scholarly journals Simian Immunodeficiency Virus (SIV) Infection Influences the Level and Function of Regulatory T Cells in SIV-Infected Rhesus Macaques but Not SIV-Infected Sooty Mangabeys

2007 ◽  
Vol 81 (9) ◽  
pp. 4445-4456 ◽  
Author(s):  
L. E. Pereira ◽  
F. Villinger ◽  
N. Onlamoon ◽  
P. Bryan ◽  
A. Cardona ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Acute Infection ◽  
T Cell Response ◽  
Immunodeficiency Virus ◽  
Sooty Mangabeys ◽  
Siv Infection

ABSTRACT Differences in clinical outcome of simian immunodeficiency virus (SIV) infection in disease-resistant African sooty mangabeys (SM) and disease-susceptible Asian rhesus macaques (RM) prompted us to examine the role of regulatory T cells (Tregs) in these two animal models. Results from a cross-sectional study revealed maintenance of the frequency and absolute number of peripheral Tregs in chronically SIV-infected SM while a significant loss occurred in chronically SIV-infected RM compared to uninfected animals. A longitudinal study of experimentally SIV-infected animals revealed a transient increase in the frequency of Tregs from baseline values following acute infection in RM, but no change in the frequency of Tregs occurred in SM during this period. Further examination revealed a strong correlation between plasma viral load (VL) and the level of Tregs in SIV-infected RM but not SM. A correlation was also noted in SIV-infected RM that control VL spontaneously or in response to antiretroviral chemotherapy. In addition, immunofluorescent cell count assays showed that while Treg-depleted peripheral blood mononuclear cells from RM led to a significant enhancement of CD4+ and CD8+ T-cell responses to select pools of SIV peptides, there was no detectable T-cell response to the same pool of SIV peptides in Treg-depleted cells from SIV-infected SM. Our data collectively suggest that while Tregs do appear to play a role in the control of viremia and the magnitude of the SIV-specific immune response in RM, their role in disease resistance in SM remains unclear.

scholarly journals With Minimal Systemic T-Cell Expansion, CD8+ T Cells Mediate Protection of Rhesus Macaques Immunized with Attenuated Simian-Human Immunodeficiency Virus SHIV89.6 from Vaginal Challenge with Simian Immunodeficiency Virus

2008 ◽  
Vol 82 (22) ◽  
pp. 11181-11196 ◽  
Author(s):  
Meritxell Genescà ◽  
Pamela J. Skinner ◽  
Jung Joo Hong ◽  
Jun Li ◽  
Ding Lu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
T Cell Response ◽  
Lymphoid Tissues ◽  
Vaginal Mucosa ◽  
Challenge Virus ◽  
Immunodeficiency Virus

ABSTRACT The presence, at the time of challenge, of antiviral effector T cells in the vaginal mucosa of female rhesus macaques immunized with live-attenuated simian-human immunodeficiency virus 89.6 (SHIV89.6) is associated with consistent and reproducible protection from pathogenic simian immunodeficiency virus (SIV) vaginal challenge (18). Here, we definitively demonstrate the protective role of the SIV-specific CD8+ T-cell response in SHIV-immunized monkeys by CD8+ lymphocyte depletion, an intervention that abrogated SHIV-mediated control of challenge virus replication and largely eliminated the SIV-specific T-cell responses in blood, lymph nodes, and genital mucosa. While in the T-cell-intact SHIV-immunized animals, polyfunctional and degranulating SIV-specific CD8+ T cells were present in the genital tract and lymphoid tissues from the day of challenge until day 14 postchallenge, strikingly, expansion of SIV-specific CD8+ T cells in the immunized monkeys was minimal and limited to the vagina. Thus, protection from uncontrolled SIV replication in animals immunized with attenuated SHIV89.6 is primarily mediated by CD8+ T cells that do not undergo dramatic systemic expansion after SIV challenge. These findings demonstrate that despite, and perhaps because of, minimal systemic expansion of T cells at the time of challenge, a stable population of effector-cytotoxic CD8+ T cells can provide significant protection from vaginal SIV challenge.

scholarly journals Normal T-Cell Turnover in Sooty Mangabeys Harboring Active Simian Immunodeficiency Virus Infection

2000 ◽  
Vol 74 (3) ◽  
pp. 1209-1223 ◽  
Author(s):  
Lisa A. Chakrabarti ◽  
Sharon R. Lewin ◽  
Linqi Zhang ◽  
Agegnehu Gettie ◽  
Amara Luckay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Rhesus Macaques ◽  
T Cell Proliferation ◽  
Cell Turnover ◽  
Ki 67 ◽  
Monkey Species ◽  
Immunodeficiency Virus ◽  
Sooty Mangabeys ◽  
Siv Infection

