Chimpanzee CD4⁺ T cells are relatively insensitive to HIV‐1 envelope‐mediated inhibition of CD154 up‐regulation

Abstract

CD40-CD154 interaction forms a key event in regulation of crosstalk between dendritic cells and CD4 T cells. In human immunodeficiency virus (HIV)-1 infected patients CD154 expression is impaired, and the resulting loss of immune responsiveness by CD4+ T cells contributes to a progressive state of immunodeficiency in humans. Although chimpanzees are susceptible to chronic HIV-1/SIVcpz infection, they are relatively resistant to the onset of AIDS. This relative resistance is characterized by maintenance of CD4 + T cell populations and function, which is highly compromised in human patients. In our cohort of chronically HIV-1-and SIVcpz-infected chimpanzees, we demonstrated the capacity to produce IL-2, following CD3/CD28 stimulation, as well as preserved CD154 up-regulation. Cross-linking of CD4 with mAb was found to inhibit CD3/CD28-induced up-regulation of CD154 equally in chimpanzees and humans. However, specific cross-linking with trimeric recombinant HIV-1 gp140 revealed reduced sensitivity for inhibition of CD154 up-regulation in chimpanzees, requiring fourfold higher concentrations of viral protein. Chimpanzee CD4 + T cells are thus less sensitive to the immune-suppressive effect of low-dose HIV-1 envelope protein than human CD4 + T cells.Key words: Chimpanzee Á CD154 Á Cytokine Á HIV-1 Á Pathogenesis IntroductionHuman immunodeficiency virus type 1 (HIV-1) infection in humans is characterized by a precipitous loss of immune competence, eventually allowing the establishment of opportunistic infections and cancers [1,2]. This loss of immune function is ultimately observed at later stages as a peripheral decrease in the number of CD4 + T cells [3,4]. However, before the numerical loss of CD4 + T cells is apparent, HIV-1-infected individuals already have reduced antigen-specific and mitogen-stimulated CD4 + T cell responses [5][6][7][8][9][10][11][12]. These defects include diminished proliferative capacity and a functional loss in the ability to produce key cytokines. Induction of these important immunomodulatory cytokines is strongly dependent on dendritic cell (DC)-T cell interaction. Exposure to antigen will lead to DC activation [13][14][15], induce migration to lymphoid tissues and result in antigen presentation to T cells via MHC-TCR/CD3 interaction [16]. Subsequent activation of antigen-specific T cells leads to CD154 up-regulation which, via binding to CD40 on the DC, induces DC maturation, which is accompanied by up-regulation of the costimulatory molecules CD80 and CD86 and by IL-12 secretion [21,[27][28][29][30][31][32]. In addition, reduced capacity to produce IL-2 and consequential reduced antigen-specific T cell proliferation were reported [8,26], which can be restored via addition of IL-2 or via CD28 costimulation [5,33]. Cross-linking of CD4 with mAb or with HIV-1 envelope protein results in an inhibition of the CD3-mediated up-regulation of CD154 via an impairment of the normal CD3 signal transduction cascade [34,35]. This perturbation of the normal cell activation and CD154 upregulatory pat...

Impaired CD4 T Cell Memory Response to Streptococcus pneumoniae Precedes CD4 T Cell Depletion in HIV-Infected Malawian Adults

“…Several studies have shown that the induction of CD154 is decreased in HIV-1-infected individuals and it is noteworthy that chimpanzees that are susceptible to chronic infection by HIV-1 but rarely develop subsequent immunodeficiency or disease progression, retain their ability to upregulate CD154 in the context of HIV[46]. In keeping with previous reports[47], we have found that cross-linking of CD4 with a monoclonal antibody to domain 1 also leads to inhibition of CD154 upregulation in response to pneumococcal antigens (data not shown).…”

The Evolution of SIV in Primates and the Emergence of the Pathogen of AIDS

“…As with the HIV-1-infected chimpanzees, these two SIVcpz-infected chimpanzees seem to lack the profound changes to the immune system that are found in HIV-1-infected humans (Gougeon et al 1997 ;Rutjens et al 2008Rutjens et al , 2010. Given the apparent pathogenic outcome of SIVcpz infection of wild chimpanzees, it should be possible to identify, in these captive animals, disease mechanisms that are shared with HIV-1-infected humans.…”