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 sAC 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.