetic determinants responsible for the induction of immunodeficiency disease in vivo, we have generated chimeras between the two major viral genomes in the original virus isolate, designated common form clone 61E and major variant clone 61C, which were molecularly cloned directly from DNA of the same animal and tissue. Each of three 61E/C chimeras, containing at minimum a 34-amino-acid segment (including a 6-amino-acid insertion and one amino acid substitution) near the C terminus of the 61C surface glycoprotein (gp7O), induced fatal immunodeficiency disease in all (12 of 12) infected animals over a course of 33 10 weeks. By contrast, animals infected with virus 6iE, although persistently antigenemic, remained asymptomatic throughout a 48-week observation period. Beginning 14 weeks after infection, a significant decrease (8 to 10%) in the percent of circulating CD4+ T lymphocytes developed in the 61E/C chimera-infected cats, compared with either 61E-infected or control animals. At this time, no significant changes were seen in CD8 cells, B cells, or mitogen-induced blastogenesis. Prior to this initial decline in CD4 cells, the ability of all antigenemic 61E/C-infected cats to generate a primary antibody response to the T-cell-dependent antigen keyhole limpet hemocyanin was markedly impaired, whereas all 61E-infected cats, one 61E/C-infected but nonviremic cat, and all uninfected control cats produced normal antibody responses. The results reported here demonstrate that a major determinant of in vivo immunodeficiency induction by FeLV-FAIDS is contained within a 34-amino-acid C-terminal segment of its surface glycoprotein and that this gp7O alteration determines the early and persistent deficits in CD4+ T lymphocytes and T-cell-dependent antibody responses. We hypothesize that these early immunologic alterations could result from early deletion of a CD4+ helper T-cell subset.

Clinical aspects of feline immunodeficiency and feline leukemia virus infection

“…In addition, neutrophils of progressively infected cats have decreased chemotactic and phagocytic function compared with those of normal cats. In some cats, lymphopenia may be characterized by preferential loss of CD4 + helper T cells, resulting in an inverted CD4/CD8 ratio (like typically seen in FIV infection) (Quackenbush et al, 1990;Hoffmann-Fezer et al, 1996), but more commonly, substantial losses of helper cells and cytotoxic suppressor cells (CD8 + cells) occur (Hoffmann-Fezer et al, 1996). Many immune function tests of naturally FeLV-infected cats are abnormal, including decreased response to T-cell mitogens, prolonged allograft reaction, reduced immunoglobulin production, depressed neutrophil function, and complement depletion.…”

4 Haematological disorders associated with feline retrovirus infections

“…Recently, an FeLV strain that induces an acute immunodeficiency syndrome (FeLV-FA1DS) has been isolated, and a number of replication-defective FeLV variants have been directly cloned from tissues of cats infected with FeLV-FAIDS (Overbaugh et al, 1988b). Experimental infection with the FeLV-FAIDS isolate, the major variant molecular clone (FeLV-61C), or chimeric molecular clones, causes signifi-cant T-lymphopenia, functional lymphocyte defects, and a fatal immunodeficiency syndrome (wasting, diarrhoea, and opportunistic infections) Overbaugh et al, 1988b;Quackenbush et al, 1989Quackenbush et al, , 1990Diehl and Hoover, 1992). High levels of unintegrated viral DNA have been detected in marrow cells of cats infected with the FeLV-FAIDS strain, suggesting that host cell death in vivo is related to a lack of superinfection interference by the FeLV-FAIDS variant (Mullins et al, 1986).…”

Mutations within a putative cysteine loop of the transmembrane protein of an attenuated immunodeficiency-inducing feline leukemia virus variant inhibit envelope protein processing

“…Parentheses in the names of subsequent chimeras indicate a subdivision of the fourth segment, and brackets denote a further subdivision of part of that segment. The triangle denotes the location of the six-amino-acid insertion that is a primary determinant of pathogenicity (12,45), and the vertical lines indicate the locations of amino acid differences in 61B relative to 61C or 61E in TM (53). (B) Amino acids identical to those in the 61C reference sequence are denoted by dots.…”

“…The envelope protein has been implicated as the determinant of disease specificity for variants of feline leukemia virus (FeLV) that cause immunodeficiency (12,45). Viral chimeras that encode the SU of immunodeficiency-inducing replicationdefective variants 61C or 61B in the context of a mildly pathogenic, replication-competent provirus, 61E, cause cytopathic effects in feline T cells and immunodeficiency disease in cats (12,39,45). However, 61B is delayed compared with 61C in its ability to cause cytopathic effects in T cells and immunodeficiency in cats as a result of four amino acid differences in the envelope TM protein (40,53).…”