MODULATION OF HIV-MEDIATED IMMUNE ACTIVATION, AICD, AND EFFECT OF ANTIRETROVIRAL THERAPY
Interventions that directly target T cell activation or the determinants of activation are being investigated as adjuvants to antiretroviral therapy. In an interesting in vivo study,94 Rizzardi et al.
gave the immune-modulating drug cyclosporin A (CsA) in combination with highly active antiretroviral therapy (HAART) to nine adults during primary HIV-1 infection. The CsA was discontinued at week 8, and patients were maintained on HAART alone. Although this was not a controlled trial, the results were impressive. CsA restored normal CD4 T cell levels, and at week 48, the proportion of IFN-γ secreting CD4 T cells was significantly higher in the CsA + HAART cohort than in the HAART-alone cohort. Thus, the early shutdown of T cell activation in primary HIV infection seemed to have a beneficial effect. It had a more favorable immunologic set point than that in the absence of CsA intervention. This concept is currently undergoing investigation in a larger controlled multicenter study.Another strategy was tested in the acute SIV infection of rhesus macaques.95 In vivo blockade of CD28 and CD40 T cell co-stimulation pathways during acute infection by the transient administration of CTLA4-Ig and anti-CD40L mAb resulted in dramatic inhibition of SIV-specific cellular and humoral immune responses, implying that proliferating CD4+ T cells function both as sources of virus production and as antiviral effectors. Thus, further studies are needed to determine the best approach to reducing immune activation without impairing the antigen-specific prospective immune response. It is of the authors’ opinion that approaches that can manipulate DC to induce T regs to keep the immune activation under control need to be researched.
Modulation of AICD presents itself as a potential strategy to slow the progressive loss of T cells in HIV-infected subjects.
Because apoptosis is regulated at a variety of different levels, there are many targets that offer themselves as attractive candidates, and insights into possible approaches are evolving. Cytokines, in particular IL-2 and IL-15, can influence apoptosis.96 Although IL-2 can both protect and augment apoptosis depending on the state of activation of target cells, IL-15 is characteristically antiapoptotic. Exogenous addition of IL-2 can partially prevent Bcl-2 downregulation,97,98 and IL-15 is able to induce expression of both Bcl-2 and Bcl-xL in HIV-specific CD8 T cells.93,99 The chemoattractant cytokine IL-16, which is a ligand for CD4, was reported to suppress lymphocyte activation100 and was found to significantly reduce the percentage of lymphocytes undergoing AICD, and it also caused a decrease in Fas expression in CD4 T cells from HIV-infected patients.101Antiretroviral therapy (ART) of HIV-infected patients also results in a decrease in immune activation and in apoptosis, but these remain elevated in comparison to uninfected controls.102-105 The decrease in apoptosis in response to ART has been attributed to a decrease in viremia, to a decrease in immune activation, and also to the effects of the treatment drugs. Institution of ART significantly reduces the proportion of low Bcl-2-expressing lymphocytes in patients’ peripheral blood.97 Treatment of uninfected lymphocytes with the HIV protease inhibitor Ritonavir leads to decreases in FasL expression, suggesting that these drugs may function to directly and indirectly influence the Fas/FasL pathway in patients.104 A cysteine protease inhibitor was also shown to inhibit FasL expression in PBLs from HIV-infected persons.106 Incubation of PBMCs from HIV- infected individuals with all-trans retinoic acid in vitro results in decreased AICD,107 presumably via downmodulation of FasL.108 Chemokines also exert an antiapoptoic effect on lymphocytes in vitro.109