PubMed · 10463546
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E D Prentice. 1999. Informed consent: the most important protector.. https://doi.org/10.1111/j.1553-2712.1999.tb01204.x
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Brain infection by the laboratory strain challenge virus standard (CVS), a highly neurotropic strain of rabies virus, causes splenocytes to become less responsive to in vitro stimulation with ConA. CVS-induced immune unresponsiveness is less severe in mice lacking the p55 Kd TNF-alpha receptor (p55TNFR(-/-)) than in C57BL/6 mice, despite a similar invasion of the brain. Comparison of CVS infection in these two strains of mice indicated that decreased immune responsiveness is associated with: (1) an in vivo reduction of the percentages of Th1 (IL-2, IFN-gamma and TNF-alpha) but not of Th2 (IL-4) cytokine-secreting T cells; and (2) an in vivo increase of the percentages of CD25 and CD69-expressing splenocytes. In contrast, CVS-induced immune unresponsiveness is not associated with abnormal percentage of T, B, NK cells or monocytes in vivo. The reductions of the CD4/CD8 ratio and of splenocyte expression of I-A(b) during CVS infection are similar in p55TNFR(-/-) and C57BL/6 mice indicating that these two parameters are not linked to the decreased responsiveness of splenocytes. These data suggest that CVS-induced immune unresponsiveness is under the control of the p55 Kd TNF-alpha receptor. We propose that T cell activation through this receptor, in an environment of poor antigen presentation, results in a state of T cells characterized by the reduced production of IL-2, TNF-alpha and IFN-gamma in vivo, the decreased responsiveness of splenocytes to ConA stimulation in vitro and the expression of the activation markers CD25 and CD69.
Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection.
Cytotoxic T lymphocytes (CTLs) play a vital part in controlling viral replication during human viral infections. Most studies in human infections have focused on CTL specificities in chronic infection and few data exist regarding the specificity of the initial CTL response induced in acute infection. In this study, HIV-1 infection in persons expressing human histocompatibility leukocyte antigen (HLA)-A*0201 was used as a means of addressing this issue. In chronic infection, the dominant HLA-A*0201-restricted CTL response is directed towards the epitope SLYNTVATL ("SL9") in p17 Gag (residues 77-85). This epitope is targeted by 75% of HLA-A*0201-positive adults, and the magnitude of this A*0201-SL9 response shows a strong negative association with viral load in progressive infection. Despite using the highly sensitive peptide-major histocompatibility complex tetramer and intracellular cytokine assays, responses to the SL9 epitope were not detectable in any of 11 HLA-A*0201-positive subjects with acute HIV-1 infection (P = 2 x 10(-6)), even when assays were repeated using the SL9 peptide variant that was encoded by their autologous virus. In contrast, multiple responses (median 3) to other epitopes were evident in 7 of the 11 A*0201-positive subjects. Longitudinal study of two subjects confirmed that the A*0201-SL9 response emerged later than other CTL responses, and after viral set point had been reached. Together, these data show that the CTL responses that are present and that even may dominate in chronic infection may differ substantially from those that constitute the initial antiviral CTL response. This finding is an important consideration in vaccine design and in the evaluation of vaccine candidates.