scholarly journals Of mice, macaques and men: scaling of virus dynamics and immune responses

2015 ◽  
Author(s):  
Christian L Althaus
Keyword(s):  
Body Size ◽  
Viral Infections ◽  
Rhesus Macaques ◽  
Lymphocytic Choriomeningitis ◽  
The Body ◽  
Cell Responses ◽  
Infection Dynamics ◽  
Immunodeficiency Virus ◽  
Cellular Immune ◽  
Kinetics Of

In this Opinion piece, I argue that the dynamics of viruses and the cellular immune response depend on the body size of the host. I use allometric scaling theory to interpret observed quantitative differences in the infection dynamics of lymphocytic choriomeningitis virus (LCMV) in mice (Mus musculus), simian immunodeficiency virus (SIV) in rhesus macaques (Macaca mulatta) and human immunodeficiency virus (HIV) in humans. However, additional data on the kinetics of virus replication and the dynamics of T cell responses in different host species will be required to shed more light on the question whether the nature of viral infections is affected by the body size of their hosts.

scholarly journals Of mice, macaques and men: scaling of virus dynamics and immune responses

2015 ◽  
Author(s):  
Christian L Althaus
Keyword(s):  
Immune Responses ◽  
Allometric Scaling ◽  
Rhesus Macaques ◽  
Lymphocytic Choriomeningitis ◽  
The Body ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Infection Dynamics ◽  
Immunodeficiency Virus ◽  
Cellular Immune

In this Opinion piece, I argue that the dynamics of viruses and the cellular immune response depend on the body size of the host. I use allometric scaling theory to interpret observed quantitative differences in the infection dynamics of lymphocytic choriomeningitis virus (LCMV) in mice (Mus musculus), simian immunodeficiency virus (SIV) in rhesus macaques (Macaca mulatta) and human immunodeficiency virus (HIV) in humans. There are indications that viral replication and the proliferation of CD8+ T cell responses are slower in larger animals. Whether this influences the ability of the cellular immune responses to eradicate viruses during the acute phase of an infection remains unclear, however.

scholarly journals Of mice, macaques and men: scaling of virus dynamics and immune responses

2015 ◽  
Author(s):  
Christian L Althaus
Keyword(s):  
Immune Responses ◽  
Allometric Scaling ◽  
Rhesus Macaques ◽  
Lymphocytic Choriomeningitis ◽  
The Body ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Infection Dynamics ◽  
Immunodeficiency Virus ◽  
Cellular Immune

In this Opinion piece, I argue that the dynamics of viruses and the cellular immune response depend on the body size of the host. I use allometric scaling theory to interpret observed quantitative differences in the infection dynamics of lymphocytic choriomeningitis virus (LCMV) in mice (Mus musculus), simian immunodeficiency virus (SIV) in rhesus macaques (Macaca mulatta) and human immunodeficiency virus (HIV) in humans. There are indications that viral replication and the proliferation of CD8+ T cell responses are slower in larger animals. Whether this influences the ability of the cellular immune responses to eradicate viruses during the acute phase of an infection remains unclear, however.

scholarly journals Adoptive Transfer of Engineered Rhesus Simian Immunodeficiency Virus-Specific CD8 + T Cells Reduces the Number of Transmitted/Founder Viruses Established in Rhesus Macaques

2016 ◽  
Vol 90 (21) ◽  
pp. 9942-9952 ◽  
Author(s):  
Victor I. Ayala ◽  
Matthew T. Trivett ◽  
Eugene V. Barsov ◽  
Sumiti Jain ◽  
Michael Piatak ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Rhesus Macaques ◽  
High Dose ◽  
Cell Responses ◽  
Large Numbers ◽  
Immunodeficiency Virus ◽  
Virus Exposure ◽  
Cellular Immune