ABSTRACT Sooty mangabeys naturally infected with simian immunodeficiency virus (SIV) remain healthy though they harbor viral loads comparable to those in rhesus macaques that progress to AIDS. To assess the immunologic basis of disease resistance in mangabeys, we compared the effect of SIV infection on T-cell regeneration in both monkey species. Measurement of the proliferation marker Ki-67 by flow cytometry showed that mangabeys harbored proliferating T cells at a level of 3 to 4% in peripheral blood irrespective of their infection status. In contrast, rhesus macaques demonstrated a naturally high fraction of proliferating T cells (7%) that increased two- to threefold following SIV infection. Ki-67+ T cells were predominantly CD45RA−, indicating increased proliferation of memory cells in macaques. Quantitation of an episomal DNA product of T-cell receptor α rearrangement (termed α1 circle) showed that the concentration of recent thymic emigrants in blood decreased with age over a 2-log unit range in both monkey species, consistent with age-related thymic involution. SIV infection caused a limited decrease of α1 circle numbers in mangabeys as well as in macaques. Dilution of α1 circles by T-cell proliferation likely contributed to this decrease, since α1 circle numbers and Ki-67+ fractions correlated negatively. These findings are compatible with immune exhaustion mediated by abnormal T-cell proliferation, rather than with early thymic failure, in SIV-infected macaques. Normal T-cell turnover in SIV-infected mangabeys provides an explanation for the long-term maintenance of a functional immune system in these hosts.

scholarly journals Perturbations of Cell Cycle Control in T Cells Contribute to the Different Outcomes of Simian Immunodeficiency Virus Infection in Rhesus Macaques and Sooty Mangabeys

2006 ◽  
Vol 80 (2) ◽  
pp. 634-642 ◽  
Author(s):  
M. Paiardini ◽  
B. Cervasi ◽  
B. Sumpter ◽  
H. M. McClure ◽  
D. L. Sodora ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Rhesus Macaques ◽  
Cell Cycle Control ◽  
Cyclin B ◽  
T Cell Apoptosis ◽  
Immunodeficiency Virus ◽  
Sooty Mangabeys ◽  
Siv Infection

ABSTRACT In contrast to human immunodeficiency virus (HIV) infection of humans and experimental simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs), SIV infection of sooty mangabeys (SMs), a natural host African monkey species, is typically nonpathogenic and associated with preservation of CD4+ T-cell counts despite chronic high levels of viral replication. In previous studies, we have shown that the lack of SIV disease progression in SMs is related to lower levels of immune activation and bystander T-cell apoptosis compared to those of pathogenic HIV/SIV infection (G. Silvestri, D. Sodora, R. Koup, M. Paiardini, S. O’Neil, H. M. McClure, S. I. Staprans, and M. B. Feinberg, Immunity 18:441-452, 2003; G. Silvestri, A. Fedanov, S. Germon, N. Kozyr, W. J. Kaiser, D. A. Garber, H. M. McClure, M. B. Feinberg, and S. I. Staprans, J. Virol. 79:4043-4054, 2005). In HIV-infected patients, increased T-cell susceptibility to apoptosis is associated with a complex cell cycle dysregulation (CCD) that involves increased activation of the cyclin B/p34-cdc2 complex and abnormal nucleolar structure with dysregulation of nucleolin turnover. Here we report that CCD is also present during pathogenic SIV infection of RMs, and its extent correlates with the level of immune activation and T-cell apoptosis. In marked contrast, naturally SIV-infected SMs show normal regulation of cell cycle control (i.e., normal intracellular levels of cyclin B and preserved nucleolin turnover) and a low propensity to apoptosis in both peripheral blood- and lymph node-derived T cells. The absence of significant CCD in the AIDS-free, non-immune-activated SMs despite high levels of viral replication indicates that CCD is a marker of disease progression during lentiviral infection and supports the hypothesis that the preservation of cell cycle control may help to confer the disease-resistant phenotype of SIV-infected SMs.

scholarly journals Gut Mucosal FOXP3+ Regulatory CD4+ T Cells and Nonregulatory CD4+ T Cells Are Differentially Affected by Simian Immunodeficiency Virus Infection in Rhesus Macaques

2010 ◽  
Vol 84 (7) ◽  
pp. 3259-3269 ◽  
Author(s):  
Kristina Allers ◽  
Christoph Loddenkemper ◽  
Jörg Hofmann ◽  
Anett Unbehaun ◽  
Désirée Kunkel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Cd4 T Cells ◽  
Rhesus Macaques ◽  
Virus Production ◽  
Cell Pool ◽  
Immunodeficiency Virus ◽  
Gut Mucosa ◽  
Siv Infection

