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 Identifying the Target Cell in Primary Simian Immunodeficiency Virus (SIV) Infection: Highly Activated Memory CD4+ T Cells Are Rapidly Eliminated in Early SIV Infection In Vivo

2000 ◽  
Vol 74 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Ronald S. Veazey ◽  
Irene C. Tham ◽  
Keith G. Mansfield ◽  
MaryAnn DeMaria ◽  
Amy E. Forand ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Cell Depletion ◽  
Cell Type ◽  
T Cell Depletion ◽  
Cell Counts ◽  
Immunodeficiency Virus ◽  
Siv Infection

ABSTRACT It has recently been shown that rapid and profound CD4+T-cell depletion occurs almost exclusively within the intestinal tract of simian immunodeficiency virus (SIV)-infected macaques within days of infection. Here we demonstrate (by three- and four-color flow cytometry) that this depletion is specific to a definable subset of CD4+ T cells, namely, those having both a highly and/or acutely activated (CD69+ CD38+HLA-DR+) and memory (CD45RA−Leu8−) phenotype. Moreover, we demonstrate that this subset of helper T cells is found primarily within the intestinal lamina propria. Viral tropism for this particular cell type (which has been previously suggested by various studies in vitro) could explain why profound CD4+ T-cell depletion occurs in the intestine and not in peripheral lymphoid tissues in early SIV infection. Furthermore, we demonstrate that an acute loss of this specific subset of activated memory CD4+ T cells may also be detected in peripheral blood and lymph nodes in early SIV infection. However, since this particular cell type is present in such small numbers in circulation, its loss does not significantly affect total CD4+ T cell counts. This finding suggests that SIV and, presumably, human immunodeficiency virus specifically infect, replicate in, and eliminate definable subsets of CD4+ T cells in vivo.

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 Virus Subtype-Specific Features of Natural Simian Immunodeficiency Virus SIVsmm Infection in Sooty Mangabeys

2007 ◽  
Vol 81 (15) ◽  
pp. 7913-7923 ◽  
Author(s):  
Cristian Apetrei ◽  
Rajeev Gautam ◽  
Beth Sumpter ◽  
Anders C. Carter ◽  
Thaidra Gaufin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Genetic Distances ◽  
Primate Research ◽  
Systematic Analysis ◽  
Cell Counts ◽  
Immunodeficiency Virus ◽  
Sooty Mangabeys ◽  
Direct Killing

ABSTRACT Simian immunodeficiency virus (SIV) SIVsmm naturally infects sooty mangabeys (SMs) and is the source virus of pathogenic infections with human immunodeficiency virus type 2 (HIV-2) and SIVmac of humans and macaques, respectively. In previous studies we characterized SIVsmm diversity in naturally SIV-infected SMs and identified nine different phylogenetic subtypes whose genetic distances are similar to those reported for the different HIV-1 group M subtypes. Here we report that, within the colony of SMs housed at the Yerkes National Primate Research Center, at least four SIVsmm subtypes cocirculate, with the vast majority of animals infected with SIVsmm subtype 1, 2, or 3, resulting in the emergence of occasional recombinant forms. While SIVsmm-infected SMs show a typically nonpathogenic course of infection, we have observed that different SIVsmm subtypes are in fact associated with specific immunologic features. Notably, while subtypes 1, 2, and 3 are associated with a very benign course of infection and preservation of normal CD4+ T-cell counts, three out of four SMs infected with subtype 5 show a significant depletion of CD4+ T cells. The fact that virus replication in SMs infected with subtype 5 is similar to that in SMs infected with other SIVsmm subtypes suggests that the subtype 5-associated CD4+ T-cell depletion is unlikely to simply reflect higher levels of virus-mediated direct killing of CD4+ T-cells. Taken together, this systematic analysis of the subtype-specific features of SIVsmm infection in natural SM hosts identifies subtype-specific differences in the pathogenicity of SIVsmm infection.

scholarly journals Next-Generation mRNA Sequencing Reveals Pyroptosis-Induced CD4+T Cell Death in Early Simian Immunodeficiency Virus-Infected Lymphoid Tissues

2015 ◽  
Vol 90 (2) ◽  
pp. 1080-1087 ◽  
Author(s):  
Wuxun Lu ◽  
Andrew J. Demers ◽  
Fangrui Ma ◽  
Guobin Kang ◽  
Zhe Yuan ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Immune Activation ◽  
Lymphoid Tissues ◽  
Host Interactions ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Hiv 1

