Gastrointestinal Tract as a Major Site of CD4
            <sup>+</sup>
            T Cell Depletion and Viral Replication in SIV Infection

Veazey, Ronald S.; DeMaria, Mary Ann; Chalifoux, Laura V.; Shvetz, Daniel E.; Pauley, Douglas R.; Knight, Heather; Rosenzweig, Michael; Johnson, R. Paul; Desrosiers, Ronald C.; Lackner, Andrew A.

doi:10.1126/science.280.5362.427

Cited by 1,292 publications

(1,165 citation statements)

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“…Lymphocytes from the intestine and mesenteric LN were isolated as described earlier [12,25]. In brief, epithelial cells were separated from intestinal pieces using serial incubations with EDTA.…”

Section: Isolation Of Lymphocytes From Intestine and Lymph Nodesmentioning

confidence: 99%

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Intestinal double‐positive CD4⁺CD8⁺ T cells are highly activated memory cells with an increased capacity to produce cytokines

2006

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Peripheral blood and intestinal CD4 + CD8 + double-positive (DP) T cells have been described in several species including humans, but their function and immunophenotypic characteristics are still not clearly understood. Here we demonstrate that DP T cells are abundant in the intestinal lamina propria of normal rhesus macaques (Macaca mulatta). Moreover, DP T cells have a memory phenotype and are capable of producing different and/or higher levels of cytokines and chemokines in response to mitogen stimulation compared to CD4 + single-positive T cells. Intestinal DP T cells are also highly activated and have higher expression of CCR5, which makes them preferred targets for simian immunodeficiency virus/HIV infection. Increased levels of CD69, CD25 and HLA-DR, and lower CD62L expression were found on intestinal DP T cells populations compared to CD4 + single-positive T cells. Collectively, these findings demonstrate that intestinal and peripheral blood DP T cells are effector cells and may be important in regulating immune responses, which distinguishes them from the immature DP cells found in the thymus. Finally, these intestinal DP T cells may be important target cells for HIV infection and replication due to their activation, memory phenotype and high expression of CCR5. IntroductionCD4 + CD8 + double positive (DP) T cells in the intestine have been shown to be a major early target in primary simian immunodeficiency virus (SIV) infection [1]. Rapid depletion of intestinal DP cells occurs faster and more profoundly than that of intestinal CD4 + singlepositive (SP) cells which we have previously correlated with increased levels of CCR5 expression on the former [1]. Although DP T cells have been described in the blood and intestine of humans, nonhuman primates, swine and rodents [2][3][4][5][6][7][8][9][10][11][12], little is known regarding their function or immunophenotypic (naive versus memory status etc.) characteristics. DP T cells are perhaps best known in the thymus, where they are T cell precursors in early states of T cell maturation. However, DP T cells in the peripheral blood have been shown to differ from those in the thymus [2].Several investigators have reported the presence of circulating blood DP T cells, in both healthy [13,14] and diseased individuals [15][16][17][18][19][20][21][22]. Existence of this unconventional and rare lymphocyte population in peripheral blood has been hypothesized to result from premature release of immature CD4 + CD8 + T cells from the thymus to the periphery, where their maturation into functionally competent SP cell continues [23]. However, in HIV and Epstein-Barr virus infections, the percentage of DP T cells can increase to 20% of circulating lymphocytes, suggesting they are effector cells responding to infection [14,15]. In humans and animals DP T cells have also been shown to have antiviral activity, further suggesting they are indeed antigen-specific effector cells rather than immature cells from the thymus [2, 4,24]. The intestine is the major target organ of HIV...

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Section: Isolation Of Lymphocytes From Intestine and Lymph Nodesmentioning

confidence: 99%

“…Intestinal effector lymphoid tissues (i.e. lamina propria) have been shown to be the major site of viral replication and CD4 + T cell depletion in primary HIV and SIV infection [7,[25][26][27][28]. Our earlier studies demonstrated that DP T cells co-expressing CCR5 in the intestine were rapidly eliminated in primary SIV infection.…”

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Intestinal double‐positive CD4⁺CD8⁺ T cells are highly activated memory cells with an increased capacity to produce cytokines

2006

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“…4 Accumulating data also indicate that gut-associated lymphoid tissue (GALT), which contains inductive sites, Peyer's patches and mesenteric (Mes) LNs, and effectors sites located within lamina propria and epithelium of the intestinal wall, is also an early and predominant tissue site of viral replication and may be a reservoir for HIV/SIV. 5,6 Because T cells from the GALT are required to maintain a state of immunological tolerance toward a myriad of dietary and resident bacterial antigens, the chronic exposure of HIV/ SIV-specific antigens could have an impact on the capacity of CD8 þ T cells to control viral replication in the GALT.Addressing these complex pathways in HIV-1 infected patients is limited by the access to internal tissue biopsies, and therefore macaques provide a useful model to address and explore these fundamental questions of the anatomical viral reservoirs and the dynamics of effector cells that control viral replication. We examined organs from 12 monkeys (controllers versus non-controllers), sampling peripheral blood, Ing and Mes LNs, spleen, jejunum, colon, ileum, lung, kidney and liver.…”