ABSTRACT AIDS virus infections are rarely controlled by cell-mediated immunity, in part due to viral immune evasion and immunodeficiency resulting from CD4 + T-cell infection. One likely aspect of this failure is that antiviral cellular immune responses are either absent or present at low levels during the initial establishment of infection. To test whether an extensive, timely, and effective response could reduce the establishment of infection from a high-dose inoculum, we adoptively transferred large numbers of T cells that were molecularly engineered with anti-simian immunodeficiency virus (anti-SIV) activity into rhesus macaques 3 days following an intrarectal SIV inoculation. To measure in vivo antiviral activity, we assessed the number of viruses transmitted using SIVmac239X, a molecularly tagged viral stock containing 10 genotypic variants, at a dose calculated to transmit 12 founder viruses. Single-genome sequencing of plasma virus revealed that the two animals receiving T cells expressing SIV-specific T-cell receptors (TCRs) had significantly fewer viral genotypes than the two control animals receiving non-SIV-specific T cells (means of 4.0 versus 7.5 transmitted viral genotypes; P = 0.044). Accounting for the likelihood of transmission of multiple viruses of a particular genotype, the calculated means of the total number of founder viruses transmitted were 4.5 and 14.5 in the experimental and control groups, respectively ( P = 0.021). Thus, a large antiviral T-cell response timed with virus exposure can limit viral transmission. The presence of strong, preexisting T-cell responses, including those induced by vaccines, might help prevent the establishment of infection at the lower-exposure doses in humans that typically transmit only a single virus. IMPORTANCE The establishment of AIDS virus infection in an individual is essentially a race between the spreading virus and host immune defenses. Cell-mediated immune responses induced by infection or vaccination are important contributors in limiting viral replication. However, in human immunodeficiency virus (HIV)/SIV infection, the virus usually wins the race, irreversibly crippling the immune system before an effective cellular immune response is developed and active. We found that providing an accelerated response by adoptively transferring large numbers of antiviral T cells shortly after a high-dose mucosal inoculation, while not preventing infection altogether, limited the number of individual viruses transmitted. Thus, the presence of strong, preexisting T-cell responses, including those induced by vaccines, might prevent infection in humans, where the virus exposure is considerably lower.

scholarly journals Comprehensive Epitope Analysis of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T-Cell Responses Directed against the Entire Expressed HIV-1 Genome Demonstrate Broadly Directed Responses, but No Correlation to Viral Load

2003 ◽  
Vol 77 (3) ◽  
pp. 2081-2092 ◽  
Author(s):  
M. M. Addo ◽  
X. G. Yu ◽  
A. Rathod ◽  
D. Cohen ◽  
R. L. Eldridge ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Protein Subunits ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Immunodeficiency Virus ◽  
Total Magnitude ◽  
Cellular Immune ◽  
Hiv 1

ABSTRACT Cellular immune responses play a critical role in the control of human immunodeficiency virus type 1 (HIV-1); however, the breadth of these responses at the single-epitope level has not been comprehensively assessed. We therefore screened peripheral blood mononuclear cells (PBMC) from 57 individuals at different stages of HIV-1 infection for virus-specific T-cell responses using a matrix of 504 overlapping peptides spanning all expressed HIV-1 proteins in a gamma interferon-enzyme-linked immunospot (Elispot) assay. HIV-1-specific T-cell responses were detectable in all study subjects, with a median of 14 individual epitopic regions targeted per person (range, 2 to 42), and all 14 HIV-1 protein subunits were recognized. HIV-1 p24-Gag and Nef contained the highest epitope density and were also the most frequently recognized HIV-1 proteins. The total magnitude of the HIV-1-specific response ranged from 280 to 25,860 spot-forming cells (SFC)/106 PBMC (median, 4,245) among all study participants. However, the number of epitopic regions targeted, the protein subunits recognized, and the total magnitude of HIV-1-specific responses varied significantly among the tested individuals, with the strongest and broadest responses detectable in individuals with untreated chronic HIV-1 infection. Neither the breadth nor the magnitude of the total HIV-1-specific CD8+-T-cell responses correlated with plasma viral load. We conclude that a peptide matrix-based Elispot assay allows for rapid, sensitive, specific, and efficient assessment of cellular immune responses directed against the entire expressed HIV-1 genome. These data also suggest that the impact of T-cell responses on control of viral replication cannot be explained by the mere quantification of the magnitude and breadth of the CD8+-T-cell response, even if a comprehensive pan-genome screening approach is applied.

scholarly journals Aviremia 10 Years Postdiscontinuation of Antiretroviral Therapy Initiated During Primary Human Immunodeficiency Virus-1 Infection and Association With Gag-Specific T-Cell Responses

2015 ◽  
Vol 2 (4) ◽  
Author(s):  
Sabine Kinloch-de Loes ◽  
Lucy Dorrell ◽  
Hongbing Yang ◽  
Gareth A. D. Hardy ◽  
Sabine Yerly ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Viral Reservoir ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Cellular Immune ◽  
Drug Free ◽  
Human Immunodeficiency Virus 1

Abstract Combination antiretroviral therapy during primary human immunodeficiency virus-1 infection may enable long-term drug-free virological control in rare individuals. We describe a female who maintained aviremia and a normal CD4+/CD8+ T cell ratio for 10 years after stopping therapy, despite a persistent viral reservoir. Cellular immune responses may have contributed to this outcome.

scholarly journals Neonates Mount Robust and Protective Adult-Like CD8+-T-Cell Responses to DNA Vaccines

