Human Immunodeficiency Virus Type 1 Infection of CD4+ T Cells Down-Regulates the Expression of CD28: Effect on T Cell Activation and Cytokine Production

Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA.
Clinical Immunology and Immunopathology 01/1996; 77(3):262-70. DOI: 10.1006/clin.1995.1152
Source: PubMed


Infection with human immunodeficiency virus type 1 (HIV-1) results in dysregulation of normal T cell function. To study the effects of HIV-1 at the cellular level, primary T cell lines were generated by alloantigen stimulation of CD4+ T cells collected from peripheral blood of HIV-1-infected donors. Using Epstein-Barr virus-infected B lymphocytes (EBV-LCL) as a source of alloantigen, the T cell lines were expanded in vitro for 7 weeks. Uninfected T cell lines were cultured in parallel. Virus was inducible from the infected lines with stimulation, and complete infection was achieved after 4-7 weeks depending on the line. The down-modulation of CD28 expression correlated with virus replication and spread. Furthermore, CD28 mRNA was not inducible in the infected lines after stimulation with alloantigen. Loss of CD28 correlated with reduced responsiveness to costimulation with a monoclonal antibody to CD28 following similar engagement of the CD3 protein. In contrast, activation with alloantigen was not affected. HIV-1 infection and down-modulation of CD28 did not alter the relative levels of IL-2, IFN-gamma, and IL-4 mRNA. Production of the various cytokine mRNAs following alloantigen stimulation was inhibited by CTLA4Ig and thus remained under the regulation of CD80 and CD86 expressed on the EBV-LCL. Taken together, our data suggest that dysregulation of normal T cell function associated with HIV-1 infection may result in part form the loss of CD28 expression.

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    • "One would expect that interference with CD28 expression would therefore lead to decreased cytokine production, anergy and apoptosis, all of which would significantly impair T-cell regulated functions, including activation of APCs and B cells. Indeed, during HIV-1 infection, the expression of CD28 significantly decreases (Gamberg et al., 2004; Park et al., 1998; Kammerer et al., 1996; Haffar et al., 1995; Caruso et al., 1994), subsequently resulting in Tcell dysregulation such as abnormal cytokine production , anergy and apoptosis (Linsley and Ledbetter, 1993; Groux et al., 1992). The precise mechanism of CD28 down-regulation during HIV-1 infection has yet to be fully elucidated, but the discovery of viral-encoded miRNA from Epstein-Barr virus (EBV) (Pfeffer et al., 2004) offers a new venue of possibilities. "
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    ABSTRACT: It is well-known that HIV-1 infection results in a gradual decline of the CD4+ T-lymphocytes, but the underlying mechanism of this decline is not completely understood. Research has shown that HIV-1 infection of CD4+ T cells results in decreased CD28 expression, but the mechanism of this repression is unknown. There is also substantial evidence demonstrating regulatory involvement of microRNA (miRNA) during protein expression in plants and some animals, and reports have recently been published confirming the existence of viral-encoded miRNAs. Based on these findings, we hypothesize that viral-encoded miRNA from HIV-1 may directly alter T cell, macrophage and dendritic cell activity. To investigate a potential correlation between the genomic complementarity of HIV-1 and host cell protein expression, a local alignment search was performed to assess for regions of complementarity between the HIV-1 proviral genome and the mRNA coding sequence of various proteins expressed by CD+ T cells and macrophages. Regions of complementarity with strong correlations to the currently established criteria for miRNA:target mRNA activity were found between HIV-1 and CD28, CTLA-4 and some interleukins, suggesting that HIV-1 may produce translational repression in host cells.
    Journal of Theoretical Biology 08/2005; 235(2):169-84. DOI:10.1016/j.jtbi.2005.01.001 · 2.12 Impact Factor
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    • "ϩ / TCR␣␤ ϩ T-cell compartment. CD8 ϩ /TCR␣␤ ϩ T-cells showed an intriguing stable immunophenotypic pattern— CD2 ϩhigh , CD7 ϩdim , CD11a ϩhigh , CD28 Ϫ/ϩdim , CD38 ϩhigh , CD45RO ϩhigh , CD45RA Ϫ/ϩdim , HLA-DR ϩhigh —which has been associated with a state of recent T-cell activation [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] "
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    Blood Cells Molecules and Diseases 01/2003; 30(1):1-12. DOI:10.1016/S1079-9796(03)00014-7 · 2.65 Impact Factor
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    • "Several investigators have shown that CTLA4Ig, a soluble form of CTLA-4, can decrease or prevent HIV infection of CD4 T cells. DC-mediated transmission of X4 strains to CD4 cells was increased by anti-CD28 and blocked by CTLA4Ig 47. Haffar et al. found that infected T cells could present alloantigen to fresh, uninfected CD4 T cells, leading to increased proliferation and virus spread to the activated cells, and that both of these events were blocked by CTLA4Ig 48. Mature DCs in peripheral blood were shown to bind HIV and induce infection when added to autologous CD4 T cells in the absence of added stimuli, and this infection was inhibited by CTLA4Ig 40. "
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    ABSTRACT: CD4 T cells activated in vitro by anti-CD3/28-coated beads are resistant to infection by CC chemokine receptor 5 (CCR5)-dependent HIV-1 isolates. In vivo, antigen-presenting cells (APCs) activate CD4 T cells in part by signaling through the T cell receptor and CD28, yet cells stimulated in this manner are susceptible to HIV-1 infection. We show that cytotoxic T lymphocyte antigen 4 (CTLA-4) engagement counteracts the CD28 antiviral effects, and that the ratio of CTLA-4 to CD28 engagement determines the susceptibility of HIV-1 infection. Furthermore, unopposed CTLA-4 signaling provided by CD28 blockade promotes vigorous HIV-1 replication, despite minimal T cell proliferation. Finally, CTLA-4 antibodies decrease the susceptibility of antigen-activated CD4 T cells to HIV, suggesting a potential approach to prevent or limit viral spread in HIV-1-infected individuals.
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