Prolonged Dominance of Clonally Restricted CD4+T Cells in Macaques Infected with Simian Immunodeficiency Viruses

Autor: Ling Shen, Prahbat K. Sehgal, Christine Bogle, Paul T. Morrison, Dejiang Zhou, Yun Shen, Zhongchen Kou, Andre J. Nahmias, Norman L. Letvin, Zheng W. Chen, Harold M. McClure, Chris C. Ibegbu
Rok vydání: 2000
Předmět:
Zdroj: Journal of Virology. 74:7442-7450
ISSN: 1098-5514
0022-538X
DOI: 10.1128/jvi.74.16.7442-7450.2000
Popis: CD4+ T cells are likely to play an important role in maintaining the human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-lymphocyte and humoral immune responses in HIV-1-infected individuals. Interleukin-2 (IL-2) produced by CD4+ T cells has been shown in vitro to enhance CD8+ T-lymphocyte-mediated suppression of HIV-1 replication (16). CD4+ T-cell loss has been shown to be associated with waning anti-HIV-1 antibody responses in infected individuals (2). Moreover, potent HIV-1-specific proliferative CD4+ T-cell responses are associated with the control of viremia in a small group of infected humans whose viremia is controlled in the absence of antiretroviral treatment (26). Yet, virus-specific CD4+ T-cell responses have proven difficult to characterize in most HIV-1-infected individuals. Although proliferative responses of HIV-1-specific CD4+ T cells can be detected in peripheral blood lymphocytes (PBLs) of some HIV-1-infected humans (1, 18, 28, 29), the magnitude and frequency of detectable CD4+ T-cell proliferation are low in the majority of chronically infected individuals (18, 28). Determination of the extent to which the difficulty in detecting virus-specific CD4+ T cells in vitro is attributable to the suppressive nature of an AIDS virus infection or the virus-induced deletion of reactive CD4+ memory T cells is important. In vivo studies assessing molecular aspects of T-cell receptor (TCR) repertoires will be an important contribution to our understanding of HIV-1-specific CD4+ T cells in virus-infected individuals. While a rapid turnover of CD4+ T cells is observed during HIV-1 infections (21, 27), little is known about the evolution of HIV-1-specific CD4+ T cells in infected humans. It is generally thought that the CD4+ T cells activated through TCR signaling are susceptible to a productive viral infection and virus-induced death. This activation-dependent viral infection and cell death has been seen in vitro in CD4+ T-cell infections (11, 13). However, it is not clear to what extent HIV-1 infections can drive an expansion rather than simply a depletion of viral-antigen-specific CD4+ T cells in infected individuals. Although a dominance of CD4+ T cell clones has been identified at single points in time during clinical progression to AIDS in HIV-1-infected humans (10, 12, 20), longitudinal studies of these clonally dominant CD4+ T cells have not formally been done. It has been argued that such a dominance of CD4+ T cells in advanced infection may be driven by opportunistic pathogens rather than HIV-1. It has also been argued that dominant CD4+ T-cell clones identified during chronic infection may represent selected Vβ-expressing lymphocyte subpopulations remaining following virus-induced polyclonal lymphocyte deletion (14). Further studies are needed to characterize the dynamics of HIV-1-specific CD4+ T-cell population changes in infected individuals. We have recently initiated studies of CD4+ T-cell repertoires in simian immunodeficiency virus (SIV) SIVmac-infected rhesus monkeys (3, 4, 30). Our previous studies using PCR-based quantitation of Vβ family expression did not demonstrate a consistent expansion or deletion of selected Vβ family-expressing CD4+ PBL subpopulations in genetically unselected SIVmac-infected monkeys (3). This observation suggests that mechanisms other than superantigen-mediated depletion contribute to the CD4+ T-lymphocyte decline in SIVmac-infected monkeys. Nevertheless, it still remains possible that clonal expansion or depletion within individual Vβ family-expressing CD4+ T-lymphocyte subpopulations occurs as a result of persistent antigen stimulation in these virus-infected individuals. We reasoned that prospective studies of macaque TCR complementarity-determining region 3 (CDR3) profiles during SIV infections might provide a useful setting in which to test the hypothesis that an AIDS virus can drive a prolonged CD4+ T-cell clonal response. We therefore utilized CDR3 profile and sequence analyses to evaluate the dynamics of macaque CD4+ T-cell repertoire changes during persistent SIV infections. We report that SIV infection of macaques can result in prolonged periods of clonal dominance of CDR3-restricted CD4+ T cells despite the decline of CD4+ PBL counts.
Databáze: OpenAIRE
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