HIV infection is characterized by a host response composed of adaptive and innate immunity that partially limits viral replication; however, it ultimately fails in eradicating the virus. To model host gene expression during acute HIV infection, we infected cynomolgus macaques with the SIV/HIV-1 chimeric virus, SHIV89.6P, and profiled gene expression in peripheral blood over a 5-wk period using a high density cDNA microarray. We demonstrate that viral challenge induced a widespread suppression of genes regulating innate immunity, including the LPS receptors, CD14 and TLR4. An overexpression of 16 IFN-stimulated genes was also observed in response to infection; however, it did not correlate with control over viral titers. A statistical analysis of the dataset identified 10 genes regulating apoptosis with differential expression during the first 2 wk of infection (p < 0.004). Quantitative real-time PCR verified transcriptional increases in IFN-␣-inducible genes and decreases in genes regulating innate immunity. Therefore, the persistence of high viral loads despite an extensive IFN response suggests that HIV can resist in vivo IFN treatment despite published reports of in vitro efficacy. The transcriptional suppression of genes regulating innate immunity may allow HIV to evade acute host responses and establish a chronic infection and may reduce innate host defense against opportunistic infections.

We determined the role of cytokines in regulating the pattern of rejection and recipient susceptibility to cyclosporine (CsA) in a mouse cardiac allograft model. Hearts from C3H mice transplanted into untreated BALB/c (Th2-dominant) and C57BL/6 (Th1-dominant) mice showed different patterns of rejection. C3H allografts in BALB/c mice showed typical acute vascular rejection (AVR) with strong intragraft deposition and high serum levels of anti-donor IgG with predominant IgG1, while C3H allografts in C57BL/6 mice showed typical acute cellular rejection (ACR) with massive intragraft infiltration of CD4+ and CD8+ lymphocytes and low serum levels of anti-donor IgG with predominant IgG2a. Elevated intragraft mRNA expression of IL-2, IFN-γ, and IL-12 mRNA was present in C57BL/6 recipients, whereas allografts in BALB/c mice displayed increased IL-4 and IL-10 mRNA levels. CsA therapy completely inhibited ACR and induced indefinite allograft survival in C57BL/6 recipients, while the same therapy failed to prevent AVR, and only marginally prolonged graft survival in BALB/c recipients. In contrast, rapamycin blocked AVR, achieving indefinite survival in BALB/c recipients, but was less effective at preventing ACR in C57BL/6 recipients. The disruption of the IL-12 or IFN-γ genes in C57BL/6 mice shifted ACR to AVR, and resulted in concomitant recipient resistance to CsA therapy. Conversely, disruption of IL-4 gene in BALB/c mice markedly attenuated AVR and significantly prolonged allograft survival. These data suggest that the distinct cytokine profiles expressed by different mouse strains play an essential role in regulating the pattern of rejection and outcome of CsA/rapamycin therapy.

The necessity for pathogen recognition of viral infection by the innate immune system in initiating early innate and adaptive host defenses is well documented. However, little is known about the role these receptors play in the maintenance of adaptive immune responses and their contribution to resolution of persistent viral infections. In this study, we demonstrate a nonredundant functional requirement for both nucleic acid-sensing TLRs and RIG-I–like receptors in the control of a mouse model of chronic viral infection. Whereas the RIG-I–like receptor pathway was important for production of type I IFNs and optimal CD8+ T cell responses, nucleic acid-sensing TLRs were largely dispensable. In contrast, optimal anti-viral Ab responses required intact signaling through nucleic acid-sensing TLRs, and the absence of this pathway correlated with less virus-specific Ab and deficient long-term virus control of a chronic infection. Surprisingly, absence of the TLR pathway had only modest effects on Ab production in an acute infection with a closely related virus strain, suggesting that persistent TLR stimulation may be necessary for optimal Ab responses in a chronic infection. These results indicate that innate virus recognition pathways may play critical roles in the outcome of chronic viral infections through distinct mechanisms.

OX40 and 4-1BB are members of the tumor necrosis factor (TNF) family of costimulatory receptors whose signaling is important for differential immune responses mediated by CD4 ؉ or CD8 ؉ T cells. Although activated T cells may acquire OX40/4-1BB double-positive phenotype and signaling from each receptor is expected to influence cell functions, the relevance between OX40 and 4-1BB has never been investigated before. While we were investigating the expression of OX40 and 4-1BB on activated human T cells, we found that they colocalize. The study of receptor gene-transfected cells showed that both receptors coendocytose and the complex of OX40 and 4-1BB was detected by specific ligands or antibodies (Abs). The heterodimer of OX40 and 4-1BB was identified by sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE) under nonreduced conditions and was associated with the tumor receptorassociated factor (TRAF) family proteins in a unique manner. Furthermore, the stimulation of OX40/4-1BB rendered cells IntroductionCostimulatory receptor signaling is a necessary element for antigenspecific T-cell immune response by regulating proliferation, differentiation, and apoptosis. [1][2][3] Studies demonstrated that the repertoire of costimulatory receptors on T cells increases following the primary activation via antigen-specific receptor and CD28 costimulatory receptor. 1-3 OX40 (CD134) and 4-1BB (CD137) belong to the tumor necrosis factor (TNF) receptor (TNFR) family and represent T-cell costimulatory receptors expressed on cell activation. [1][2][3] In several immunologic conditions such as viral infection, contact hypersensitivity, and protein-antigenic challenge, the signal resulting from the ligation of OX40 with OX40 ligand (OX40L) expressed on antigen-presenting cells (APCs) facilitates the generation of CD4 ϩ memory T cells. [4][5][6][7] The OX40/OX40L signal also regulates Th1 and Th2 responses in vivo in various Th1-specific or Th2-specific disease models. [7][8][9][10][11][12][13][14][15] The 4-1BB/4-1BBL-mediated signaling has been shown to play a role in T-cell proliferation, activation-induced cell death prevention, promotion of the rejection of cardiac and skin allografts, eradication of established tumors, enhancement of integrin-mediated cell adherence, and increase of T-cell cytolytic potential. [16][17][18] In support with the accumulating evidence indicating that OX40 signal and 4-1BB signal play different roles in T-cell immune response, it has been demonstrated that the intracellular signaling mechanism of OX40 differs from 4-1BB signaling. 19 Consequently, T cells expressing both OX40 and 4-1BB would be influenced by the interplay of concomitant signals on cognate interaction with OX40L ϩ 4-1BBL ϩ APCs. It is, however, virtually unknown how such redundancy of TNFR family costimulatory receptors regulates antigen-induced T-cell responses.We have investigated T cells simultaneously expressing OX40 and 4-1BB to understand how a concomitant expression of different costimulatory receptors modulates ...