Type I Interferon at the Interface of Antiviral Immunity and Immune Regulation: The Curious Case of HIV-1.

Type I interferon (IFN-I) play a critical role in the innate immune response against viral infections. They actively participate in antiviral immunity by inducing molecular mechanisms of viral restriction and by limiting the spread of the infection, but they also orchestrate the initial phases of the adaptive immune response and influence the quality of T cell immunity. During infection with the human immunodeficiency virus type 1 (HIV-1), the production of and response to IFN-I may be severely altered by the lymphotropic nature of the virus. In this review I consider the different aspects of virus sensing, IFN-I production, signalling, and effects on target cells, with a particular focus on the alterations observed following HIV-1 infection

Alloantigen-based AIDS vaccine: revisiting a "rightfully" discarded promising strategy.

This report revisits the accidental discovery that protection against simian immunodeficiency virus (SIV) infection in the early successful experimental AIDS vaccine studies in Rhesus macaques was due to antibodies directed against human leukocyte antigens (HLAs). The inactivated virus vaccine approach was discarded because protection was due to the hosts immune reaction against the HLA acquired by SIV from the human cell lines in which it was grown, rather than against antigenic determinants of SIV itself. Subsequent studies have revealed that immune recognition of HLA on uninfected leukocytes also induces other factors that inhibit infection by both SIV and the human immunodeficiency virus. Pro and con aspects of immunization against HLA as a potential AIDS vaccine strategy are discussed. © 2011 Faculty of 1000 Ltd

Effect of Immunoglobin-Like Transcript 7 Cross-Linking on Plasmacytoid Dendritic Cells Differentiation into Antigen-Presenting Cells

Plasmacytoid dendritic cells (pDC) are innate immunity effector cells which play a critical role in the transition from innate to adaptive immune response. Circulating blood pDC present an immature phenotype and can differentiate into either antigen-presenting cells (APC) or type I interferon (IFN-I)-producing cells (IPC). The immunoglobulin-like transcript (ILT)7 is a surface receptor expressed by immature pDC, and ILT7 cross-linking (XL-ILT7) inhibits IFN-I production by pDC in response to toll-like receptor (TLR)7 and 9 stimulation. We used peripheral blood mononuclear cells (PBMC) from healthy donors to test the effect of XL-ILT7 on 1) TLR7/9-mediated regulation of gut mucosal (α4β7 integrin) and lymph node (CCR7) migration markers; and 2) the maturation of pDC into APC. We found that XL-ILT7 mitigated the upregulation of CCR7 and enhanced that of β7 on TLR7/9-stimulated pDC. TLR7/9 stimulation induced upregulation of CD40, CD80 and CD86. CD40 expression was partially reduced by XL-ILT7, whereas CD86 was further enhanced. Plasmacytoid DC stimulated with TLR9 ligand in presence of XL-ILT7 retained the ability to induce T cell proliferation and activation in response to staphylococcal enterotoxin B (SEB) in pDC-T cell co-cultures. Our results suggest that XL-ILT7 favours the differentiation of immature pDC into APC rather than IPC

HIV-Induced Type I Interferon and Tryptophan Catabolism Drive T Cell Dysfunction Despite Phenotypic Activation

Infection by the human immunodeficiency virus (HIV) is characterized by functional impairment and chronic activation of T lymphocytes, the causes of which are largely unexplained. We cultured peripheral blood mononuclear cells (PBMC) from HIV-uninfected donors in the presence or absence of HIV. HIV exposure increased expression of the activation markers CD69 and CD38 on CD4 and CD8 T cells. IFN-α/β, produced by HIV-activated plasmacytoid dendritic cells (pDC), was necessary and sufficient for CD69 and CD38 upregulation, as the HIV-induced effect was inhibited by blockade of IFN-α/β receptor and mimicked by recombinant IFN-α/β. T cells from HIV-exposed PBMC showed reduced proliferation after T cell receptor stimulation, partially prevented by 1-methyl tryptophan, a competitive inhibitor of the immunesuppressive enzyme indoleamine (2,3)-dioxygenase (IDO), expressed by HIV-activated pDC. HIV-induced IDO inhibited CD4 T cell proliferation by cell cycle arrest in G1/S, and prevented CD8 T cell from entering the cell cycle by downmodulating the costimulatory receptor CD28. Finally, the expression of CHOP, a marker of the stress response activated by IDO, was upregulated by HIV in T cells in vitro and is increased in T cells from HIV-infected patients. Our data provide an in vitro model for HIV-induced T cell dysregulation and support the hypothesis that activation of pDC concomitantly contribute to phenotypic T cell activation and inhibition of T cell proliferative capacity during HIV infection