ABSTRACTLymphoid tissues (LTs) are the principal sites where human immunodeficiency virus type 1 (HIV-1) replicates and virus-host interactions take place, resulting in immunopathology in the form of inflammation, immune activation, and CD4+T cell death. The HIV-1 pathogenesis in LTs has been extensively studied; however, our understanding of the virus-host interactions in the very early stages of infection remains incomplete. We investigated virus-host interactions in the rectal draining lymph nodes (dLNs) of rhesus macaques at different times after intrarectal inoculation (days postinoculation [dpi]) with simian immunodeficiency virus (SIV). At 3 dpi, 103 differentially expressed genes (DEGs) were detected using next-generation mRNA sequencing (RNA-seq). At 6 and 10 dpi, concomitant with increased SIV replication, 366 and 1,350 DEGs were detected, respectively, including upregulation of genes encoding proteins that play a role in innate antiviral immune responses, inflammation, and immune activation. Notably, genes (IFI16, caspase-1, and interleukin 1β [IL-1β]) in the canonical pyroptosis pathway were significantly upregulated in expression. We further validated increased pyroptosis using flow cytometry and found that the number of CD4+T cells expressing activated caspase-1 protein, the hallmark of ongoing pyroptosis, were significantly increased, which is correlated with decreased CD4+T cells in dLNs. Our results demonstrated that pyroptosis contributes to the CD4+T cell deathin vivoin early SIV infection, which suggests that pyroptosis may play a pivotal role in the pathogenesis of SIV, and by extension, that of HIV-1, since pyroptosis not only induces CD4+T cell death but also amplifies inflammation and immune activation. Thus, blocking CD4+T cell pyroptosis could be a complementary treatment to antiretroviral therapy.IMPORTANCEAlthough secondary lymphoid tissues (LTs) are principal sites of human immunodeficiency virus type 1 (HIV-1) replication, inflammation, immune activation, and CD4+T cell death, immunopathogenesis in LTs during early infection remains largely unknown. Using the simian immunodeficiency virus (SIV)/rhesus monkey model of HIV rectal infection, we investigated early virus-host interactions. Our results revealed elevated potent host responses in early infection in LTs, including upregulation of genes involved in antiviral immune response, inflammation, and immune activation. Importantly, genes involved in the canonical pyroptosis pathway were significantly upregulated, and there was a strong correlation between CD4+T cell decrease and increased number of CD4+T cells expressing activated caspase-1 protein, demonstrating that pyroptosis contributes to CD4+T cell deathin vivoin very early SIV infection. Our finding suggests that blocking pyroptosis may be able to decrease CD4+T cell loss during early SIV infection.

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 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 Relative Resistance in the Development of T Cell Anergy in CD4+T Cells from Simian Immunodeficiency Virus Disease-Resistant Sooty Mangabeys

2001 ◽  
Vol 166 (1) ◽  
pp. 506-516 ◽  
Author(s):  
Pavel Bostik ◽  
Ann E. Mayne ◽  
Francois Villinger ◽  
Kenneth P. Greenberg ◽  
Jonathan D. Powell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Cd4 T Cells ◽  
Virus Disease ◽  
Relative Resistance ◽  
T Cell Anergy ◽  
Immunodeficiency Virus ◽  
Sooty Mangabeys ◽  
Cell Anergy

scholarly journals Intestinal Intraepithelial Lymphocytes Are Primed for Gamma Interferon and MIP-1β Expression and Display Antiviral Cytotoxic Activity despite Severe CD4+ T-Cell Depletion in Primary Simian Immunodeficiency Virus Infection

1998 ◽  
Vol 72 (8) ◽  
pp. 6421-6429 ◽  
Author(s):  
Joseph J. Mattapallil ◽  
Zeljka Smit-McBride ◽  
Michael McChesney ◽  
Satya Dandekar
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Intraepithelial Lymphocytes ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Ifn Γ ◽  
Ctl Activity

ABSTRACT Intraepithelial lymphocytes (IEL) are a critical effector component of the gut-associated lymphoid tissue (GALT) and play an important role in mucosal immunity as well as in the maintenance of the epithelial cell integrity and barrier function. The objective of this study was to determine whether simian immunodeficiency virus (SIV) infection of rhesus macaques would cause alterations in the immunophenotypic profiles of IEL and their mitogen-specific cytokine (gamma interferon [IFN-γ] and MIP-1β) responses (by flow cytometry) and virus-specific cytotoxic T-cell (CTL) activity (by the chromium release assay). Virally infected IEL were detected through the entire course of SIV infection by in situ hybridization. Severe depletion of CD4+ single-positive and CD4+CD8+ double-positive T cells occurred early in primary SIV infection, which was coincident with an increased prevalence of CD8+ T cells. This was in contrast to a gradual depletion of CD4+ T cells in peripheral blood. The CD8+ IEL were the primary producers of IFN-γ and MIP-1β and were found to retain their potential to produce both IFN-γ and MIP-1β through the entire course of SIV infection. SIV-specific CTL activity was detected in primary IEL at 1, 2, and 4 weeks post-SIV infection. These results demonstrated that IEL may be involved in generating antiviral immune responses early in SIV infection and in suppressing viral infection thereafter. Alterations in homeostasis in epithelia due to severe CD4+ T-cell depletion accompanied by changes in the cytokine and chemokine production by IEL may play a role in the enteropathogenesis of SIV infection.

