scholarly journals Rapid Appearance of Secondary Immune Responses and Protection from Acute CD4 Depletion after a Highly Pathogenic Immunodeficiency Virus Challenge in Macaques Vaccinated with a DNA Prime/Sendai Virus Vector Boost Regimen

2001 ◽  
Vol 75 (23) ◽  
pp. 11891-11896 ◽  
Author(s):  
Tetsuro Matano ◽  
Munehide Kano ◽  
Hiromi Nakamura ◽  
Akiko Takeda ◽  
Yoshiyuki Nagai
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Sendai Virus ◽  
Cell Depletion ◽  
Highly Pathogenic ◽  
T Cell Depletion ◽  
Boost Regimen ◽  
Viral Loads ◽  
Immunodeficiency Virus

ABSTRACT Heterologous prime/boost regimens are AIDS vaccine candidates because of their potential for inducing cellular immune responses. Here, we have developed a prime/boost regimen leading to rapid control of highly pathogenic immunodeficiency virus infection in macaques. The strategy, priming by an env and nefdeletion-containing simian-human immunodeficiency virus (SHIV) proviral DNA followed by a single booster with a Gag-expressing Sendai virus (SeV-Gag), efficiently induced virus-specific T cells, which were maintained for more than 3 months until challenge. While all naive control macaques showed acute CD4+ T-cell depletion at week 2 after an intravenous SHIV89.6PD challenge, all the macaques vaccinated with the prime/boost regimen were protected from depletion and showed greatly reduced peak viral loads compared with controls. Vaccination with the DNA alone or SeV-Gag alone was not enough to confer the consistent protection from the depletion, although it led to efficient secondary CD8+ T-cell responses at week 2 after challenge. At week 1, a difference in the secondary responses between the protected and the unprotected macaques was clear; rapid augmentation of virus-specific CD8+ T cells was detected in the former but not in the latter. Thus, our results indicate the importance of rapid secondary responses for reduction in the peak viral loads and protection from acute CD4+ T-cell depletion.

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 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 Activation of the CD95 (APO-1/Fas) system in T cells from human immunodeficiency virus type-1-infected children

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1741-1746 ◽  
Author(s):  
CB Baumler ◽  
T Bohler ◽  
I Herr ◽  
A Benner ◽  
PH Krammer ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Immunodeficiency Virus ◽  
Hiv 1

Abstract Increased apoptosis of CD4+ T cells is considered to be involved in CD4+ T-cell depletion in human immunodeficiency virus type-1 (HIV-1)- infected individuals progressing toward acquired immunodeficiency syndrome (AIDS). We have recently shown that CD95 (APO-1/Fas) expression is strongly increased in T cells of HIV-1-infected children. In this report we provide further evidence for a deregulated CD95 system in AIDS. CD95 expression in HIV-1+ children is not restricted to previously activated CD45RO+ T cells but is also increased on freshly isolated naive CD45RA+ T cells. In addition, specific CD95-mediated apoptosis is enhanced in both CD4+ and CD8+ T cells. Furthermore, levels of CD95 ligand mRNA are profoundly increased. Specific T-cell receptor/CD3-triggered apoptosis in HIV-1+ children is more enhanced in CD8+ than in CD4+ T cells. Accelerated activation induced cell death of T cells could partially be inhibited by blocking anti-CD95 antibody fragments. These data suggest an involvement of the CD95 receptor/ligand system in T-cell depletion and apoptosis in AIDS and may open new avenues of rational intervention strategies.

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 Small Intestine CD4+ T Cells Are Profoundly Depleted during Acute Simian-Human Immunodeficiency Virus Infection, Regardless of Viral Pathogenicity

2007 ◽  
Vol 82 (12) ◽  
pp. 6039-6044 ◽  
Author(s):  
Yoshinori Fukazawa ◽  
Ariko Miyake ◽  
Kentaro Ibuki ◽  
Katsuhisa Inaba ◽  
Naoki Saito ◽  
...  
Keyword(s):  
T Cells ◽  
Small Intestine ◽  
T Cell ◽  
Virus Replication ◽  
Acute Infection ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Immunodeficiency Virus ◽  
Human Immunodeficiency Viruses ◽  
The Relationship

