Progressive loss of CD8(+) T cell-mediated control of a gamma-herpesvirus in the absence of CD4(+) T cells

A unique experimental model has been developed for dissecting the integrity of CD8(+) T cell-mediated immunity to a persistent gammaherpesvirus under conditions of CD4(+) T cell deficiency. Respiratory challenge of major histocompatibility complex class II -/- and +/+ C57BL/6J mice with the murine gammaherpesvirus 68 (MHV-68) leads to productive infection of both lung and adrenal epithelial cells. Virus titers peak within 5-10 d, and are no longer detected after day 15. Persistent, latent infection is established concurrently in splenic and lymph node B cells, with higher numbers of MHV-68(+) lymphocytes being found in all lymphoid sites analyzed from the +/+ mice concurrent with the massive, but transient splenomegaly that occurred only in this group. From day 17, however, the numbers of infected B lymphocytes were consistently higher in the -/- group, while the frequency of this population diminished progressively in the +/+ controls. Infectious MHV-68 was again detected in the respiratory tract and the adrenals of the -/- (but not the +/+) mice from day 22 after infection. The titers in these sites rose progressively, with the majority of the -/- mice dying between days 120 and 133. Even so, some CD8(+) effectors were still functioning as late as 100 d after infection. Depletion of CD8(+) T cells at this stage led to higher virus titers in the -/- lung, and to the development of wasting in some of the -/- mice. Elimination of the CD8(+) T cells from the +/+ group (day 80) increased the numbers of MHV-68(+) cells in the spleen, but did not reactivate the infection in the respiratory tract. The results are consistent with the interpretation that CD8(+) T cell-mediated control of this persistent gammaherpesvirus is progressively lost in the absence of the CD4(+) T cell subset. This parallels what may be happening in AIDS patients who develop Kaposi's sarcoma and various Epstein Barr virus-associated disease processes.