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 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 Evaluation of CD8+ T-cell and antibody responses following transient increased viraemia in rhesus macaques infected with live, attenuated simian immunodeficiency virus

2005 ◽  
Vol 86 (12) ◽  
pp. 3375-3384 ◽  
Author(s):  
Karin J. Metzner ◽  
Walter J. Moretto ◽  
Sean M. Donahoe ◽  
Xia Jin ◽  
Agegnehu Gettie ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Immunodeficiency Virus ◽  
Transient Period ◽  
Antibody Titres

In vivo depletion of CD8+ T cells results in an increase in viral load in macaques chronically infected with simian immunodeficiency virus (SIVmac239Δnef). Here, the cellular and humoral immune responses associated with this transient period of enhanced viraemia in macaques infected with SIVmac239Δnef were characterized. Fourteen days after in vivo CD8+ T-cell depletion, two of six macaques experienced a 1–2 log10 increase in anti-gp130 and p27 antibody titres and a three- to fivefold increase in gamma interferon-secreting SIV-specific CD8+ T cells. Three other macaques had modest or no increase in anti-gp130 antibodies and significantly lower titres of anti-p27 antibodies, with minimal induction of functional CD8+ T cells. Four of the five CD8-depleted macaques experienced an increase in neutralizing antibody titres to SIVmac239. Induction of SIV-specific immune responses was associated with increases in CD8+ T-cell proliferation and fluctuations in the levels of signal-joint T-cell receptor excision circles in peripheral blood cells. Five months after CD8+ T-cell depletion, only the two high-responding macaques were protected from intravenous challenge with pathogenic SIV, whilst the remaining animals were unable to control replication of the challenge virus. Together, these findings suggest that a transient period of enhanced antigenaemia during chronic SIV infection may serve to augment virus-specific immunity in some, but not all, macaques. These findings have relevance for induction of human immunodeficiency virus (HIV)-specific immune responses during prophylactic and therapeutic vaccination and for immunological evaluation of structured treatment interruptions in patients chronically infected with HIV-1.

scholarly journals Effects of in Vivo Cd8+ T Cell Depletion on Virus Replication in Rhesus Macaques Immunized with a Live, Attenuated Simian Immunodeficiency Virus Vaccine

1999 ◽  
Vol 191 (11) ◽  
pp. 1921-1932 ◽  
Author(s):  
Karin J. Metzner ◽  
Xia Jin ◽  
Fred V. Lee ◽  
Agegnehu Gettie ◽  
Daniel E. Bauer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Cd8 T Cells ◽  
Rhesus Macaques ◽  
Cd8 T Cell ◽  
T Cell Depletion ◽  
Challenge Virus ◽  
Immunodeficiency Virus

The role of CD8+ T lymphocytes in controlling replication of live, attenuated simian immunodeficiency virus (SIV) was investigated as part of a vaccine study to examine the correlates of protection in the SIV/rhesus macaque model. Rhesus macaques immunized for >2 yr with nef-deleted SIV (SIVmac239Δnef) and protected from challenge with pathogenic SIVmac251 were treated with anti-CD8 antibody (OKT8F) to deplete CD8+ T cells in vivo. The effects of CD8 depletion on viral load were measured using a novel quantitative assay based on real-time polymerase chain reaction using molecular beacons. This assay allows simultaneous detection of both the vaccine strain and the challenge virus in the same sample, enabling direct quantification of changes in each viral population. Our results show that CD8+ T cells were depleted within 1 h after administration of OKT8F, and were reduced by as much as 99% in the peripheral blood. CD8+ T cell depletion was associated with a 1–2 log increase in SIVmac239Δnef plasma viremia. Control of SIVmac239Δnef replication was temporally associated with the recovery of CD8+ T cells between days 8 and 10. The challenge virus, SIVmac251, was not detectable in either the plasma or lymph nodes after depletion of CD8+ T cells. Overall, our results indicate that CD8+ T cells play an important role in controlling replication of live, attenuated SIV in vivo.

scholarly journals Simian immunodeficiency virus types 1 and 2 (SIV mnd 1 and 2) have different pathogenic potentials in rhesus macaques upon experimental cross-species transmission