ABSTRACT To analyze the relationship between acute virus-induced injury and the subsequent disease phenotype, we compared the virus replication and CD4+ T-cell profiles for monkeys infected with isogenic highly pathogenic (KS661) and moderately pathogenic (#64) simian-human immunodeficiency viruses (SHIVs). Intrarectal infusion of SHIV-KS661 resulted in rapid, systemic, and massive virus replication, while SHIV-#64 replicated more slowly and reached lower titers. Whereas KS661 systemically depleted CD4+ T cells, #64 caused significant CD4+ T-cell depletion only in the small intestine. We conclude that SHIV, regardless of pathogenicity, can cause injury to the small intestine and leads to CD4+ T-cell depletion in infected animals during acute infection.

scholarly journals Distinct Mechanisms of CD4+ and CD8+ T-Cell Activation and Bystander Apoptosis Induced by Human Immunodeficiency Virus Type 1 Virions

2005 ◽  
Vol 79 (10) ◽  
pp. 6299-6311 ◽  
Author(s):  
Geoffrey H. Holm ◽  
Dana Gabuzda
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Hla Dr ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Apoptosis of uninfected bystander T cells contributes to T-cell depletion during human immunodeficiency virus type 1 (HIV-1) infection. HIV-1 envelope/receptor interactions and immune activation have been implicated as contributors to bystander apoptosis. To better understand the relationship between T-cell activation and bystander apoptosis during HIV-1 pathogenesis, we investigated the effects of the highly cytopathic CXCR4-tropic HIV-1 variant ELI6 on primary CD4+ and CD8+ T cells. Infection of primary T-cell cultures with ELI6 induced CD4+ T-cell depletion by direct cell lysis and bystander apoptosis. Exposure of primary CD4+ and CD8+ T cells to nonreplicating ELI6 virions induced bystander apoptosis through a Fas-independent mechanism. Bystander apoptosis of CD4+ T cells required direct contact with virions and Env/CXCR4 binding. In contrast, the apoptosis of CD8+ T cells was triggered by a soluble factor(s) secreted by CD4+ T cells. HIV-1 virions activated CD4+ and CD8+ T cells to express CD25 and HLA-DR and preferentially induced apoptosis in CD25+HLA-DR+ T cells in a CXCR4-dependent manner. Maximal levels of binding, activation, and apoptosis were induced by virions that incorporated MHC class II and B7-2 into the viral membrane. These results suggest that nonreplicating HIV-1 virions contribute to chronic immune activation and T-cell depletion during HIV-1 pathogenesis by activating CD4+ and CD8+ T cells, which then proceed to die via apoptosis. This mechanism may represent a viral immune evasion strategy to increase viral replication by activating target cells while killing immune effector cells that are not productively infected.

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 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 Activation of the CD95 (APO-1/Fas) system in T cells from human immunodeficiency virus type-1-infected children

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1741-1746 ◽  
Author(s):  
CB Baumler ◽  
T Bohler ◽  
I Herr ◽  
A Benner ◽  
PH Krammer ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Immunodeficiency Virus ◽  
Hiv 1

Increased apoptosis of CD4+ T cells is considered to be involved in CD4+ T-cell depletion in human immunodeficiency virus type-1 (HIV-1)- infected individuals progressing toward acquired immunodeficiency syndrome (AIDS). We have recently shown that CD95 (APO-1/Fas) expression is strongly increased in T cells of HIV-1-infected children. In this report we provide further evidence for a deregulated CD95 system in AIDS. CD95 expression in HIV-1+ children is not restricted to previously activated CD45RO+ T cells but is also increased on freshly isolated naive CD45RA+ T cells. In addition, specific CD95-mediated apoptosis is enhanced in both CD4+ and CD8+ T cells. Furthermore, levels of CD95 ligand mRNA are profoundly increased. Specific T-cell receptor/CD3-triggered apoptosis in HIV-1+ children is more enhanced in CD8+ than in CD4+ T cells. Accelerated activation induced cell death of T cells could partially be inhibited by blocking anti-CD95 antibody fragments. These data suggest an involvement of the CD95 receptor/ligand system in T-cell depletion and apoptosis in AIDS and may open new avenues of rational intervention strategies.

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.

Sign in / Sign up

Export Citation Format

Share Document