scholarly journals Experimental Coinfection of Rhesus Macaques with Rhesus Cytomegalovirus and Simian Immunodeficiency Virus: Pathogenesis

2002 ◽  
Vol 76 (15) ◽  
pp. 7661-7671 ◽  
Author(s):  
Getachew Sequar ◽  
William J. Britt ◽  
Fred D. Lakeman ◽  
Kristen M. Lockridge ◽  
Ross P. Tarara ◽  
...  
Keyword(s):  
Immune Response ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Rapid Development ◽  
Pathogenic Potential ◽  
Copy Numbers ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Antibody Titers ◽  
Rhesus Cytomegalovirus

ABSTRACT Human cytomegalovirus (HCMV) possesses low pathogenic potential in an immunocompetent host. In the immunosuppressed host, however, a wide spectrum of infection outcomes, ranging from asymptomatic to life threatening, can follow either primary or nonprimary infection. The variability in the manifestations of HCMV infection in immunosuppressed individuals implies that there is a threshold of host antiviral immunity that can effectively limit disease potential. We used a nonhuman primate model of CMV infection to assess the relationship between CMV disease and the levels of developing anti-CMV immunity. Naive rhesus macaques were inoculated with rhesus cytomegalovirus (RhCMV) followed 2 or 11 weeks later by inoculation with pathogenic simian immunodeficiency virus SIVmac239. Two of four monkeys inoculated with SIV at 2 weeks after inoculation with RhCMV died within 11 weeks with simian AIDS (SAIDS), including activated RhCMV infection. Neither animal had detectable anti-SIV antibodies. The other two animals died 17 and 27 weeks after SIV inoculation with either SAIDS or early lymphoid depletion, although no histological evidence of activated RhCMV was observed. Both had weak anti-SIV antibody titers. RhCMV antibody responses for this group of monkeys were significantly below those of control animals inoculated with only RhCMV. In addition, all animals of this group had persistent RhCMV DNA in plasma and high copy numbers of RhCMV in tissues. In contrast, animals that were inoculated with SIV at 11 weeks after RhCMV infection rarely exhibited RhCMV DNA in plasma, had low copy numbers of RhCMV DNA in most tissues, and did not develop early onset of SAIDS or activated RhCMV. SIV antibody titers were mostly robust and sustained in these monkeys. SIV inoculation blunted further development of RhCMV humoral responses, unlike the normal pattern of development in control monkeys following RhCMV inoculation. Anti-RhCMV immunoglobulin G levels and avidity were slightly below control values, but levels maintained were higher than those observed following SIV infection at 2 weeks after RhCMV inoculation. These findings demonstrate that SIV produces long-lasting insults to the humoral immune system beginning very early after SIV infection. The results also indicate that anti-RhCMV immune development at 11 weeks after infection was sufficient to protect the host from acute RhCMV sequelae following SIV infection, in contrast to the lack of protection afforded by only 2 weeks of immune response to RhCMV. As previously observed, monkeys that were not able to mount a significant immune response to SIV were the most susceptible to SAIDS, including activated RhCMV infection. Rapid development of SAIDS in animals inoculated with SIV 2 weeks after RhCMV inoculation suggests that RhCMV can augment SIV pathogenesis, particularly during primary infection by both viruses.

scholarly journals Enhanced Intestinal TGF-β/SMAD-Dependent Signaling in Simian Immunodeficiency Virus Infected Rhesus Macaques

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 806
Author(s):  
Nongthombam Boby ◽  
Alyssa Ransom ◽  
Barcley T. Pace ◽  
Kelsey M. Williams ◽  
Christopher Mabee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Simian Immunodeficiency Virus ◽  
Transforming Growth Factor ◽  
Rhesus Macaques ◽  
Transforming Growth Factor Β ◽  
Immunodeficiency Virus ◽  
Cellular Source ◽  
Siv Infection ◽  
Β Receptor ◽  
Differentiation And Proliferation

