Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and IL-17 production in the absence of SIV infection

Klatt, Nichole R.; Harris, Levelle D.; Vinton, Carol L.; Sung, Hannah C.; Briant, Judith A.; Tabb, Brian; Morcock, David R.; McGinty, John W.; Lifson, Jeffrey D.; Lafont, Bernard A. P.; Martin, Malcolm A.; Levine, Alan D.; Estes, Jacob D.; Brenchley, Jason M.

doi:10.1038/mi.2010.14

Cited by 121 publications

(124 citation statements)

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“…Importantly, very little is known about their anatomical distribution, phenotype, functional quality, and their role in host defense. A recent study characterized Tc17 cells in macaques and demonstrated that the frequency of these cells was higher in various tissues of pigtail macaques than that in rhesus macaques (32). However, very little is known about the modulation of these cells during chronic HIV/SIV infections (33), and no information is available on the status of these cells in the colorectal tissue, one of the major sites of HIV/SIV replication during chronic infection.…”

mentioning

confidence: 99%

Loss of IL-17–Producing CD8 T Cells during Late Chronic Stage of Pathogenic Simian Immunodeficiency Virus Infection

Nigam

Kwa

Velu

et al. 2011

The Journal of Immunology

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Progressive disease caused by pathogenic SIV/HIV infections is marked by systemic hyperimmune activation, immune dysregulation, and profound depletion of CD4+ T cells in lymphoid and gastrointestinal mucosal tissues. IL-17 is important for protective immunity against extracellular bacterial infections at mucosa and for maintenance of mucosal barrier. Although IL-17–secreting CD4 (Th17) and CD8 (Tc17) T cells have been reported, very little is known about the latter subset for any infectious disease. In this study, we characterized the anatomical distribution, phenotype, and functional quality of Tc17 and Th17 cells in healthy (SIV−) and SIV+ rhesus macaques. In healthy macaques, Tc17 and Th17 cells were present in all lymphoid and gastrointestinal tissues studied with predominance in small intestine. About 50% of these cells coexpressed TNF-α and IL-2. Notably, ∼50% of Tc17 cells also expressed the co-inhibitory molecule CTLA-4, and only a minority (<20%) expressed granzyme B suggesting that these cells possess more of a regulatory than cytotoxic phenotype. After SIV infection, unlike Th17 cells, Tc17 cells were not depleted during the acute phase of infection. However, the frequency of Tc17 cells in SIV-infected macaques with AIDS was lower compared with that in healthy macaques demonstrating the loss of these cells during end-stage disease. Antiretroviral therapy partially restored the frequency of Tc17 and Th17 cells in the colorectal mucosa. Depletion of Tc17 cells was not observed in colorectal mucosa of chronically infected SIV+ sooty mangabeys. In conclusion, our results suggest a role for Tc17 cells in regulating disease progression during pathogenic SIV infection.

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mentioning

confidence: 99%

Loss of IL-17–Producing CD8 T Cells during Late Chronic Stage of Pathogenic Simian Immunodeficiency Virus Infection

Nigam

Kwa

Velu

et al. 2011

The Journal of Immunology

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“…LN biopsies were processed as described previously. 47 Animals were housed and cared in accordance with American Association for Accreditation of Laboratory Animal Care standards in accredited facilities, and all animal procedures were performed according to protocols approved by the Institutional Animal Care and Use Committees of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. …”

mentioning

confidence: 99%

SIV infection of rhesus macaques results in dysfunctional T- and B-cell responses to neo and recall Leishmania major vaccination