ABSTRACT The gastrointestinal tract represents a major site for human and simian immunodeficiency virus (HIV and SIV) replication and CD4+ T-cell depletion. Despite severe depletion of mucosal CD4+ T cells, FOXP3+ regulatory CD4+ T cells (Treg) are highly increased in the gut mucosa of chronically HIV-infected individuals and may contribute to HIV pathogenesis, either by their immunosuppressive function or as a significant target cell population for virus production. Little is known about the susceptibility of mucosal Treg to viral infection and the longitudinal effect of HIV/SIV infection on Treg dynamics. In this study, we determined the level of SIV infection in Treg and nonregulatory CD4+ T cells (non-Treg) isolated from the colon of SIV-infected rhesus macaques. The dynamics of mucosal Treg and alterations in the mucosal CD4+ T-cell pool were examined longitudinally. Our findings indicate that mucosal Treg were less susceptible to productive SIV infection than non-Treg and thus were selectively spared from SIV-mediated cell death. In addition to improved survival, local expansion of Treg by SIV-induced proliferation of the mucosal CD4+ T-cell pool facilitated the accumulation of mucosal Treg during the course of infection. High frequency of mucosal Treg in chronic SIV infection was strongly related to a reduction of perforin-expressing cells. In conclusion, this study suggests that mucosal Treg are less affected by productive SIV infection than non-Treg and therefore spared from depletion. Although SIV production is limited in mucosal Treg, Treg accumulation may indirectly contribute to viral persistence by suppressing antiviral immune responses.

scholarly journals A Five-Year Longitudinal Analysis of Sooty Mangabeys Naturally Infected with Simian Immunodeficiency Virus Reveals a Slow but Progressive Decline in CD4+ T-Cell Count Whose Magnitude Is Not Predicted by Viral Load or Immune Activation

2010 ◽  
Vol 84 (11) ◽  
pp. 5476-5484 ◽  
Author(s):  
Jessica Taaffe ◽  
Ann Chahroudi ◽  
Jessica Engram ◽  
Beth Sumpter ◽  
Tracy Meeker ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Immune Activation ◽  
Progressive Decline ◽  
Cell Counts ◽  
Immunodeficiency Virus ◽  
Sooty Mangabeys ◽  
Siv Infection ◽  
Time Point

ABSTRACT Natural simian immunodeficiency virus (SIV) infection in sooty mangabeys (SMs) typically does not result in AIDS, despite high-level viremia and significant depletion of mucosal CD4+ T cells. Here, we report the results of the first longitudinal study of a large cohort of SMs naturally infected with SIV (n = 78) housed at the Yerkes National Primate Research Center from which samples were obtained three times over a 5-year period. In this study, we observed (i) no signs of simian AIDS, (ii) stable SIV loads, (iii) a slow but progressive decline in CD4+ T-cell counts (from a mean of 1,067.0 cells/mm3 at time point 1 to 764.8 cells/mm3 at time point 3) and increases in the numbers of animals with CD4+ T-cell levels below 500 and 200 cells/mm3 (from 8 to 28 of 78 and from 1 to 4 of 78, respectively), (iv) progressive declines in percentages of naïve CD4+ and CD8+ T cells (from 37.7 to 24.8% and from 21.0 to 13.0%, respectively), and (v) stably low levels of activated/proliferating T cells as well as CD4+ CCR5+ T cells. Since the level of total CD4+ T cells and the fraction of naïve T cells in SIV-uninfected SMs also declined, it is possible that some of these observations are related to aging, as the SIV-infected animals were significantly older than the uninfected animals. In contrast to the decline in CD4+ T cell counts in individuals infected with human immunodeficiency virus (HIV), the decline in CD4+ T cell counts in SMs naturally infected with SIV over a 5-year period was not predicted by either plasma viremia or levels of T-cell activation. Taken together, these results confirm that natural SIV infection is nonprogressive from a clinical, virological, and immunological point of view and that stable levels of viremia associated with persistently low-level immune activation represent key differences from the natural course of HIV infection in humans.

scholarly journals Increased Loss of CCR5+ CD45RA− CD4+ T Cells in CD8+ Lymphocyte-Depleted Simian Immunodeficiency Virus-Infected Rhesus Monkeys

2008 ◽  
Vol 82 (11) ◽  
pp. 5618-5630 ◽  
Author(s):  
Ronald S. Veazey ◽  
Paula M. Acierno ◽  
Kimberly J. McEvers ◽  
Susanne H. C. Baumeister ◽  
Gabriel J. Foster ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Simian Immunodeficiency Virus ◽  
Peripheral Blood ◽  
T Cell Responses ◽  
Lymphocyte Depletion ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Siv Infection