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TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

et al. 2007

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SIV-infected macaques exhibit distinct rates of progression to AIDS and despite significant increases in CD8 þ T cells, immune cells fail to control and eradicate SIV in vivo. Here, we investigated the interplay between viral reservoir sites, CD8 þ T-cell activation/death and outcome. Our data provide strong evidence that mesenteric (Mes) lymph nodes represent major reservoirs not only for SIV-infected macaques progressing more rapidly toward AIDS but also in controllers. We demonstrate that macaques progressing faster display greater expression of TGF-b and Indoleamine 2,3 dioxygenase in particular in intestinal tissues associated with a phosphorylation of the p53 protein on serine 15 in CD8 þ T cells from Mes lymph nodes. These factors may act as a negative regulator of CD8 þ T-cell function by inducing a Bax/Bak/Puma-dependent death pathway of effector/ memory CD8 þ T cells. Greater T-cell death and viral dissemination was associated with a low level of TIA-1 þ expressing cells. Finally, we provide evidence that abrogation of TGF-b in vitro enhances T-cell proliferation and reduces CD8 þ T-cell death. Our data identify a mechanism of T-cell exhaustion in intestinal lymphoid organs and define a potentially effective immunological strategy for the modulation of progression to AIDS. Cell Death and Differentiation (2007) 14, 1747-1758; doi:10.1038/sj.cdd.4402192; published online 6 July 2007Virus production in Human Immunodeficiency Virus 1 (HIV-1)-infected individuals is largely the result of a dynamic process involving continuous rounds of de novo infection and replication in CD4 þ cells with rapid turnover of both free virus and virus producing cells. Moreover, an increasing body of evidence suggests that reservoirs, cell types or anatomical sites ('sanctuaries'), represent a major barrier to virus eradication. 1 HIV-specific CD8 þ T lymphocytes (CTL) are considered crucial in the control of viral replication. 2 Excessive induction of apoptosis has been proposed as one major mechanism of abnormal T-cell response during HIV and Simian Immunodeficiency Virus (SIV) infections. 3 However, most studies, which investigated the potential relationship between HIV and SIV infections and apoptosis have focused on cells from peripheral blood, rather than on cells from lymphoid organs.Peripheral lymphoid tissues such as the axillary and inguinal (Ing) lymph nodes (LNs), which drain the arms and legs, respectively, and the spleen, are considered major sites of HIV/SIV replication. 4 Accumulating data also indicate that gut-associated lymphoid tissue (GALT), which contains inductive sites, Peyer's patches and mesenteric (Mes) LNs, and effectors sites located within lamina propria and epithelium of the intestinal wall, is also an early and predominant tissue site of viral replication and may be a reservoir for HIV/SIV. 5,6 Because T cells from the GALT are required to maintain a state of immunological tolerance toward a myriad of dietary and resident bacterial antigens, the chronic exposure of HIV/ SIV-specific antigens coul...

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“…Specifically, within days to up to three weeks of initial exposure, there is a burst in viremia that can reach levels exceeding one million copies/ml [1]. This high magnitude of viral titer accelerates the dissemination and seeding of HIV to various tissue compartment, most significantly in gut-associated mucosal tissue [2][3][4]. Tissue dissemination of HIV is accompanied by direct HIV-mediated cytopathic effects on CD4+ memory T cells, leading to their loss, as was evident in acute Simian Immunodeficiency Virus (SIV) infection [5].…”

Section: Introductionmentioning

confidence: 99%

Immunophenotypic alterations in acute and early HIV infection

Al‐Harthi¹,

MaWhinney²,

Connick³

et al. 2007

Clinical Immunology

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To understand the extent of immune dysregulation in primary HIV infection (PHI) and the impact of antiretroviral therapy (ART) on restoring these abnormalities, we longitudinally evaluated 52 subjects {Acute Treated (AT); Early Treated (ET); Early Untreated (EU)) for markers of activation, proliferation, and function on T cells. ET and AT patients differed by 0.54 log viral load (VL) at baseline but did not differ thereafter by more than 0.34 log10 VL. AT subjects had higher CD8+ T cell counts and expression of markers indicative of CD8+ T cell activation (CD38), and proliferation (Ki67), at baseline, than ET subjects but were not different post-48 weeks of ART. Although acute PHI is marked by higher level of immune activation than early PHI, virologic and immunologic responses were similar post-ART, suggesting that the extent of immunologic recovery is not negatively impacted by a delay of treatment beyond the acute stage of disease.

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Gastrointestinal Tract as a Major Site of CD4 ⁺ T Cell Depletion and Viral Replication in SIV Infection

Cited by 1,292 publications

References 11 publications

Intestinal double‐positive CD4⁺CD8⁺ T cells are highly activated memory cells with an increased capacity to produce cytokines

Intestinal double‐positive CD4⁺CD8⁺ T cells are highly activated memory cells with an increased capacity to produce cytokines

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

Immunophenotypic alterations in acute and early HIV infection

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Gastrointestinal Tract as a Major Site of CD4 + T Cell Depletion and Viral Replication in SIV Infection

Cited by 1,292 publications

References 11 publications

Intestinal double‐positive CD4+CD8+ T cells are highly activated memory cells with an increased capacity to produce cytokines

Intestinal double‐positive CD4+CD8+ T cells are highly activated memory cells with an increased capacity to produce cytokines

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

Immunophenotypic alterations in acute and early HIV infection

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Product

Resources

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Gastrointestinal Tract as a Major Site of CD4 ⁺ T Cell Depletion and Viral Replication in SIV Infection

Intestinal double‐positive CD4⁺CD8⁺ T cells are highly activated memory cells with an increased capacity to produce cytokines

Intestinal double‐positive CD4⁺CD8⁺ T cells are highly activated memory cells with an increased capacity to produce cytokines