Transforming growth factor-β signaling (TGF-β) maintains a balanced physiological function including cell growth, differentiation, and proliferation and regulation of immune system by modulating either SMAD2/3 and SMAD7 (SMAD-dependent) or SMAD-independent signaling pathways under normal conditions. Increased production of TGF-β promotes immunosuppression in Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection. However, the cellular source and downstream events of increased TGF-β production that attributes to its pathological manifestations remain unknown. Here, we have shown increased production of TGF-β in a majority of intestinal CD3−CD20−CD68+ cells from acute and chronically SIV infected rhesus macaques, which negatively correlated with the frequency of jejunum CD4+ T cells. No significant changes in intestinal TGF-β receptor II expression were observed but increased production of the pSMAD2/3 protein and SMAD3 gene expression in jejunum tissues that were accompanied by a downregulation of SMAD7 protein and gene expression. Enhanced TGF-β production by intestinal CD3−CD20−CD68+ cells and increased TGF-β/SMAD-dependent signaling might be due to a disruption of a negative feedback loop mediated by SMAD7. This suggests that SIV infection impacts the SMAD-dependent signaling pathway of TGF-β and provides a potential framework for further study to understand the role of viral factor(s) in modulating TGF-β production and downregulating SMAD7 expression in SIV. Regulation of mucosal TGF-β expression by therapeutic TGF-β blockers may help to create effective antiviral mucosal immune responses.

scholarly journals Differential CD4+ T-Lymphocyte Apoptosis and Bystander T-Cell Activation in Rhesus Macaques and Sooty Mangabeys during Acute Simian Immunodeficiency Virus Infection

2008 ◽  
Vol 83 (2) ◽  
pp. 572-583 ◽  
Author(s):  
Mareike Meythaler ◽  
Amanda Martinot ◽  
Zichun Wang ◽  
Sarah Pryputniewicz ◽  
Melissa Kasheta ◽  
...  
Keyword(s):  
Immune Response ◽  
T Lymphocytes ◽  
T Lymphocyte ◽  
Immune Activation ◽  
Rhesus Macaques ◽  
Lymphocyte Apoptosis ◽  
Immunodeficiency Virus ◽  
Sooty Mangabeys ◽  
Siv Infection ◽  
Species Specific

ABSTRACT In contrast to pathogenic lentiviral infections, chronic simian immunodeficiency virus (SIV) infection in its natural host is characterized by a lack of increased immune activation and apoptosis. To determine whether these differences are species specific and predicted by the early host response to SIV in primary infection, we longitudinally examined T-lymphocyte apoptosis, immune activation, and the SIV-specific cellular immune response in experimentally infected rhesus macaques (RM) and sooty mangabeys (SM) with controlled or uncontrolled SIV infection. SIVsmE041, a primary SIVsm isolate, reproduced set-point viremia levels of natural SIV infection in SM but was controlled in RM, while SIVmac239 replicated to high levels in RM. Following SIV infection, increased CD8+ T-lymphocyte apoptosis, temporally coinciding with onset of SIV-specific cellular immunity, and elevated plasma Th1 cytokine and gamma interferon-induced chemokine levels were common to both SM and RM. Different from SM, SIV-infected RM showed a significantly higher frequency of peripheral blood activated CD8+ T lymphocytes despite comparable magnitude of the SIV-specific gamma interferon enzyme-linked immunospot response. Furthermore, an increase in CD4+ and CD4−CD8− T-lymphocyte apoptosis and plasma tumor necrosis factor-related apoptosis-inducing ligand were observed only in RM and occurred in both controlled SIVsmE041 and uncontrolled SIVmac239 infection. These data suggest that the “excess” activated T lymphocytes in RM soon after SIV infection are predominantly of non-virus-specific bystander origin. Thus, species-specific differences in the early innate immune response appear to be an important factor contributing to differential immune activation in natural and nonnatural hosts 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 Analysis and Prospects of Using Recombinant Vaccinia Virus MVA Strain as a Vector in the Development of the Vaccines against Human and Simian Immunodeficiency Virus Diseases

2019 ◽  
pp. 37-44
Author(s):  
L. F. Stovba ◽  
V. T. Krotkov ◽  
D. I. Paveli’ev ◽  
S. A. Mel’nikov ◽  
V. N. Lebedev ◽  
...  
Keyword(s):  
Immune Response ◽  
Simian Immunodeficiency Virus ◽  
Structural Changes ◽  
Rhesus Macaques ◽  
Laboratory Animals ◽  
Cell Immune Response ◽  
Effective Vaccine ◽  
Protective Efficiency ◽  
Immunodeficiency Virus ◽  
Immunodominant Antigens

