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 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 Antiviral Therapy during Primary Simian Immunodeficiency Virus Infection Fails To Prevent Acute Loss of CD4+ T Cells in Gut Mucosa but Enhances Their Rapid Restoration through Central Memory T Cells

2008 ◽  
Vol 82 (8) ◽  
pp. 4016-4027 ◽  
Author(s):  
David Verhoeven ◽  
Sumathi Sankaran ◽  
Melanie Silvey ◽  
Satya Dandekar
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Peripheral Blood ◽  
Viral Suppression ◽  
T Cell Responses ◽  
Cell Loss ◽  
Central Memory ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT Gut-associated lymphoid tissue (GALT) is an early target of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) and a site for severe CD4+ T-cell depletion. Although antiretroviral therapy (ART) is effective in suppressing HIV replication and restoring CD4+ T cells in peripheral blood, restoration in GALT is delayed. The role of restored CD4+ T-cell help in GALT during ART and its impact on antiviral CD8+ T-cell responses have not been investigated. Using the SIV model, we investigated gut CD4+ T-cell restoration in infected macaques, initiating ART during either the primary stage (1 week postinfection), prior to acute CD4+ cell loss (PSI), or during the chronic stage at 10 weeks postinfection (CSI). ART led to viral suppression in GALT and peripheral blood mononuclear cells of PSI and CSI animals at comparable levels. CSI animals had incomplete CD4+ T-cell restoration in GALT. In PSI animals, ART did not prevent acute CD4+ T-cell loss by 2 weeks postinfection in GALT but supported rapid and complete CD4+ T-cell restoration thereafter. This correlated with an accumulation of central memory CD4+ T cells and better suppression of inflammation. Restoration of CD4+ T cells in GALT correlated with qualitative changes in SIV gag-specific CD8+ T-cell responses, with a dominance of interleukin-2-producing responses in PSI animals, while both CSI macaques and untreated SIV-infected controls were dominated by gamma interferon responses. Thus, central memory CD4+ T-cell levels and qualitative antiviral CD8+ T-cell responses, independent of viral suppression, were the immune correlates of gut mucosal immune restoration during ART.

scholarly journals Reduced Protection from Simian Immunodeficiency Virus SIVmac251 Infection Afforded by Memory CD8+ T Cells Induced by Vaccination during CD4+ T-Cell Deficiency

2008 ◽  
Vol 82 (19) ◽  
pp. 9629-9638 ◽  
Author(s):  
Monica Vaccari ◽  
Joseph Mattapallil ◽  
Kaimei Song ◽  
Wen-Po Tsai ◽  
Anna Hryniewicz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Memory Cd8 T Cells ◽  
Cell Responses ◽  
Modified Vaccinia Virus Ankara ◽  
Immunodeficiency Virus

ABSTRACT Adaptive CD4+ and CD8+ T-cell responses have been associated with control of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication. Here, we have designed a study with Indian rhesus macaques to more directly assess the role of CD8 SIV-specific responses in control of viral replication. Macaques were immunized with a DNA prime-modified vaccinia virus Ankara (MVA)-SIV boost regimen under normal conditions or under conditions of antibody-induced CD4+ T-cell deficiency. Depletion of CD4+ cells was performed in the immunized macaques at the peak of SIV-specific CD4+ T-cell responses following the DNA prime dose. A group of naïve macaques was also treated with the anti-CD4 depleting antibody as a control, and an additional group of macaques immunized under normal conditions was depleted of CD8+ T cells prior to challenge exposure to SIVmac251. Analysis of the quality and quantity of vaccine-induced CD8+ T cells demonstrated that SIV-specific CD8+ T cells generated under conditions of CD4+ T-cell deficiency expressed low levels of Bcl-2 and interleukin-2 (IL-2), and plasma virus levels increased over time. Depletion of CD8+ T cells prior to challenge exposure abrogated vaccine-induced protection as previously shown. These data support the notion that adaptive CD4+ T cells are critical for the generation of effective CD8+ T-cell responses to SIV that, in turn, contribute to protection from AIDS. Importantly, they also suggest that long-term protection from disease will be afforded only by T-cell vaccines for HIV that provide a balanced induction of CD4+ and CD8+ T-cell responses and protect against early depletion of CD4+ T cells postinfection.

scholarly journals Inactivated Simian Immunodeficiency Virus-Pulsed Autologous Fresh Blood Cells as an Immunotherapy Strategy

