• Antimicrobial CD8 ϩ MAIT cells are activated, exhausted, and progressively and persistently depleted during chronic HIV-1 infection.• This decline in MAIT cell level and function may seriously impair the ability to mount immune responses to bacterial and fungal pathogens. IntroductionHIV-1 infection is associated with a range of pathologic changes to the immune system, including systemic immune activation, CD4 T-cell loss and CD8 T-cell expansion. The state of broad and persistent immune activation develops early during infection, 1,2 contributes to the rapid aging of the immune system seen during chronic progressive HIV-1 disease, and persists despite effective long-term virologic suppression by combination antiretroviral therapy (cART; reviewed in by Deeks, 3 Appay et al, 4 and Desai and Landay 5 ). These pathologic processes lead to the progressive destruction of lymphoid organs and loss of CD4 helper T cells. 6,7 Already during primary infection, HIV-1 depletes intestinal CD4 T cells and disrupts the structure and function of the intestinal immune system. [8][9][10][11][12][13] One consequence of this is increased permeability of the intestinal epithelium with translocation of microbial products into the local tissue, the portal circulation, the liver and eventually into systemic circulation. 14 This process may continue despite effective long-term cART. 15,16 Disruption of immune homeostasis and barrier function at the mucosa is a considerable challenge for the host immune system because the microbial proteins, carbohydrates, and lipids form a range of antigens that will engage innate as well as adaptive immune mechanisms (reviewed by Brenchley and Douek 17 ). Despite considerable advances in the treatment and management of HIV-1 disease, certain infections still present a significant clinical challenge particularly among HIV-infected individuals who are diagnosed at advanced stages, those who lack access to antiretroviral therapy, and those who cannot maintain adherence to therapy and clinical care. [18][19][20] This includes an increased risk of developing bacterial pneumonia even in HIV-1-infected patients with relatively normal CD4 counts, 21 indicating that impaired CD4 T-cell independent control of certain infections still exists even in the context of treated HIV-1 disease. Mucosal-associated invariant T (MAIT) cells are a relatively recently discovered subset of unconventional, innate-like T cells that are highly abundant in mucosal tissues, liver, and peripheral blood. [22][23][24][25] Human MAIT cells express an invariant T-cell receptor (TCR) carrying the V␣7.2 ␣-chain segment, a restricted V␤ repertoire (V␤2 or V␤13), and recognize antigens in complex with the evolutionarily conserved MHC-Ib-related protein (MR1). 24,25 In addition to the V␣7.2 TCR segment, MAIT cells are defined by Submitted July 27, 2012; accepted November 26, 2012. Prepublished online as Blood First Edition paper, December 13, 2012; DOI 10.1182 DOI 10. /blood-2012 The online version of this article contains a data suppleme...

FK506 binding proteins (FKBPs), also called immunophilins, are prolyl-isomerases (PPIases) that participate in a wide variety of cellular functions including hormone signaling and protein folding. Recent studies indicate that proteins that contain PPIase activity can also alter the processing of Alzheimer's Amyloid Precursor Protein (APP). Originally identified in hematopoietic cells, FKBP52 is much more abundantly expressed in neurons, including the hippocampus, frontal cortex, and basal ganglia. Given the fact that the high molecular weight immunophilin FKBP52 is highly expressed in CNS regions susceptible to Alzheimer's, we investigated its role in Aβ toxicity. Towards this goal, we generated Aβ transgenic Drosophila that harbor gain of function or loss of function mutations of FKBP52. FKBP52 overexpression reduced the toxicity of Aβ and increased lifespan in Aβ flies, whereas loss of function of FKBP52 exacerbated these Aβ phenotypes. Interestingly, the Aβ pathology was enhanced by mutations in the copper transporters Atox1, which interacts with FKBP52, and Ctr1A and was suppressed in FKBP52 mutant flies raised on a copper chelator diet. Using mammalian cultures, we show that FKBP52 (−/−) cells have increased intracellular copper and higher levels of Aβ. This effect is reversed by reconstitution of FKBP52. Finally, we also found that FKBP52 formed stable complexes with APP through its FK506 interacting domain. Taken together, these studies identify a novel role for FKBP52 in modulating toxicity of Aβ peptides.

The gastrointestinal mucosa is an important site of HIV acquisition, viral replication and pathogenesis. Immune cells in mucosal tissues frequently differ in phenotype and function from their non-mucosal counterparts. Although perforin-mediated cytotoxicity as measured in blood is a recognized correlate of HIV immune control, its role in gastrointestinal tissues is unknown. We sought to elucidate the cytotoxic features of rectal mucosal CD8+ T-cells in HIV infected and uninfected subjects. Perforin expression and lytic capacity were significantly reduced in rectal CD8+ T-cells compared to their blood counterparts, regardless of HIV clinical status; granzyme B (GrzB) was reduced to a lesser extent. Mucosal perforin and GrzB expression were higher in participants not on antiretroviral therapy compared to those on therapy and controls. Reduction in perforin and GrzB was not explained by differences in memory/effector subsets. Expression of T-bet and Eomesodermin was significantly lower in gut CD8+ T-cells compared to blood, and in vitro neutralization of TGF-β partially restored perforin expression in gut CD8+ T-cells. These findings suggest that rectal CD8+ T-cells are primarily non-cytotoxic, and phenotypically shaped by the tissue microenvironment. Further elucidation of rectal immune responses to HIV will inform the development of vaccines and immunotherapies targeted to mucosal tissues.