2009 ◽  
Vol 90 (2) ◽  
pp. 488-499 ◽  
Author(s):  
Sandrine Souquière ◽  
Richard Onanga ◽  
Maria Makuwa ◽  
Ivona Pandrea ◽  
Paul Ngari ◽  
...  
Keyword(s):  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Virus Replication ◽  
Rhesus Macaques ◽  
Natural Infection ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Viral Loads ◽  
Cell Counts ◽  
Immunodeficiency Virus

The mandrill (Mandrillus sphinx) is naturally infected by two types of simian immunodeficiency virus (SIV): SIVmnd types 1 and 2. Both of these viruses cause long-term, non-progressive infections in their natural host despite high plasma viral loads. This study assessed the susceptibility of rhesus macaques to infection by these two types of SIVmnd and compared the virological and basic immunological characteristics of the resulting infections with those observed in natural infection in mandrills. Whilst both SIVmnd types induced similar levels of virus replication during acute infection in both mandrills and macaques, they produced a more pronounced CD4+ T-cell depletion in rhesus macaques that persisted longer during the initial stage of infection. Pro-inflammatory cytokine responses were also induced at higher levels in rhesus macaques early in the infection. During the chronic phase of infection in mandrills, which in this case was followed for up to 2 years after infection, high levels of chronic virus replication did not induce significant changes in CD4+ or CD8+ T-cell counts. In rhesus macaques, the overall chronic virus replication level was lower than in mandrills. At the end of the follow-up period, although the viral loads of SIVmnd-1 and SIVmnd-2 were relatively similar in rhesus macaques, only SIVmnd-1-infected rhesus macaques showed significant CD4+ T-cell depletion, in the context of higher levels of CD4+ and CD8+ T-cell activation, compared with SIVmnd-infected mandrills. The demonstration of the ability of both SIVmnd types to induce persistent infections in rhesus macaques calls for a careful assessment of the potential of these two viruses to emerge as new human pathogens.

scholarly journals Dysregulation of the Polo-Like Kinase Pathway in CD4+ T Cells Is Characteristic of Pathogenic Simian Immunodeficiency Virus Infection

2004 ◽  
Vol 78 (3) ◽  
pp. 1464-1472 ◽  
Author(s):  
Pavel Bostik ◽  
Geraldine L. Dodd ◽  
Francois Villinger ◽  
Ann E. Mayne ◽  
Aftab A. Ansari
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Intracellular Signaling ◽  
Immunodeficiency Virus ◽  
M Phase ◽  
Siv Infection

ABSTRACT CD4+ T-cell dysfunction highlighted by defects within the intracellular signaling cascade and cell cycle has long been characterized as a direct and/or indirect consequence of human immunodeficiency virus (HIV) infection in humans and simian immunodeficiency virus (SIV) infection in rhesus macaques (RM). Dysregulation of the M phase of the cell cycle is a well-documented effect of HIV or SIV infection both in vivo and in vitro. In this study the effect of SIV infection on the modulation of two important regulators of the M phase—polo-like kinases Plk3 and Plk1—was investigated. We have previously shown that Plk3 is markedly downregulated in CD4+ T cells from SIV-infected disease-susceptible RM but not SIV-infected disease-resistant sooty mangabeys (SM), denoting an association of downregulation with disease progression. Here we show that, in addition to the downregulation, Plk3 exhibits aberrant activation patterns in the CD4+ T cells from SIV-infected RM following T-cell receptor stimulation. Interestingly, in vitro SIV infection of CD4+ T cells leads to the upregulation, rather than downregulation, of Plk3, suggesting that different mechanisms operate in vitro and in vivo. In addition, CD4+ T cells from RM with high viral loads exhibited consistent and significant upregulation of Plk1, concurrent with an aberrant activation-induced Plk1 response, suggesting complex mechanisms of SIV-induced M-phase abnormalities in vivo. Altogether this study presents a novel mechanism underlying M-phase defects observed in CD4+ T cells from HIV or SIV-infected disease-susceptible humans and RM which may contribute to aberrant T-cell responses and disease pathogenesis.

