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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 (gp70), induced fatal immunodeficiency disease in all (12 of 12) infected animals over a course of 33 +/- 10 weeks. By contrast, animals infected with virus 61E, 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 gp70 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.