Tissue-resident memory (TRM) CD8+ T-cells are non-recirculating, long-lived cells housed in tissues that can confer protection against mucosal pathogens. HIV-1 is a mucosal pathogen and the gastrointestinal tract is an important site of viral pathogenesis and transmission. Thus, CD8+ TRM cells may be an important effector subset for controlling HIV-1 in mucosal tissues. This study sought to determine the abundance, phenotype, and functionality of CD8+ TRM cells in the context of chronic HIV-1 infection. We found that the majority of rectosigmoid CD8+ T-cells were CD69+CD103+S1PR1− and T-betLowEomesoderminNeg, indicative of a tissue-residency phenotype similar to that described in murine models. HIV-1-specific CD8+ TRM responses appeared strongest in individuals naturally controlling HIV-1 infection. Two CD8+ TRM subsets, distinguished by CD103 expression intensity, were identified. CD103Low CD8+ TRM primarily displayed a transitional memory phenotype and contained HIV-1-specific cells and cells expressing high levels of Eomesodermin, whereas CD103High CD8+ TRM primarily displayed an effector memory phenotype and were EomesoderminNeg. These findings suggest a large fraction of CD8+ T-cells housed in the human rectosigmoid mucosa are tissue-resident and that TRM contribute to the anti-HIV-1 immune response. Further exploration of CD8+ TRM will inform development of anti-HIV-1 immune-based therapies and vaccines targeted to the mucosa.

The central nervous system (CNS) is an important target of HIV, and cerebrospinal fluid (CSF) can provide a window into host-virus interactions within the CNS. The goal of this study was to determine whether HIVspecific CD8+ T cells are present in CSF of HIV controllers (HC), who maintain low to undetectable plasma viremia without antiretroviral therapy (ART). CSF and blood were sampled from 11 HC, defined based on plasma viral load (VL) consistently below 2,000 copies/ml without ART. These included nine elite controllers (EC, plasma VL <40 copies/ml) and two viremic controllers (VC, VL 40-2,000 copies/ml). All controllers had CSF VL <40 copies/ml. Three comparison groups were also sampled: six HIV noncontrollers (NC, VL >10,000 copies/ml, no ART); seven individuals with viremia suppressed due to ART (Tx, VL <40 copies/ml); and nine HIV-negative controls. CD4+ and CD8 + T cells in CSF and blood were analyzed by flow cytometry to assess expression of CCR5, activation markers CD38 and HLA-DR, and memory/effector markers CD45RA and CCR7. HIV-specific CD8 + T cells were quantified by major histocompatibility complex class I multimer staining. HIV-specific CD8 + T cells were detected ex vivo at similar frequencies in CSF of HC and noncontrollers; the highest frequencies were in individuals with CD4 counts below 500 cells/ll. The majority of HIV-specific CD8 + T cells in CSF were effector memory cells expressing CCR5. Detection of these cells in CSF suggests active surveillance of the CNS compartment by HIV-specific T cells, including in individuals with long-term control of HIV infection in the absence of therapy.

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The gastrointestinal tract (GIT) is an important site of HIV transmission and pathogenesis. Preventing or curing HIV infection will likely entail maintenance of protective anti-HIV immune responses in the GIT. Tissue resident memory T-cells (TRM) are long-lived, non-recirculating memory T-cells localized in tissues including the GIT. Positioned near sites of infection, TRM have protective efficacy against several pathogens. The precise role CD8+ TRM in HIV infection is not known. Blood and GIT CD8+ TRM cells from HIV+ and HIV- adults were identified by flow cytrometry using CD45RO, CD69, CD103, S1PR1, T-bet, and Eomesodermin (Eomes). Functionality was assessed in a 6-hour ex vivo stimulation assay. Cells were stimulated with DMSO, Gag, or Staphylococcal Enterotoxin B, and stained for CD107a, IFNγ, Mip-1β, TNFα, and IL-2. The frequency of CD103+CD69+S1PR1− CD8+ T-cells was significantly greater (P=0.005) in gut compared to blood (medians 54.8% and 0.10% respectively), indicative of tissue residency. CD45RO+ cells in this subset were classified as TRM. Consistent with murine studies, CD8+TRM were mainly T-betLowEomesNeg; however a population of EomesHigh CD8+ TRM emerged in HIV+ individuals not on antiretroviral therapy. Although polyfunctional Gag-specific CD8+ TRM responses (CD107a+, IFNγ+, Mip-1β+) appeared strongest in participants who control HIV without therapy (“controllers”), they constituted a smaller proportion of the total rectal Gag-specific CD8+ T-cell response compared to viremic participants not on ART (approximately 15% and 29% respectively). In summary, a large subset of CD8+ T-cells in rectal mucosa are TRM and likely play an important role in HIV-1 containment.