ABSTRACT Previously we have shown that CD8+ T cells are critical for containment of simian immunodeficiency virus (SIV) viremia and that rapid and profound depletion of CD4+ T cells occurs in the intestinal tract of acutely infected macaques. To determine the impact of SIV-specific CD8+ T-cell responses on the magnitude of the CD4+ T-cell depletion, we investigated the effect of CD8+ lymphocyte depletion during primary SIV infection on CD4+ T-cell subsets and function in peripheral blood, lymph nodes, and intestinal tissues. In peripheral blood, CD8+ lymphocyte-depletion changed the dynamics of CD4+ T-cell loss, resulting in a more pronounced loss 2 weeks after infection, followed by a temporal rebound approximately 2 months after infection, when absolute numbers of CD4+ T cells were restored to baseline levels. These CD4+ T cells showed a markedly skewed phenotype, however, as there were decreased levels of memory cells in CD8+ lymphocyte-depleted macaques compared to controls. In intestinal tissues and lymph nodes, we observed a significantly higher loss of CCR5+ CD45RA− CD4+ T cells in CD8+ lymphocyte-depleted macaques than in controls, suggesting that these SIV-targeted CD4+ T cells were eliminated more efficiently in CD8+ lymphocyte-depleted animals. Also, CD8+ lymphocyte depletion significantly affected the ability to generate SIV Gag-specific CD4+ T-cell responses and neutralizing antibodies. These results reemphasize that SIV-specific CD8+ T-cell responses are absolutely critical to initiate at least partial control of SIV infection.

scholarly journals Perforin Expression in the Gastrointestinal Mucosa Is Limited to Acute Simian Immunodeficiency Virus Infection

2006 ◽  
Vol 80 (6) ◽  
pp. 3083-3087 ◽  
Author(s):  
Máire F. Quigley ◽  
Kristina Abel ◽  
Bartek Zuber ◽  
Christopher J. Miller ◽  
Johan K. Sandberg ◽  
...  
Keyword(s):  
T Cells ◽  
Simian Immunodeficiency Virus ◽  
Cd8 T Cells ◽  
Positive Response ◽  
Rhesus Macaques ◽  
Gastrointestinal Mucosa ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Perforin Expression ◽  
Important Site

ABSTRACT Perforin-mediated cytotoxicity is a major effector function of virus-specific CD8 T cells. We have investigated the expression of perforin in the gut, an important site of simian immunodeficiency virus (SIV) pathogenesis, during experimental SIV infection of rhesus macaques. We observed significant increases in perforin protein and mRNA expression levels in the colons of SIV-infected macaques as early as 21 days after infection. However, during chronic infection, despite ongoing viral replication, perforin expression returned to levels similar to those detected in SIV-naïve animals. These findings demonstrate the presence of a robust perforin-positive response in gastrointestinal CD8 T cells during acute, but not chronic, SIV infection.

scholarly journals Loss of Naïve Cells Accompanies Memory CD4+ T-Cell Depletion during Long-Term Progression to AIDS in Simian Immunodeficiency Virus-Infected Macaques

2006 ◽  
Vol 81 (2) ◽  
pp. 893-902 ◽  
Author(s):  
Yoshiaki Nishimura ◽  
Tatsuhiko Igarashi ◽  
Alicia Buckler-White ◽  
Charles Buckler ◽  
Hiromi Imamichi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Progression ◽  
Simian Immunodeficiency Virus ◽  
Peripheral Blood ◽  
Acute Infection ◽  
Virus Production ◽  
Recovery Phase ◽  
Lymphoid Tissues ◽  
Immunodeficiency Virus

ABSTRACT Human immunodeficiency virus and simian immunodeficiency virus (SIV) induce a slow progressive disease, characterized by the massive loss of memory CD4+ T cells during the acute infection followed by a recovery phase in which virus replication is partially controlled. However, because the initial injury is so severe and virus production persists, the immune system eventually collapses and a symptomatic fatal disease invariably occurs. We have assessed CD4+ T-cell dynamics and disease progression in 12 SIV-infected rhesus monkeys for nearly 2 years. Three macaques exhibiting a rapid progressor phenotype experienced rapid and irreversible loss of memory, but not naïve, CD4+ T lymphocytes from peripheral blood and secondary lymphoid tissues and died within the first 6 months of virus inoculation. In contrast, SIV-infected conventional progressor animals sustained marked but incomplete depletions of memory CD4+ T cells and continuous activation/proliferation of this T-lymphocyte subset. This was associated with a profound loss of naïve CD4+ T cells from peripheral blood and secondary lymphoid tissues, which declined at rates that correlated with disease progression. These data suggest that the persistent loss of memory CD4+T cells, which are being eliminated by direct virus killing and activation-induced cell death, requires the continuous differentiation of naïve into memory CD4+ T cells. This unrelenting replenishment process eventually leads to the exhaustion of the naïve CD4+T-cell pool and the development of disease.

Sign in / Sign up

Export Citation Format

Share Document