scholarly journals Naive T cells are dispensable for memory CD4+ T cell homeostasis in progressive simian immunodeficiency virus infection

2012 ◽  
Vol 209 (4) ◽  
pp. 641-651 ◽  
Author(s):  
Afam A. Okoye ◽  
Mukta Rohankhedkar ◽  
Chike Abana ◽  
Audrie Pattenn ◽  
Matthew Reyes ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Progression ◽  
Simian Immunodeficiency Virus ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Naïve T Cells ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Siv Infection

The development of AIDS in chronic HIV/simian immunodeficiency virus (SIV) infection has been closely linked to progressive failure of CD4+ memory T cell (TM) homeostasis. CD4+ naive T cells (TN) also decline in these infections, but their contribution to disease progression is less clear. We assessed the role of CD4+ TN in SIV pathogenesis using rhesus macaques (RMs) selectively and permanently depleted of CD4+ TN before SIV infection. CD4+ TN-depleted and CD4+ TN-repleted RMs were created by subjecting juvenile RMs to thymectomy versus sham surgery, respectively, followed by total CD4+ T cell depletion and recovery from this depletion. Although thymectomized and sham-treated RMs manifested comparable CD4+ TM recovery, only sham-treated RMs reconstituted CD4+ TN. CD4+ TN-depleted RMs responded to SIVmac239 infection with markedly attenuated SIV-specific CD4+ T cell responses, delayed SIVenv-specific Ab responses, and reduced SIV-specific CD8+ T cell responses. However, CD4+ TN-depleted and -repleted groups showed similar levels of SIV replication. Moreover, CD4+ TN deficiency had no significant effect on CD4+ TM homeostasis (either on or off anti-retroviral therapy) or disease progression. These data demonstrate that the CD4+ TN compartment is dispensable for CD4+ TM homeostasis in progressive SIV infection, and they confirm that CD4+ TM comprise a homeostatically independent compartment that is intrinsically capable of self-renewal.

scholarly journals Decreased Levels of Recent Thymic Emigrants in Peripheral Blood of Simian Immunodeficiency Virus-Infected Macaques Correlate with Alterations within the Thymus

2002 ◽  
Vol 76 (19) ◽  
pp. 9981-9990 ◽  
Author(s):  
Donald L. Sodora ◽  
Jeffrey M. Milush ◽  
Felecia Ware ◽  
Aneta Wozniakowski ◽  
Lisa Montgomery ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Peripheral Blood ◽  
T Cell Proliferation ◽  
Cell Populations ◽  
Recent Thymic Emigrants ◽  
Immunodeficiency Virus ◽  
Siv Infection

ABSTRACT The thymus is responsible for de novo production of CD4+ and CD8+ T cells and therefore is essential for T-cell renewal. The goal of this study was to assess the impact of simian immunodeficiency virus (SIV) infection on the production of T cells by the thymus. Levels of recent thymic emigrants within the peripheral blood were assessed through quantification of macaque T-cell receptor excision circles (TREC). Comparison of SIV-infected macaques (n = 15) to uninfected macaques (n = 23) revealed stable or increased TREC levels at 20 to 34 weeks postinfection. Further assessment of SIV-infected macaques (n = 4) determined that TREC levels decreased between 24 and 48 weeks postinfection. Through the assessment of longitudinal time points in three additional SIVmac239-infected macaques, the SIV infection was divided into two distinct phases. During phase 1 (16 to 30 weeks), TREC levels remained stable or increased within both the CD4 and CD8 T-cell populations. During phase 2 (after 16 to 30 weeks), TREC levels declined in both T-cell populations. As has been described for human immunodeficiency virus (HIV)-infected patients, this decline in TREC levels did at times correlate with an increased level of T-cell proliferation (Ki67+ cells). However, not all TREC decreases could be attributed to increased T-cell proliferation. Further evidence for thymic dysfunction was observed directly in a SIVmac239-infected macaque that succumbed to simian AIDS at 65 weeks postinfection. The thymus of this macaque contained an increased number of memory/effector CD8+ T cells and an increased level of apoptotic cells. In summary, reduced levels of TREC can be observed beginning at 16 to 30 weeks post-SIV infection and correlate with changes indicative of dysfunction within the thymic tissue. SIV infection of macaques will be a useful model system to elucidate the mechanisms responsible for the thymic dysfunction observed in HIV-infected patients.

Sign in / Sign up

Export Citation Format

Share Document