Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that induces in humans a disease characterized by fever, rash, and pain in muscles and joints. The recent emergence or reemergence of CHIKV in the Indian Ocean Islands and India has stressed the need to better understand the pathogenesis of this disease. Previous CHIKV disease models have used young or immunodeficient mice, but these do not recapitulate human disease patterns and are unsuitable for testing immune-based therapies. Herein, we describe what we believe to be a new model for CHIKV infection in adult, immunocompetent cynomolgus macaques. CHIKV infection in these animals recapitulated the viral, clinical, and pathological features observed in human disease. In the macaques, long-term CHIKV infection was observed in joints, muscles, lymphoid organs, and liver, which could explain the long-lasting CHIKV disease symptoms observed in humans. In addition, the study identified macrophages as the main cellular reservoirs during the late stages of CHIKV infection in vivo. This model of CHIKV physiopathology should allow the development of new therapeutic and/or prophylactic strategies.

Plasmacytoid dendritic cells (pDCs) are antigen-presenting cells that develop into type-I interferon (IFN-I IntroductionPlasmacytoid dendritic cells (pDCs) are major type I interferon (IFN-I) producing cells in response to viral infections 1 as a result of selective expression of Toll-like receptors 7 and 9 and constitutive expression of interferon response factor 7. They migrate to inflamed lymph nodes (LN) through high endothelium venules during viral and bacterial infections 2,3 and provide an important link between innate and adaptive immunity, enhancing natural killer (NK) cell activity and adaptive immune responses.Blood pDC counts and pDC-dependent IFN-I production levels in vitro decrease in patients infected with human immunodeficiency virus (HIV). [4][5][6][7][8] These decreases are generally correlated with a fall in CD4 ϩ T-cell counts, inversely correlated with plasma viral load, and are associated with opportunistic infections. 5,6,[9][10][11][12] The reduction in circulating pDC numbers during HIV infection may be related to their direct infection, 6,9,13 or to redistribution to lymphoid organs, as suggested in the chronic asymptomatic stage of HIV infection. 14 In nonhuman primate models of HIV infection, the IFN-I innate response is an early immunologic event. [15][16][17] Rhesus macaque (Macaca mulatta) pDCs are activated and produce IFN-I in vitro in response to pathogenic simian immunodeficiency virus (SIV) 18,19 like their human counterparts in response to HIV. 20,21 Strong depletion of pDCs from blood and lymphoid tissues are reported in the end stage of SIV infection 19,22 and attributed to infection and to higher levels of apoptosis.However, although the HIV/SIV interplay with the host immune response during primary infection is a key event, probably determining the later progression to disease, little is known about the role of pDCs in immune regulation at this early stage.We predicted that HIV/SIV infection may have an impact on the dynamics of circulating and LN dendritic cells (DCs) and on their functions in the first few days of infection 23,24 and that it may induce immune suppression through IFN-I production and indoleamine-2,3-dioxygenase (IDO) activity. IDO is the ratelimiting enzyme responsible for the extrahepatic catabolism of the essential amino acid tryptophan (Trp) and is triggered by type I and type II interferons. [25][26][27] Abnormal production/activation of IDO is associated with inefficient immunologic responses to infections, including HIV/SIV and cancer 26,[28][29][30] and is induced by HIV in human pDCs in vitro. 20,21 Growing evidence suggests that pDCs are involved in the induction of tolerance through IDO-dependent mechanisms. 31 This suggests that pDCs may target immune suppression during the acute phase of HIV/SIV infection.We focused on the dynamics of pDCs during primary infection by carrying out fine time-resolution sampling of blood, and a longitudinal analysis of peripheral lymph nodes, using absolute quantification, to investigate the possible homing of ...

BackgroundPrimary HIV-infected patients display severe and irreversible damage to different blood B-cell subsets which is not restored by highly efficient anti-retroviral therapy (HAART). Because longitudinal investigations of primary HIV-infection is limited by the availability of lymphoid organs, we studied the tissue-specific B-cell dysfunctions in acutely simian immunodeficiency virus (SIV) mac251-infected Cynomolgus macaques.Methods and FindingsExperiments were performed on three groups of macaques infected for 14, 21 or 28 days and on three groups of animals treated with HAART for two-weeks either initiated at 4 h, 7 or 14 days post-infection (p.i.). We have simultaneously compared changes in B-cell phenotypes and functions and tissue organization of B-cell areas in various lymphoid organs. We showed that SIV induced a steady decline in SIgG-expressing memory (SIgD−CD27+) B-cells in spleen and lymph nodes during the first 4 weeks of infection, concomitant to selective homing/sequestration of B-cells to the small intestine and spleen. SIV non-specific Ig production was transiently increased before D14p.i., whereas SIV-specific Ig production was only detectable after D14p.i., coinciding with the presence of CD8+ T-cells and IgG-expressing plasma cells within germinal centres. Transient B-cell apoptosis on D14p.i. and commitment to terminal differentiation contributed to memory B-cell loss. HAART abrogated B-cell apoptosis, homing to the small intestine and SIV-specific Ig production but had minimal effect on early Ig production, increased B-cell proportions in spleen and loss of memory B-cells. Therefore, virus–B-cell interactions and SIV-induced inflammatory cytokines may differently contribute to early B-cell dysfunction and impaired SIV/HIV-specific antibody response.ConclusionsThese data establish tissue-specific impairments in B-cell trafficking and functions and a generalized and steady memory B-cell loss in secondary lymphoid organs. Characterization of underlying mechanisms would be helpful in designing new therapeutic strategies to dampen B-cell activation and increases HIV/SIV specific antibody response.