Detection of three distinct patterns of T helper cell dysfunction in asymptomatic, human immunodeficiency virus-seropositive patients. Independence of CD4+ cell numbers and clinical staging.

Abstract

We have tested the T helper cell (TH ) potential of asymptomatic, HIV seropositive (HIV+) patients, using an in vitro assay for IL-2 production. Peripheral blood leukocytes (PBL) from 74 HIV+ patients and 70 HIV-control donors were tested for TH function when stimulated with influenza A virus (FLU), tetanus toxoid (TET), HLA alloantigens (ALLO), or PHA. Of the HIV+ patients, four different response patterns were observed: (a) patients who responded to all four stimuli (16%); (b) patients who were selectively unresponsive to FLU and TET, but responded to ALLO and PHA (54%); (c) patients who were unresponsive to FLU, TET, or ALLO, but responsive to PHA (16%); and (d) patients who failed to respond to any of these stimuli (14%). Our results indicate a time-dependent progression from a stage responsive to all four stimuli to a stage unresponsive to any of the stimuli tested, progressing in the order outlined above.The earliest TH defect is the loss of responses to FLU and TET, indicating a selective defect in CD4+ MHC self-restricted TH function. The later loss of ALLO and PHA IL-2 responses suggests more severe TH dysfunction involving both CD4+ and CD8+ T cells. None of these patterns of TH unresponsiveness in asymptomatic HIV+ individuals were correlated with CD4+ cell numbers nor with Walter Reed staging criteria. This study indicates that the in vitro TH assay used can detect multiple stages of immune dysregulation early in the course of HIV infection and raises the possibility that staging of HIV+ patients should include in vitro TH functional analyses of the type described here.

Immune dysregulation to Ethiopian immigrants in Israel: relevance to helminth infections?

“…Cytokine and cytokine receptor determination IL-2 activity in SN was assessed as the ability to stimulate the proliferation of the IL-2-dependent mouse cell line, CTLL, as described [10]. Briefly, 1 2 10 4 CTLL/well and three-fold successive dilutions of SN were cultured for 24 h, pulsed with 1 Ci of 3 H-thymidine (Rotem Industries Ltd, Nuclear Research CenterNegev, Israel) and harvested 18 h later.…”

Selective CD4+ T cell deletion after specific activation in HIV-infected individuals; protection by anti-CD28 monoclonal antibodies

“…Such a mechanism may explain the gradual progressive CD4 T cell depletion observed in HIV-infected individuals, since cells should only be deleted upon encountering their specific antigen; no cell deletion would occur without specific activation. This mechanism would also explain the progressive proliferative defect in response to recall antigens observed in asymptomatic HIV-infected individuals [1][2][3]. The fact that deletion occurs only after the encounter with activating antigens is illustrated in a study comparing the proliferative response of T cells from normal control or HIV-infected individuals with fractionated cytomegalovirus (CMV) antigen.…”

“…One of the major and specific features of the HIV infection physiopathology, detected as early as seroconversion [9] before any CD4 T cell loss, is the selective failure of CD4 T cells to proliferate in vitro in response to recall antigens [1][2][3] or to superantigens [4,7], whereas their proliferative response to polyclonal mitogens is maintained [1,2,5,6]. We and others have shown that this proliferative defect after activation of peripheral blood mononuclear cells (PBMC) from HIV-infected individuals with either superantigens [4,7] or recall antigens (G. Shearer, personal communication) correlates with specific induction of CD4 T cell death.…”

“…This is preceded by an early selective defect in the proliferation of these cells to recall antigens [1][2][3], pokeweed mitogen (PWM) [4][5][6] and to superantigens (SAg) [4,7]. In contrast, the proliferative response to phytohaemagglutinin (PHA) remains intact [1,2,5].…”

Apoptotic cell death and cytokine dysregulation in human immunodeficiency virus infection: pivotal factors in disease progression

“…The progression of HIV infection is also characterized by a complex dysregulation in the function of TH cells (Lane et al, 1985;Giorgi et al, 1987;Miedema et al, 1988;Clerici et al, 1989). At least two different types of functional defects have been observed in HIV-infected individuals.…”