2008 ◽  
Vol 83 (3) ◽  
pp. 1501-1510 ◽  
Author(s):  
Rosemarie D. Mason ◽  
Sheilajen Alcantara ◽  
Viv Peut ◽  
Liyen Loh ◽  
Jeffrey D. Lifson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Blood Cells ◽  
Mononuclear Cells ◽  
T Cell Responses ◽  
T Cell Epitopes ◽  
Peripheral Blood Mononuclear ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT Practical immunotherapies for human immunodeficiency virus infection are needed. We evaluated inactivated simian immunodeficiency virus (SIV) pulsed onto fresh peripheral blood mononuclear cells in 12 pigtail macaques with chronic SIVmac251 infection for T-cell immunogenicity in a randomized cross-over design study. The immunotherapy was safe and convincingly induced high levels of SIV-specific CD4+ T-cell responses (mean, 5.9% ± 1.3% of all CD4+ T cells) and to a lesser extent SIV-specific CD8+ T-cell responses (mean, 0.7% ± 0.4%). Responses were primarily directed toward Gag and less frequently toward Env but not Pol or regulatory/accessory SIV proteins. T-cell responses against Gag were generally broad and polyfunctional, with a mean of 2.7 CD4+ T-cell epitopes mapped per animal and more than half of the SIV Gag-specific CD4+ T cells expressing three or more effector molecules. The immunogenicity was comparable to that found in previous studies of peptide-pulsed blood cells. Despite the high-level immunogenicity, no reduction in viral load was observed in the chronically viremic macaques. This contrasts with our studies of immunization with peptide-pulsed blood cells during early SIV infection in macaques. Future studies of inactivated virus-pulsed blood cell immunotherapy during early infection of patients receiving antiretroviral therapy are warranted.

scholarly journals Gag p27-Specific B- and T-Cell Responses in Simian Immunodeficiency Virus SIVagm-Infected African Green Monkeys

2008 ◽  
Vol 83 (6) ◽  
pp. 2770-2777 ◽  
Author(s):  
José-Manuel Lozano Reina ◽  
David Favre ◽  
Zeljka Kasakow ◽  
Véronique Mayau ◽  
Marie-Thérèse Nugeyre ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antibody Response ◽  
Simian Immunodeficiency Virus ◽  
Cell Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Green Monkeys

ABSTRACT Nonpathogenic simian immunodeficiency virus SIVagm infection of African green monkeys (AGMs) is characterized by the absence of a robust antibody response against Gag p27. To determine if this is accompanied by a selective loss of T-cell responses to Gag p27, we studied CD4+ and CD8+ T-cell responses against Gag p27 and other SIVagm antigens in the peripheral blood and lymph nodes of acutely and chronically infected AGMs. Our data show that AGMs can mount a T-cell response against Gag p27, indicating that the absence of anti-p27 antibodies is not due to the absence of Gag p27-specific T cells.

scholarly journals Inhibition of Adaptive Vγ2Vδ2+ T-Cell Responses during Active Mycobacterial Coinfection of Simian Immunodeficiency Virus SIVmac-Infected Monkeys

2003 ◽  
Vol 77 (5) ◽  
pp. 2998-3006 ◽  
Author(s):  
Dejiang Zhou ◽  
Xiaomin Lai ◽  
Yun Shen ◽  
Prabhat Sehgal ◽  
Ling Shen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Γδ T Cells ◽  
Subsequent Development ◽  
T Cell Responses ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT Adaptive immune responses of γδ T cells during active mycobacterial coinfection of human immunodeficiency virus-infected humans have not been studied. Macaques infected with the simian immunodeficiency virus (SIV) SIVmac were employed to determine the extent to which a coincident AIDS virus infection might compromise immune responses of mycobacterium-specific Vγ2Vδ2+ T cells during active mycobacterial infection. Control SIVmac-negative macaques developed primary and recall expansions of phosphoantigen-specific Vγ2Vδ2+ T cells after Mycobacterium bovis BCG infection and BCG reinfection, respectively. In contrast, SIVmac-infected macaques did not exhibit sound primary and recall expansions of Vγ2Vδ2+ T cells in the blood and pulmonary alveoli following BCG infection and reinfection. The absence of adaptive Vγ2Vδ2+ T-cell responses was associated with profound CD4+ T-cell deficiency and subsequent development of SIVmac-related tuberculosis-like disease in the coinfected monkeys. Consistently, Vγ2Vδ2+ T cells from coinfected monkeys displayed a reduced capacity to expand in vitro following stimulation with phosphoantigen. The reduced ability of Vγ2Vδ2+ peripheral blood lymphocytes (PBL) to expand could be restored to some extent by coculture of these cells with CD4+ T cells purified from PBL of SIV-negative monkeys. Furthermore, naïve monkeys inoculated simultaneously with SIVmac and BCG were unable to sustain expansion of Vγ2Vδ2+ T cells at the time that the coinfected monkeys developed lymphoid depletion and a fatal tuberculosis-like disease. Nevertheless, no deletion in Vδ2 T-cell receptor repertoire was identified in SIVmac-BCG-coinfected macaques, implicating an SIVmac-induced down-regulation rather than a clonal exhaustion of these cells. Thus, an SIVmac-induced compromise of the adaptive Vγ2Vδ2+ T-cell responses may contribute to the immunopathogenesis of the SIV-related tuberculosis-like disease in macaques.