scholarly journals Simian Immunodeficiency Virus Infection in Neonatal Macaques

2003 ◽  
Vol 77 (16) ◽  
pp. 8783-8792 ◽  
Author(s):  
Ronald S. Veazey ◽  
Jeffrey D. Lifson ◽  
Ivona Pandrea ◽  
Jeannette Purcell ◽  
Michael Piatak ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Simian Immunodeficiency Virus ◽  
Lamina Propria ◽  
Cell Depletion ◽  
Lymphoid Tissues ◽  
T Cell Depletion ◽  
Viral Loads ◽  
Immunodeficiency Virus

ABSTRACT Children with human immunodeficiency virus infection often have higher viral loads and progress to AIDS more rapidly than adults. Since the intestinal tract is a major site of early viral replication and CD4+ T-cell depletion in adults, we examined the effects of simian immunodeficiency virus (SIV) on both peripheral and intestinal lymphocytes from 13 neonatal macaques infected with SIVmac239. Normal neonates had more CD4+ T cells and fewer CD8+ T cells in all tissues than adults. Surprisingly, neonates had substantial percentages of CD4+ T cells with an activated, memory phenotype (effector CD4+ T cells) in the lamina propria of the intestine compared to peripheral lymphoid tissues, even when examined on the day of birth. Moreover, profound and selective depletion of jejunum lamina propria CD4+ T cells occurred in neonatal macaques within 21 days of infection, which was preceded by large numbers of SIV-infected cells in this compartment. Furthermore, neonates with less CD4+ T-cell depletion in tissues tended to have higher viral loads. The persistence of intestinal lamina propria CD4+ T cells in some neonates with high viral loads suggests that increased turnover and/or resistance to CD4+ T-cell loss may contribute to the higher viral loads and increased severity of disease in neonatal hosts.

scholarly journals Gastrointestinal T Lymphocytes Retain High Potential for Cytokine Responses but Have Severe CD4+ T-Cell Depletion at All Stages of Simian Immunodeficiency Virus Infection Compared to Peripheral Lymphocytes

1998 ◽  
Vol 72 (8) ◽  
pp. 6646-6656 ◽  
Author(s):  
Zeljka Smit-McBride ◽  
Joseph J. Mattapallil ◽  
Michael McChesney ◽  
David Ferrick ◽  
Satya Dandekar
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Lymph Nodes ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Cytokine Responses ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Ifn Γ

ABSTRACT Gastrointestinal complications in human immunodeficiency virus (HIV) infection are indicative of impaired intestinal mucosal immune system. We used simian immunodeficiency virus (SIV)-infected rhesus macaques as an animal model for HIV to determine pathogenic effects of SIV on intestinal T lymphocytes. Intestinal CD4+ T-cell depletion and the potential for cytokine responses were examined during SIV infection and compared with results for lymphocytes from lymph nodes and blood. Flow cytometric analysis demonstrated severe depletion of CD4+CD8− single-positive T cells and CD4+CD8+ double-positive T cells in intestinal lamina propria lymphocytes (LPL) and intraepithelial lymphocytes (IEL) during primary SIV infection which persisted through the entire course of SIV infection. In contrast, CD4+ T-cell depletion was gradual in peripheral lymph nodes and blood. Flow cytometric analysis of intracellular gamma interferon (IFN-γ) and interleukin-4 (IL-4) production following short-term mitogenic activation revealed that LPL retained same or higher capacity for IFN-γ production in all stages of SIV infection compared to uninfected controls, whereas peripheral blood mononuclear cells displayed a gradual decline. The CD8+ T cells were the major producers of IFN-γ. There was no detectable change in the frequency of IL-4-producing cells in both LPL and peripheral blood mononuclear cells. Thus, severe depletion of CD4+ LPL and IEL in primary SIV infection accompanied by altered cytokine responses may reflect altered T-cell homeostasis in intestinal mucosa. This could be a mechanism of SIV-associated enteropathy and viral pathogenesis. Dynamic changes in intestinal T lymphocytes were not adequately represented in peripheral lymph nodes or blood.