Klatt¹,

Vinton²,

Lynch

et al. 2011

Blood

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HIV infection is characterized by immune system dysregulation, including depletion of CD4 ؉ T cells, immune activation, and abnormal B-and T-cell responses. However, the immunologic mechanisms underlying lymphocytic dysfunctionality and whether it is restricted to immune responses against neo antigens, recall antigens, or both is unclear. Here, we immunized SIV-infected and uninfected rhesus macaques to induce immune responses against neo and recall antigens using a Leishmania major polyprotein (MML) vaccine given with poly-ICLC adjuvant. We found that vaccinated SIVuninfected animals induced high frequencies of polyfunctional MML-specific CD4 ؉ T cells. However, in SIV-infected animals, CD4 ؉ T-cell functionality decreased after both neo (P ‫؍‬ .0025) and recall (P ‫؍‬ . IntroductionHIV infection is characterized by progressive loss of CD4 ϩ T cells, eventually resulting in opportunistic infections and acquired immunodeficiency syndrome (AIDS) and, in untreated individuals, death. During acute HIV infection, CD4 ϩ T cells are massively infected and rapidly depleted from effector sites, particularly in mucosal tissues, and as infection progresses to chronic disease, there is a progressive, slow loss of peripheral CD4 ϩ T cells. [1][2][3][4][5][6][7] Furthermore, HIV specifically infects activated memory CD4 ϩ T cells, and previous studies have demonstrated that the virus preferentially infects CD4 ϩ T cells where the corresponding antigen is often present at high levels, such as HIV-specific and Mycobacterium tuberculosis-specific cells. 4,8 Hence, the immunodeficiency and dysfunctional immune responses that occur after HIV infection are of particular concern with respect to their role in providing immunity against opportunistic infections. The effectiveness of common vaccines in inducing healthy immune responses among chronically HIV-infected individuals against subsequent infection is decreased. 9 Indeed, the majority of currently effective vaccination approaches induce protective immunity against pathogens by induction of long-term antibody responses specific for the vaccinated antigen. 10 These antibodies are produced mainly by 2 subsets of B cells, plasma cells that reside primarily in the bone marrow and long-lived memory B cells. [11][12][13] Moreover, development of an effective B-cell response is reliant on helper CD4 ϩ T-cell responses that promote antigenspecific B-cell differentiation and antibody class switching. 14 Class switching by B cells from their constitutive expression and production of IgM to other antibody classes (ie, IgG and IgA) is essential to develop an effective immune response, because each type of immunoglobulin has specific functions and sites of activity. 10 IgA may be of particular importance during HIV infection, because IgA plays a significant protective role at mucosal surfaces, 10 and given the common mucosal routes of HIV exposure. 15 Thus, the overall loss of IgA that is observed during HIV infection 16,17 may play a role in driving virus replication at mucosal sites as we...

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“…SIVmac-infected pigtail macaques tend to progress rapidly to AIDS and can potentially develop thrombocytopenia [136] which is a common autoimmune disease that can also manifest in untreated HIV-1 infected individuals. Pigtail macaques in some breeding colonies may exhibit certain pre-existing immunologic conditions such as compromised mucosal integrity, increased microbial translocation and lower levels of naïve and central memory CD4+ T-cells,have been described [34,73]. SIV/SHIV infected pigtail macaques also exhibit considerable variability in set point viral loads which is a trend that is noted in HIV-1 infected humans.…”

Section: Pigtail Macaques (Macaca Nemestrina)mentioning

confidence: 99%

“…The precise mechanism that triggers the downregulated immune response is unclear, but is likely to involve a combination of proposed processes that include, (1) enhanced responses of immunosuppressive regulatory T-cells and IL-17 producing Th17 cells (2) a robust early innate immune response that is swiftly constrained, and (3) controlled regulation of cellular factors or receptors associated with activation, apoptosis, or virus binding [20][21][22][23][24][25][26][27][28][29][30][31][32]. Furthermore, in contrast to the massive immune depletion that occurs in the gastrointestinal (GI) tract of non-natural hosts of SIV or HIV infection, natural NHP SIV hosts maintain GI epithelial integrity and exhibit a lack of microbial translocation that may in part account for minimal systemic immune activation [33,34]. Limiting the pool and/or proliferative capacity of target cells may also play a role in disease resistance, as demonstrated by studies in sooty mangabeys in which SIV replication was shown to be restricted to primarily short-lived activated CD4+ T-cells, which likely contributes to the preservation of central memory CD4+ T-cells [35,36].…”

Section: Old World Nhp Natural Hostsmentioning

confidence: 99%

Simian-Human Immunodeficiency Viruses and Their Impact on Non-Human Primate Models for AIDS

Pereira¹,

Srinivasan²,

Smith³

2012

Immunodeficiency

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Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and IL-17 production in the absence of SIV infection

Cited by 121 publications

References 77 publications

Loss of IL-17–Producing CD8 T Cells during Late Chronic Stage of Pathogenic Simian Immunodeficiency Virus Infection

Loss of IL-17–Producing CD8 T Cells during Late Chronic Stage of Pathogenic Simian Immunodeficiency Virus Infection

SIV infection of rhesus macaques results in dysfunctional T- and B-cell responses to neo and recall Leishmania major vaccination

Simian-Human Immunodeficiency Viruses and Their Impact on Non-Human Primate Models for AIDS

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