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Sep 20, 2011

Investigators Figure Out One Way to Stop HIV from Dampening Adaptive Immune Response

Investigators Figure Out One Way to Stop HIV from Dampening Adaptive Immune Response

Stripping HIV envelope of cholesterol turns virus into effective recall immunogen for stimulating CD8 T-cell responses. [4designersart - Fotolia.com]

  • Stripping HIV of the cholesterol in its envelope prevents the virus from effecting the prolonged overstimulation of early immune response mechanisms that can lead to a weakened adaptive immune response against the infection, scientists claim. In vitro studies suggest that denuding HIV of cholesterol blocks lymphoid-derived plasmacytoid dendritic cells (pDC) from triggering type I IFN (IFN-α and IFN-β) production and upregulating T-cell suppressive signals. 

    Scientists at Imperial College London, Johns Hopkins Medical School, and their colleagues have found that the inability of cholesterol-depleted HIV to stimulate pDC cells to induce IFN-α/β rendered the virus a more powerful recall immunogen for stimulating CD8 T-cell responses in cells from HIV-exposed, uninfected individuals. While removing some of the cholesterol effectively dampened the IFN-α/β response, virus particles that were stripped of cholesterol and permeabilized stimulated APC activation in the absence of IFN-α/β and immunosuppressive mechanisms.

    The researchers, led by Imperial’s Adriano Boasso, M.D., and Johns Hopkins David Graham, M.D., report their findings in Blood. The paper is titled “ Over-activation of plasmacytoid dendritic cell inhibits anti-viral T cell responses: a model for HIV immunopathogenesis.”

    Type I IFN responses are critical in the early phases of immune responses, but although IFN-α/β may act as potent inhibitors of HIV replication during the acute phase of HIV infection, research has suggested that prolonged pDC activation during the chronic phase may be harmful for the immune system, dampening anti-HIV effector T-cell responses that might otherwise efficiently eliminate the infectious agent, the authors report. The upshot of this, they suggest, includes “deleterious consequences for the immune system resulting in inhibition of T-cell proliferation and promotion of cell death.”

    Prior research has shown that removal of some of the cholesterol using the starch derivative 2-hydroxy-propyl β-cyclodextrin (βCD) destabilizes envelope organization and blocks HIV from infecting CD4+ cells in vitro. Removing just about all the cholesterol causes dissociation of the envelope’s binding microdomain, resulting in noninfectious, permeabilized virions that retain most of the gp120 but have lost the soluble mature form of the gag protein p24 and generally most of their RNA.

    The team used an HIV-based in vitro model to study the effects of quantitatively depleting cholesterol from the HIV envelope using βCD, on levels of pDC activation on APC activity and T-cell responses. Culturing peripheral blood leucocytes in the presence of HIV that had been treated with low or moderate concentrations of βCD significantly reduced the induction of IFN-α IFN-β and IDO activity. This effectively reduced the pDC-activating potential of HIV; the immunosuppressive enzyme indoleamine (2,3)-dioxygenase (IDO) is also induced in pDC on recognition of HIV antigens. This suggests that βCD may have impaired the functionality of the envelope microdomain that binds with its target cells and altered the ability of HIV to interact with pDC.

    Conversely, exposure of PBL from uninfected donors to HIV that had undergone partial cholesterol removal had very little effect on the upregulation of co-stimulatory molecules CD83, CD80, and CD86 pDC. This suggests that the effects of modulating cholesterol content on IFN-α/β production occur separately to those of APC activation.

    In fact, the researchers found even permeabilized HIV selectively stimulated CD80 on pDC, in the absence of IFN-α/β and immunosuppressive and proapoptotic mechanisms, to the same levels as that induced by unadulterated HIV. “This suggests a spectrum of pDC activation that leads first to the upregulation of co-stimulatory molecules, followed by the induction of proapoptotic and antiproliferative mechanism.” In contrast, removal of most or all cholesterol from the viral envelope prevented pDC upregulation of the T-cell suppressive molecules PDL1 and TRAIL that would normally be stimulated by HIV.

    Activation of monocytes was directly dependent on the presence of pDC, but cholesterol-denuded HIV was still capable of stimulating CD80/86 upregulation (but not the activation marker CD83) in these cells, even in the absence of IFN-α/β production. The researchers suggest this may be either because pDC-derived cytokines other than type I IFN can stimulate monocyte maturation into APCs or because cell-cell interactions between activated pDCs and monocytes result in the expression of co-stimulatory molecules by monocytes after incubation with permeabilized HIV. Similar to pDC, PDL1 and TRAIL were induced in monocytes by HIV that had undergone partial cholesterol removal but not by permeabilized HIV.

    HIV-induced IFN-α/β promotes expression of the T-cell activation markers CD38 and CD69, and their expression is associated with and predictive of HIV disease progression, the researchers note. When they examined the effects of viral envelope cholesterol removal on CCR5+ and CCR5- T cells, they found that only virions exposed to the highest levels of βCD didn’t trigger increases in CD38 and CD60; HIV that had undergone partial removal of cholesterol still triggered statistically significant increases in both CD38 and CD69.

    To test whether cholesterol-denuded HIV can serve as a recall antigen in individuals with pre-existing immunity against HIV, the researchers evaluated PBL from individuals with repeated sexual exposure to HIV without signs of infection, termed HIV-exposed seronegative (HESN) individuals. Again, HIV that had been completely stripped of cholesterol induced significantly higher frequency of IFN-γ producing CD8 T cells in HESN individuals. In contrast, no HIV-specific responses were observed for CD4 T cells, and there was no increase in IFN-γ-producing CD8 T cells observed in uninfected and unexposed healthy controls.

    “The negative effect of HIV-induced IFN-α/β on HIV-specific CD8 T-cell responses is consistent with the increasing body of evidence suggesting an immunomodulatory role for type I IFN on T cell-mediated immune responses,” the authors conclude.

    “Thus, the immunostimulatory effect of IFN-α/β may be associated with the simultaneous triggering of immunoregulatory mechanisms mediated by different interferon-stimulated genes (ISGs). The ability of HIV to suppress memory T cell responses via pDC activation is an example of hijacking a pathway classically associated with protective innate immunity and represents an important hurdle for HIV vaccine-induced T cell responses.”


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