The review presents the results of preclinical use of vector vaccines against human immunodeficiency virus (HIV) disease and simian immunodeficiency virus (SIV) disease. Application of antiretroviral therapy exclusively is insufficient for elimination of HIV from patient’s body. This dictates the need for an effective vaccine which will reduce the number of new cases of the disease and reduce the risk of virus transmission. Current practice of medicinal product development showed the effectiveness of heterologous prime-boost regimens for the induction of expressed immune response in laboratory animals. Various vector constructs were used as priming vaccines: DNA vaccines, Bacille Calmette-Guerin vaccine, chimpanzee adenovirus, vesicular stomatitis virus, alphavirus repli-clone. Booster vaccine was represented by recombinant MVA strain. In all vector vaccines, different genes of immunodominant antigens of HIV and SIV agents were inserted. On rhesus macaques, murine, rabbit models, it was demonstrated that deployed vaccination schemes were safe and induced immune response. Because membrane HIV protein is highly variable, strongly glycoziled and subjected to structural changes during receptor binding, it cannot be viewed as a target for induction of virus neutralized antibodies. Therefore, we mainly studied the cell immune response that was presented by poly-functional CD8+ T-cells. However, some recent researches are aimed at such modification of envelope HIV immunogene that would provide for virus neutralizing antibody induction. The study of protective efficiency of the induced immunity in rhesus macaques, immunized with recombinant vectors expressing SIV’ s immunodominant antigens, in case of subsequent inoculation with virulent SIV strain has revealed that all monkeys developed illness. Assuming that the constructions with SIV’ s immunodominant antigens under protective efficiency testing on rhesus macaques imitate AIDS in humans, it seems that vaccines, developed up-to-date, will not be effective for collective immunity formation against AIDS. Therefore, the search for novel combinations of expressed immunodominant antigens for the inclusion into the composition of priming and booster vaccines remains a priority area at present time.

scholarly journals Downregulation of Robust Acute Type I Interferon Responses Distinguishes Nonpathogenic Simian Immunodeficiency Virus (SIV) Infection of Natural Hosts from Pathogenic SIV Infection of Rhesus Macaques

2010 ◽  
Vol 84 (15) ◽  
pp. 7886-7891 ◽  
Author(s):  
Levelle D. Harris ◽  
Brian Tabb ◽  
Donald L. Sodora ◽  
Mirko Paiardini ◽  
Nichole R. Klatt ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Acute Infection ◽  
Type I ◽  
Acute Type ◽  
Type I Ifn ◽  
Immunodeficiency Virus ◽  
Natural Hosts ◽  
Siv Infection

ABSTRACT The mechanisms underlying the AIDS resistance of natural hosts for simian immunodeficiency virus (SIV) remain unknown. Recently, it was proposed that natural SIV hosts avoid disease because their plasmacytoid dendritic cells (pDCs) are intrinsically unable to produce alpha interferon (IFN-α) in response to SIV RNA stimulation. However, here we show that (i) acute SIV infections of natural hosts are associated with a rapid and robust type I IFN response in vivo, (ii) pDCs are the principal in vivo producers of IFN-α/β at peak acute infection in lymphatic tissues, and (iii) natural SIV hosts downregulate these responses in early chronic infection. In contrast, persistently high type I IFN responses are observed during pathogenic SIV infection of rhesus macaques.

scholarly journals Rapid Development of gp120-Focused Neutralizing B Cell Responses during Acute Simian Immunodeficiency Virus Infection of African Green Monkeys

2015 ◽  
Vol 89 (18) ◽  
pp. 9485-9498 ◽  
Author(s):  
Joshua D. Amos ◽  
Jonathon E. Himes ◽  
Lawrence Armand ◽  
Thaddeus C. Gurley ◽  
David R. Martinez ◽  
...  
Keyword(s):  
B Cell ◽  
Disease Progression ◽  
Simian Immunodeficiency Virus ◽  
Rapid Development ◽  
Virus Transmission ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
B Cell Responses ◽  
Hiv 1

