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 ...

Background: CCR5-restricted (R5) human immunodeficiency virus type 1 (HIV-1) variants cause CD4+ T-cell loss in the majority of individuals who progress to AIDS, but mechanisms underlying the pathogenicity of R5 strains are poorly understood. To better understand envelope glycoprotein (Env) determinants contributing to pathogenicity of R5 viruses, we characterized 37 full-length R5 Envs from cross-sectional and longitudinal R5 viruses isolated from blood of patients with asymptomatic infection or AIDS, referred to as pre-AIDS (PA) and AIDS (A) R5 Envs, respectively.

The evolution of human immunodeficiency virus type 1 (HIV-1) coreceptor use has been described as the acquisition of CXCR4 use linked to accelerated disease progression. However, CXCR4-using virus can be isolated only from approximately one-half of individuals with progressive HIV-1 disease. The other half continue to yield only CCR5-using viruses (R5 phenotype) throughout the course of disease. In the present work, the use of receptor chimeras between CCR5 and CXCR4 allowed us to study the evolution of HIV-1 with the R5 phenotype, which was not revealed by studies of wild-type coreceptor use. All together, 246 isolates (173 with the R5 phenotype) from 31 individuals were tested for their ability to infect cells through receptor chimeras. R5 narrow virus was able to use only wild-type CCR5, whereas R5 broad(1) to R5 broad(3) viruses were able to use one to three chimeric receptors, respectively. Broad use of chimeric receptors was interpreted as an increased flexibility in the mode of receptor use. R5 broad isolates showed higher infectivity in cells expressing wild-type CCR5 than R5 narrow isolates. Also, the increased flexibility of R5 broad isolates was concomitant with a lower sensitivity to inhibition by the CC chemokine RANTES. Our results indicate a close relationship between HIV-1 phenotypic changes and the pathogenic process, since the mode and efficiency of CCR5 use as well as the decrease in the RANTES sensitivities of isolated viruses are significantly correlated with CD4؉ -T-cell decline in a patient. One possible explanation is that ligand competition at the CCR5 receptor or changed CCR5 availability may shape the outcome of HIV-1 infection.

The group B streptococcus (GBS) is the most important cause of life-threatening bacterial infections in newborn infants. Protective immunity to GBS infection is elicited by several surface proteins, one of which, the ␤ protein, is known to bind human IgA-Fc. Here, we show that the ␤ protein also binds human factor H (FH), a negative regulator of complement activation. Absorption experiments with whole human plasma demonstrated binding of FH to a GBS strain expressing ␤ protein but not to an isogenic ␤-negative mutant. This binding was due to a direct interaction between ␤ and FH, as shown by experiments with purified proteins. Inhibition tests and studies with ␤ fragments demonstrated that FH and IgA-Fc bind to separate and nonoverlapping regions in ␤. Heparin, a known ligand for FH, specifically inhibited the binding between ␤ and FH, suggesting that FH has overlapping binding sites for ␤ and heparin. Bacteria-bound FH retained its complement regulatory activity, implying that ␤-expressing GBS may use bound FH to evade complement attack. The finding that ␤ protein binds FH adds to a growing list of interactions between human pathogens and complement regulatory proteins, supporting the notion that these interactions are of general importance in bacterial pathogenesis.

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These data show that it is possible to generate new T-cell responses in treatment-naive HIV-1-infected individuals despite high viral loads, and thereby redirect immunity to target new multiple and rationally selected subdominant CTL epitopes. Further optimization could lead to stronger and more durable cellular responses to selected epitopes with the potential to control viral replication and prevent disease in HIV-1-infected individuals.

We show that one feature of spontaneous HIV-1 control is a maintained balance between regulatory T cells and TH17 cells.

Cellular immune responses make an important contribution to both the control of human immunodeficiency virus (HIV) replication and disease progression. We used a pathogenic model of SIVmac251 infection of cynomolgus macaques to longitudinally evaluate cellular immune responses in association with various rates of disease progression. We found an inverse relationship between plasma viral load and the simian immunodeficiency virus (SIV)-specific T cells responses in peripheral blood and lymph nodes. SIV-specific T-cell responses in peripheral blood were transient during primary infection, with the highest responses detected around 3 months after infection. There was also a transient increase of central memory CD8؉ T cells in peripheral blood during primary infection, and effector memory T-cell counts in peripheral lymph nodes were increased. This study emphasizes the importance of the early virus-specific immune responses in the outcome of HIV/SIV disease and provides details about the changes of virus-specific immune responses over time.