Preclinical Evaluation of HIV Eradication Strategies in the Simian Immunodeficiency Virus-Infected Rhesus Macaque: A Pilot Study Testing Inhibition of Indoleamine 2,3-Dioxygenase
1 Department of Medicine, University of California , San Francisco, California. AIDS research and human retroviruses
(Impact Factor: 2.33).
08/2012; 29(2). DOI: 10.1089/AID.2012.0162
Abstract Even in the setting of maximally suppressive antiretroviral therapy (ART), HIV persists indefinitely. Several mechanisms might contribute to this persistence, including chronic inflammation and immune dysfunction. In this study, we have explored a preclinical model for the evaluation of potential interventions that might serve to eradicate or to minimize the level of persistent virus. Given data that metabolic products of the inducible enzyme indoleamine 2,3-dioxygeanse (IDO) might foster inflammation and viral persistence, chronically simian immunodeficiency virus (SIV)-infected, ART-treated rhesus macaques were treated with the IDO inhibitor 1-methyl tryptophan (1mT). Orally administered 1mT achieved targeted plasma levels, but did not impact tryptophan metabolism or decrease viral RNA or DNA in plasma or in intestinal tissues beyond levels achieved by ART alone. Animals treated with 1mT showed no difference in the levels of T cell activation or differentiation, or in the kinetics or magnitude of viral rebound following cessation of ART. Notwithstanding these negative results, our observations suggest that the chronically SIV-infected rhesus macaque on suppressive ART can serve as a tractable model in which to test and to prioritize the selection of other potential interventions designed to eradicate HIV in vivo. In addition, this model might be used to optimize the route and dose by which such interventions are administered and the methods by which their effects are monitored.
Available from: Megan O'Connor
- "Likewise, ART-treated macaques also given 1MT therapy demonstrated transiently increased plasma levels of tryptophan, but no reduction in kynurenine . In a seemingly similar study, different results were obtained: SIV-infected ART-treated macaques also given 1MT demonstrated no effect on tryptophan catabolism or on viral load . Clearly, more work still needs to be done to fully understand the potential use of 1MT or other agents that target IDO, or the pathways involving IDO, before its potential to treat HIV/AIDS patients can be determined. "
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Indoleamine 2,3-dioxygenase (IDO) is an immunomodulatory intracellular enzyme involved in tryptophan degradation. IDO is induced during cancer and microbial infections by cytokines, ligation of co-stimulatory molecules and/or activation of pattern recognition receptors, ultimately leading to modulation of the immune response. LP-BM5 murine retroviral infection induces murine AIDS (MAIDS), which is characterized by profound and broad immunosuppression of T- and B-cell responses. Our lab has previously described multiple mechanisms regulating the development of immunodeficiency of LP-BM5-induced disease, including Programmed Death 1 (PD-1), IL-10, and T-regulatory (Treg) cells. Immunosuppressive roles of IDO have been demonstrated in other retroviral models, suggesting a possible role for IDO during LP-BM5-induced retroviral disease progression and/or development of viral load.
Mice deficient in IDO (B6.IDO−/−) and wildtype C57BL/6 (B6) mice were infected with LP-BM5 murine retrovirus. MAIDS and LP-BM5 viral load were assessed at termination.
As expected, IDO was un-inducible in B6.IDO−/− during LP-BM5 infection. B6.IDO−/− mice infected with LP-BM5 retrovirus succumbed to MAIDS as indicated by splenomegaly, serum hyper IgG2a and IgM, decreased responsiveness to B- and T-cell mitogens, conversion of a proportion of CD4+ T cells from Thy1.2+ to Thy1.2-, and increased percentages of CD11b+Gr-1+ cells. LP-BM5 infected B6.IDO−/− mice also demonstrated the development of roughly equivalent disease kinetics as compared to infected B6 mice. Splenic viral loads of B6 and B6.IDO−/− mice were also equivalent after infection as measured by LP-BM5-specific Def Gag and Eco Gag viral mRNA, determined by qRT-PCR.
Collectively, these results demonstrate IDO neither plays an essential role, nor is required, in LP-BM5-induced disease progression or LP-BM5 viral load.
Virology Journal 05/2013; 10(1):154. DOI:10.1186/1743-422X-10-154 · 2.18 Impact Factor
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ABSTRACT: Purpose of review:
Animal models will be critical for preclinical evaluations of novel HIV eradication and/or functional cure strategies in the setting of suppressive combination antiretroviral therapy (cART). Here, the strengths, limitations, and challenges of recent efforts to develop nonhuman primate (NHP) models of cART-mediated suppression for use in studies of persistent virus and curative approaches are discussed.
Several combinations of NHP species and viruses that recapitulate key aspects of human HIV infection have been adapted for cART-mediated suppression studies. Different cART regimens incorporating drugs targeting multiple different steps of the viral replication cycle have provided varying levels of virologic suppression, dependent in part upon the host species, virus, drug regimen and timing, and virologic monitoring assay sensitivity. New, increasingly sensitive virologic monitoring approaches for measurements of plasma viral RNA, cell-associated and tissue-associated viral RNA and DNA, and the replication-competent residual viral pool in the setting of cART in NHP models are being developed to allow for the assessment of persistent virus on cART and to evaluate the impact of viral induction/eradication strategies in vivo.
Given the vagaries of each specific virus and host species, and cART regimen, each model will require further development and analysis to determine their appropriate application for addressing specific experimental questions.
Current opinion in HIV and AIDS 05/2013; 8(4). DOI:10.1097/COH.0b013e328361cf40 · 4.68 Impact Factor
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ABSTRACT: Dendritic cells (DCs) are a diverse subset of innate immune cells that are key regulators of the host response to human immunodeficiency virus-1 (HIV-1) infection. HIV-1 directly and indirectly modulates DC function to hinder the formation of effective antiviral immunity and fuel immune activation. This review focuses upon the differential dysregulation of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) at various stages of HIV-1 infection providing insights into pathogenesis. HIV-1 evades innate immune sensing by mDCs resulting in suboptimal maturation, lending to poor generation of antiviral adaptive responses and contributing to T-regulatory cell (Treg) development. Dependent upon the stage of HIV-1 infection, mDC function is altered in response to Toll-like receptor ligands, which further hinders adaptive immunity and limits feasibility of therapeutic vaccine strategies. pDC interactions with HIV-1 are pleotropic, modulating immune responses on an axis between immunostimulatory and immunosuppressive. pDCs promote immune activation through an altered phenotype of persistent type I interferon secretion and weak antigen presentation capacity. Conversely, HIV-1 stimulates secretion of indolemine 2,3 dioxygenase (IDO) by pDCs resulting in Treg induction. An improved understanding of the roles and underlying mechanisms of DC dysfunction will be valuable to the development of therapeutics to enhance HIV-specific adaptive responses and to dampen immune activation.
Immunological Reviews 07/2013; 254(1):170-89. DOI:10.1111/imr.12082 · 10.12 Impact Factor
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