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 Dynamics of CCR5 Expression by CD4+ T Cells in Lymphoid Tissues during Simian Immunodeficiency Virus Infection

2000 ◽  
Vol 74 (23) ◽  
pp. 11001-11007 ◽  
Author(s):  
Ronald S. Veazey ◽  
Keith G. Mansfield ◽  
Irene C. Tham ◽  
Angela C. Carville ◽  
Daniel E. Shvetz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Simian Immunodeficiency Virus ◽  
Cell Loss ◽  
Lymphoid Tissues ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Spleen And Lymph Nodes

ABSTRACT Early viral replication and profound CD4+ T-cell depletion occur preferentially in intestinal tissues of macaques infected with simian immunodeficiency virus (SIV). Here we show that a much higher percentage of CD4+ T cells in the intestine express CCR5 compared with those found in the peripheral blood, spleen, or lymph nodes. In addition, the selectivity and extent of the CD4+ T-cell loss in SIV infection may depend upon these cells coexpressing CCR5 and having a “memory” phenotype (CD45RA−). Following intravenous infection with SIVmac251, memory CD4+ CCR5+ T cells were selectively eliminated within 14 days in all major lymphoid tissues (intestine, spleen, and lymph nodes). However, the effect on CD4+T-cell numbers was most profound in the intestine, where cells of this phenotype predominate. The CD4+ T cells that remain after 14 days of infection lacked CCR5 and/or were naive (CD45RA+). Furthermore, when animals in the terminal stages of SIV infection (with AIDS) were examined, virtually no CCR5-expressing CD4+ T cells were found in lymphoid tissues, and all of the remaining CD4+ T cells were naive and coexpressed CXCR4. These findings suggest that chemokine receptor usage determines which cells are targeted for SIV infection and elimination in vivo.

scholarly journals V3 Loop-Determined Coreceptor Preference Dictates the Dynamics of CD4+-T-Cell Loss in Simian-Human Immunodeficiency Virus-Infected Macaques

2005 ◽  
Vol 79 (19) ◽  
pp. 12296-12303 ◽  
Author(s):  
Siu-hong Ho ◽  
Lili Shek ◽  
Agegnehu Gettie ◽  
James Blanchard ◽  
Cecilia Cheng-Mayer
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Target Cell ◽  
Cell Depletion ◽  
V3 Loop ◽  
Coreceptor Usage ◽  
T Cell Depletion ◽  
Immunodeficiency Virus

ABSTRACT We used experimental infection of rhesus macaques with envelope gp120 V3 loop isogenic simian-human immunodeficiency virus (SHIV) molecular clones to more clearly define the impact of human immunodeficiency virus type 1 coreceptor usage in target cell selectivity and the rates of CD4+-T-cell depletion. Functional assays demonstrate that substitution of the V3 loop of the pathogenic CXCR4-tropic (X4) SHIVSF33A2 molecular clone with the corresponding sequences from the CCR5-tropic (R5) SHIVSF162P3 isolate resulted in a switch of coreceptor usage from CXCR4 to CCR5. The resultant R5 clone, designated SHIVSF33A2(V3), is replication competent in vivo, infecting two of two macaques by intravenous inoculation with peak viremia that is comparable to that seen in monkeys infected with X4-SHIVSF33A2. But while primary infection with the X4 clone was accompanied by rapid and significant loss of peripheral and secondary lymphoid CD4+ T lymphocytes, infection with R5-SHIVSF33A2(V3) led to only a modest and transient loss. However, substantial depletion of intestinal CD4+ T cells was observed in R5-SHIVSF33A2(V3)-infected macaques. Moreover, naïve T cells that expressed high levels of CXCR4 were rapidly depleted in X4-SHIVSF33A2-infected macaques, whereas R5-SHIVSF33A2(V3) infection mainly affected memory T cells that expressed CCR5. These findings in a unique isogenic system illustrate that coreceptor usage is the principal determinant of tissue and target cell specificity of the virus in vivo and dictates the dynamics of CD4+-T-cell depletion during SHIV infection.

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