ABSTRACTThe initial phases of acute human immunodeficiency virus type 1 (HIV-1) infection may be critical for development of effective envelope (Env)-specific antibodies capable of impeding the establishment of the latent pool of HIV-1-infected CD4+T cells, preventing virus-induced immune hyperactivation to limit disease progression and blocking vertical virus transmission. However, the initial systemic HIV-1 Env-specific antibody response targets gp41 epitopes and fails to control acute-phase viremia. African-origin, natural simian immunodeficiency virus (SIV) hosts do not typically progress to AIDS and rarely postnatally transmit virus to their infants, despite high milk viral loads. Conversely, SIV-infected rhesus macaques (RMs), Asian-origin nonnatural SIV hosts, sustain pathogenic SIV infections and exhibit higher rates of postnatal virus transmission. In this study, of acute SIV infection, we compared the initial systemic Env-specific B cell responses of AGMs and RMs in order to probe potential factors influencing the lack of disease progression observed in AGMs. AGMs developed higher-magnitude plasma gp120-specific IgA and IgG responses than RMs, whereas RMs developed more robust gp140-directed IgG responses. These gp120-focused antibody responses were accompanied by rapid autologous neutralizing responses during acute SIV infection in AGMs compared to RMs. Moreover, acute SIV infection elicited a higher number of circulating Env-specific memory B cells in peripheral blood of AGMs than in the blood of RMs. These findings indicate that AGMs have initial systemic Env-specific B cell responses to SIV infection distinct from those of a nonnatural SIV host, resulting in more functional SIV-specific humoral responses, which may be involved in impairing pathogenic disease progression and minimizing postnatal transmission.IMPORTANCEDue to the worldwide prevalence of HIV-1 infections, development of a vaccine to prevent infection or limit the viral reservoir remains an important goal. HIV-1-infected humans, as well as SIV-infected nonnatural SIV hosts, develop pathogenic infections and readily transmit the virus to their infants. Conversely, natural SIV hosts do not develop pathogenic infections and rarely transmit the virus to their infants. The immunologic factors contributing to these favorable outcomes in natural SIV hosts could prove invaluable for directing HIV-1 vaccine and therapy design. This study identified distinctions in the specificity and function of the initial systemic SIV envelope-specific B cell response that developed during acute SIV infection in natural and nonnatural SIV host species. Identification of distinct acute B cell responses in natural SIV hosts may inform vaccine strategies seeking to elicit similar responses prior to or during the initial phases of acute HIV-1 infection.

scholarly journals Sequential Evolution and Escape from Neutralization of Simian Immunodeficiency Virus SIVsmE660 Clones in Rhesus Macaques

2012 ◽  
Vol 86 (16) ◽  
pp. 8835-8847 ◽  
Author(s):  
Fan Wu ◽  
Ilnour Ourmanov ◽  
Takeo Kuwata ◽  
Robert Goeken ◽  
Charles R. Brown ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Neutralizing Antibody ◽  
Lavage Fluid ◽  
Vaccine Protection ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Intravenous Inoculation

Simian immunodeficiency virus (SIV) infection of rhesus macaques has become an important surrogate model for evaluating HIV vaccine strategies. The extreme resistance to neutralizing antibody (NAb) of many commonly used strains, such as SIVmac251/239 and SIVsmE543-3, limits their potential relevance for evaluating the role of NAb in vaccine protection. In contrast, SIVsmE660 is an uncloned virus that appears to be more sensitive to neutralizing antibody. To evaluate the role of NAb in this model, we generated full-length neutralization-sensitive molecular clones of SIVsmE660 and evaluated two of these by intravenous inoculation of rhesus macaques. All animals became infected and maintained persistent viremia that was accompanied by a decline in memory CD4+T cells in blood and bronchoalveolar lavage fluid. High titers of autologous NAb developed by 4 weeks postinoculation but were not associated with control of viremia, and neutralization escape variants were detected concurrently with the generation of NAb. Neutralization escape was associated with substitutions and insertion/deletion polymorphisms in the V1 and V4 domains of envelope. Analysis of representative variants revealed that escape variants also induced NAbs within a few weeks of their appearance in plasma, in a pattern that is reminiscent of the escape of human immunodeficiency virus type 1 (HIV-1) isolates in humans. Although early variants maintained a neutralization-sensitive phenotype, viruses obtained later in infection were significantly less sensitive to neutralization than the parental viruses. These results indicate that NAbs exert selective pressure that drives the evolution of the SIV envelope and that this model will be useful for evaluating the role of NAb in vaccine-mediated protection.

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