Chronic HIV-1 infection is characterized by immune cell dysfunctions driven by chronic immune activation. Plasma HIV-1 viral load (VL) is closely correlated with disease progression and the level of immune activation. However, the mechanism by which the persistent presence of HIV-1 damages immune cells is still not fully understood. To evaluate how HIV-1 affects disruption of T cell-mediated immune responses during chronic HIV-1 infection we determined the functional profiles of T cells from subjects with chronic HIV-1 infection. We measured the capacity of peripheral blood mononuclear cells (PBMCs) to produce 25 specific cytokines in response to nonspecific T cell stimulation, and found that the capacity to produce Th-1-related cytokines (MIP-1α, MIP-1β, RANTES, IFN-γ, and MIG), sIL-2R, and IL-17, but not Th-2-related cytokines, was inversely correlated with plasma VL. The capacities to produce these cytokines were interrelated; notably, IL-17 production had a strong direct correlation with production of MIP-1α, MIP-1β, RANTES, and IFN-γ. In both CD4(+) and CD8(+) T cells, dysfunctional production of cytokines was associated with T cell activation (CD38 expression) and exhaustion (PD-1 and/or CTLA-4 expression) status of memory subsets. Although the capacity to produce these cytokines was recovered soon after multiple log(10) reduction of plasma viral levels by antiretroviral therapy, memory CD8(+) T cells remained activated and exhausted after prolonged virus suppression. Our data suggest that HIV-1 levels directly affect the ability of memory T cells to produce specifically Th1- and Th17-related cytokines during chronic HIV-1 infection.

Summary:We transplanted 4.1 ؋ 10 7 unrelated umbilical cord blood cells into a 27-year-old patient suffering from transformed acute myelocytic leukemia. The thawing method was the same as described by Rubinstein et al (Proc Natl Acad Sci USA 1995; 92: 10119-10122). ANC reached over 500 ؋ 10 9 /l on day 19, and the patient was free from RBC and platelet transfusion on days 26 and 38, respectively. Cytogenetic and molecular analysis after transplant revealed complete chimerism. The CD3 + CD4 + lymphocyte count became greater than 100 ؋ 10 9 /l at 5 weeks after transplantation. The CD3 + CD8 + count became greater than 500 ؋ 10 9 /l at 7 weeks and thereafter progressively increased in spite of administration of CYA. This immunological reconstitution pattern after umbilical cord blood transplantation was different from that after bone marrow transplantation, and resistance of CD3 + CD8 + lymphocytes to CYA was the distinguishing characteristic. The rapid hematological recovery and immunological reconstitution may be attributed to the high dose of transfused nucleated cells and umbilical cord blood transplantation may become a promising method for treatment for such cases.