The Role of Indoleamine 2,3-Dioxygenase in LP-BPM5 Murine Retroviral Disease Progression

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

Enrichment of HLA types and single-nucleotide polymorphism associated with non-progression in a strictly defined cohort of HIV-1 controllers

HIV-1 controllers (HIC) are extremely rare patients with the ability to control viral replication, maintain unchanging CD4 T-cell count, and evade disease progression for extensive periods of time, in the absence of antiretroviral therapy. In order to establish the representation of key genetic correlates of atypical disease progression within a cohort of HIV-1+ individuals who control viral replication, we examine four-digit resolution HLA type and single-nucleotide polymorphisms (SNP) previously identified to be correlated to non-progressive infection, in strictly defined HIC. Clinical histories were examined to identify patients exhibiting HIC status. Genomic DNA was extracted, and high definition HLA typing and genome-wide SNP analysis was performed. Data were compared with frequencies of SNP in European long-term non-progressors (LTNP) and primary infection cohorts. HLA-B alleles associated with atypical disease progression were at very high frequencies in the group of five HIC studied. All four HIC of European ancestry were HLA-B*57+ and half were also HLA-B*27+. All HIC, including one of self-reported African ethnicity, had the HLA-Cw*0602 allele, and the HLA-DQ9 allele was present only in HIC of European ancestry. A median 95% of the top 19 SNP known to be associated with LTNP status was observed in European HIC (range 78–100%); 17/19 of the SNP considered mapped to chromosome 6 in the HLA region, whereas 2/19 mapped to chromosome 8. The HIC investigated here demonstrated high enrichment of HLA types and SNP previously associated with long-term non-progression. These findings suggest that the extreme non-progressive phenotype considered here is associated with a genetic signature characterized by a single-genetic unit centered around the HLA-B*57 haplotype and the possible additive effect of HLA-B*27

Blocking TLR7- and TLR9-mediated IFN-α Production by Plasmacytoid Dendritic Cells Does Not Diminish Immune Activation in Early SIV Infection

Persistent production of type I interferon (IFN) by activated plasmacytoid dendritic cells (pDC) is a leading model to explain chronic immune activation in human immunodeficiency virus (HIV) infection but direct evidence for this is lacking. We used a dual antagonist of Toll-like receptor (TLR) 7 and TLR9 to selectively inhibit responses of pDC but not other mononuclear phagocytes to viral RNA prior to and for 8 weeks following pathogenic simian immunodeficiency virus (SIV) infection of rhesus macaques. We show that pDC are major but not exclusive producers of IFN-α that rapidly become unresponsive to virus stimulation following SIV infection, whereas myeloid DC gain the capacity to produce IFN-α, albeit at low levels. pDC mediate a marked but transient IFN-α response in lymph nodes during the acute phase that is blocked by administration of TLR7 and TLR9 antagonist without impacting pDC recruitment. TLR7 and TLR9 blockade did not impact virus load or the acute IFN-α response in plasma and had minimal effect on expression of IFN-stimulated genes in both blood and lymph node. TLR7 and TLR9 blockade did not prevent activation of memory CD4+ and CD8+ T cells in blood or lymph node but led to significant increases in proliferation of both subsets in blood following SIV infection. Our findings reveal that virus-mediated activation of pDC through TLR7 and TLR9 contributes to substantial but transient IFN-α production following pathogenic SIV infection. However, the data indicate that pDC activation and IFN-α production are unlikely to be major factors in driving immune activation in early infection. Based on these findings therapeutic strategies aimed at blocking pDC function and IFN-α production may not reduce HIV-associated immunopathology. © 2013 Kader et al