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.

scholarly journals Patterns of CD8+ Immunodominance May Influence the Ability of Mamu-B*08-Positive Macaques To Naturally Control Simian Immunodeficiency Virus SIVmac239 Replication

2007 ◽  
Vol 82 (4) ◽  
pp. 1723-1738 ◽  
Author(s):  
John T. Loffredo ◽  
Alex T. Bean ◽  
Dominic R. Beal ◽  
Enrique J. León ◽  
Gemma E. May ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Viral Replication ◽  
Simian Immunodeficiency Virus ◽  
Mhc Class I ◽  
T Cell Responses ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Memory T Lymphocytes

ABSTRACT Certain major histocompatibility complex (MHC) class I alleles are strongly associated with control of human immunodeficiency virus and simian immunodeficiency virus (SIV). CD8+ T cells specific for epitopes restricted by these molecules may be particularly effective. Understanding how CD8+ T cells contribute to control of viral replication should yield important insights for vaccine design. We have recently identified an Indian rhesus macaque MHC class I allele, Mamu-B*08, associated with elite control and low plasma viremia after infection with the pathogenic isolate SIVmac239. Here, we infected four Mamu-B*08-positive macaques with SIVmac239 to investigate why some of these macaques control viral replication. Three of the four macaques controlled SIVmac239 replication with plasma virus concentrations below 20,000 viral RNA copies/ml at 20 weeks postinfection; two of four macaques were elite controllers (ECs). Interestingly, two of the four macaques preserved their CD4+ memory T lymphocytes during peak viremia, and all four recovered their CD4+ memory T lymphocytes in the chronic phase of infection. Mamu-B*08-restricted CD8+ T-cell responses dominated the acute phase and accounted for 23.3% to 59.6% of the total SIV-specific immune responses. Additionally, the ECs mounted strong and broad CD8+ T-cell responses against several epitopes in Vif and Nef. Mamu-B*08-specific CD8+ T cells accounted for the majority of mutations in the virus at 18 weeks postinfection. Interestingly, patterns of viral variation in Nef differed between the ECs and the other two macaques. Natural containment of AIDS virus replication in Mamu-B*08-positive macaques may, therefore, be related to a combination of immunodominance and viral escape from CD8+ T-cell responses.

scholarly journals Vaccination of Macaques with DNA Followed by Adenoviral Vectors Encoding Simian Immunodeficiency Virus (SIV) Gag Alone Delays Infection by Repeated Mucosal Challenge with SIV

2019 ◽  
Vol 93 (21) ◽  
Author(s):  
Neil Almond ◽  
Neil Berry ◽  
Richard Stebbings ◽  
Mark Preston ◽  
Claire Ham ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
T Cell Responses ◽  
Virus Load ◽  
Macaque Model ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Hiv 1

ABSTRACT Vaccines aimed at inducing T cell responses to protect against human immunodeficiency virus (HIV) infection have been under development for more than 15 years. Replication-defective adenovirus (rAd) vaccine vectors are at the forefront of this work and have been tested extensively in the simian immunodeficiency virus (SIV) challenge macaque model. Vaccination with rAd vectors coding for SIV Gag or other nonenvelope proteins induces T cell responses that control virus load but disappointingly is unsuccessful so far in preventing infection, and attention has turned to inducing antibodies to the envelope. However, here we report that Mauritian cynomolgus macaques (MCM), Macaca fascicularis, vaccinated with unmodified SIV gag alone in a DNA prime followed by an rAd boost exhibit increased protection from infection by repeated intrarectal challenge with low-dose SIVmac251. There was no evidence of infection followed by eradication. A significant correlation was observed between cytokine expression by CD4 T cells and delayed infection. Vaccination with gag fused to the ubiquitin gene or fragmented, designed to increase CD8 magnitude and breadth, did not confer resistance to challenge or enhance immunity. On infection, a significant reduction in peak virus load was observed in all vaccinated animals, including those vaccinated with modified gag. These findings suggest that a nonpersistent viral vector vaccine coding for internal virus proteins may be able to protect against HIV type 1 (HIV-1) infection. The mechanisms are probably distinct from those of antibody-mediated virus neutralization or cytotoxic CD8 cell killing of virus-infected cells and may be mediated in part by CD4 T cells. IMPORTANCE The simian immunodeficiency virus (SIV) macaque model represents the best animal model for testing new human immunodeficiency virus type 1 (HIV-1) vaccines. Previous studies employing replication-defective adenovirus (rAd) vectors that transiently express SIV internal proteins induced T cell responses that controlled virus load but did not protect against virus challenge. However, we show for the first time that SIV gag delivered in a DNA prime followed by a boost with an rAd vector confers resistance to SIV intrarectal challenge. Other partially successful SIV/HIV-1 protective vaccines induce antibody to the envelope and neutralize the virus or mediate antibody-dependent cytotoxicity. Induction of CD8 T cells which do not prevent initial infection but eradicate infected cells before infection becomes established has also shown some success. In contrast, the vaccine described here mediates resistance by a different mechanism from that described above, which may reflect CD4 T cell activity. This could indicate an alternative approach for HIV-1 vaccine development.

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