Functional dichotomy of CD4⁺ T helper lymphocytes in asymptomatic human immunodeficiency virus infection

The majority of asymptomatic, human immune deficiency virus seropositive (HIV⁺) individuals exhibit a defect in CD4⁺ T helper cell (T_h) function that is selective for responses to recall antigens, but not to HLA alloantigens. The CD4-dependent T_h response to HLA alloantigens (Allo) can be mediated by two distinct T_h pathways: self-restricted CD4⁺ T_h that recognize allogeneic determinants processed and presented by autologous or self accessory or antigen-presenting cells (sAC); and allo-restricted, CD4⁺ T_h that recognize allogeneic determinants directly on allogeneic accessory or antigen-presenting cells (aAC). In contrast, the T_h response to recall antigens requires CD4⁺ T_h and s AC and is therefore limited to the major histocompatibility complex (MHC) self-restricted pathway. Peripheral blood leukocytes from 56 asymptomatic HIV⁺ patients that exhibited a selective defect in CD4⁺ T_h function were analyzed to determine whether the T_h response to Allo was entirely functional, or whether one of the CD4-mediated components of the Allo T_h response was also defective. By depletion of AC and/or CD8⁺ T_h subsets (to analyze CD4⁺ T_h function), we demonstrated that HIV⁺ patients who were selectively deficient in T_h function to recall antigens were also unresponsive to Allo presented by autologous AC (HLA self-restricted T_h pathway), but retained Allo T_h activity presented by allogeneic AC (allo-restricted CD4⁺ T_h pathway).These findings indicate that the CD4⁺ T_h defect seen in the majority of asymptomatic, HIV⁺ individuals is not limited to recall antigens, but also extends to the component of the response to HLA alloantigens that involves the self-restricted, CD4⁺ T_h pathway. Thus, the T_h defect observed in asymptomatic, HIV⁺ patients does not involve a CD4⁺ T_h defect per se, but is limited to the HLA self-restricted component of T_h function.