2002 ◽  
Vol 76 (23) ◽  
pp. 11911-11919 ◽  
Author(s):  
Jie Zhang ◽  
Nicole Silvestri ◽  
J. Lindsay Whitton ◽  
Daniel E. Hassett
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Viral Infections ◽  
Dna Vaccines ◽  
Neonatal Period ◽  
Cytotoxic T Cells ◽  
Lymphocytic Choriomeningitis ◽  
Cell Responses ◽  
Rapid Induction

ABSTRACT Neonates are thought to mount less vigorous adaptive immune responses than adults to antigens and infectious agents. This concept has led to a delay in the administration of many currently available vaccines until late infancy or early childhood. It has recently been shown that vaccines composed of plasmid DNA can induce both humoral and cell-mediated antimicrobial immunity when administered within hours of birth. In most of these studies, immune responses were measured weeks or months after the initial vaccination, and it is therefore questionable whether the observed responses were actually the result of priming of splenocytes within the neonatal period. Here we show that DNA vaccination at birth results in the rapid induction of antigen-specific CD8+ T cells within neonatal life. Analyses of T-cell effector functions critical for the resolution of many viral infections revealed that neonatal and adult CD8+ T cells produce similar arrays of cytokines. Furthermore, the avidities of neonatal and adult CD8+ T cells for peptide and the rapidity with which they upregulate cytokine production after recall encounters with antigen are similar. Protective immunity against the arenavirus lymphocytic choriomeningitis virus, which is mediated by CD8+ cytotoxic T cells, is also rapidly acquired within the neonatal period. Collectively these data imply that, at least in the case of CD8+ T cells, neonates are not as immunodeficient as previously supposed and that DNA vaccines may be an effective and safe means of providing critical cell-mediated antiviral immunity extremely early in life.

scholarly journals Resolution of a chronic viral infection after interleukin-10 receptor blockade

2006 ◽  
Vol 203 (11) ◽  
pp. 2461-2472 ◽  
Author(s):  
Mette Ejrnaes ◽  
Christophe M. Filippi ◽  
Marianne M. Martinic ◽  
Eleanor M. Ling ◽  
Lisa M. Togher ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Infections ◽  
Neutralizing Antibody ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Lymphocytic Choriomeningitis ◽  
Persistently Infected ◽  
Functional Inactivation ◽  
Cellular Immune

A defining characteristic of persistent viral infections is the loss and functional inactivation of antiviral effector T cells, which prevents viral clearance. Interleukin-10 (IL-10) suppresses cellular immune responses by modulating the function of T cells and antigen-presenting cells. In this paper, we report that IL-10 production is drastically increased in mice persistently infected with lymphocytic choriomeningitis virus. In vivo blockade of the IL-10 receptor (IL-10R) with a neutralizing antibody resulted in rapid resolution of the persistent infection. IL-10 secretion was diminished and interferon γ production by antiviral CD8+ T cells was enhanced. In persistently infected mice, CD8α+ dendritic cell (DC) numbers declined early after infection, whereas CD8α− DC numbers were not affected. CD8α− DCs supported IL-10 production and subsequent dampening of antiviral T cell responses. Therapeutic IL-10R blockade broke the cycle of IL-10–mediated immune suppression, preventing IL-10 priming by CD8α− DCs and enhancing antiviral responses and thereby resolving infection without causing immunopathology.

scholarly journals Gamma Interferon-Mediated Inflammation Is Associated with Lack of Protection from Intravaginal Simian Immunodeficiency Virus SIVmac239 Challenge in Simian-Human Immunodeficiency Virus 89.6-Immunized Rhesus Macaques

2004 ◽  
Vol 78 (2) ◽  
pp. 841-854 ◽  
Author(s):  
Kristina Abel ◽  
Lisa La Franco-Scheuch ◽  
Tracy Rourke ◽  
Zhong-Min Ma ◽  
Veronique de Silva ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Rhesus Macaques ◽  
T Cell Responses ◽  
Lymphoid Tissues ◽  
Mrna Levels ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Ifn Γ

ABSTRACT Although gamma interferon (IFN-γ) is a key mediator of antiviral defenses, it is also a mediator of inflammation. As inflammation can drive lentiviral replication, we sought to determine the relationship between IFN-γ-related host immune responses and challenge virus replication in lymphoid tissues of simian-human immunodeficiency virus 89.6 (SHIV89.6)-vaccinated and unvaccinated rhesus macaques 6 months after challenge with simian immunodeficiency virus SIVmac239. Vaccinated-protected monkeys had low tissue viral RNA (vRNA) levels, vaccinated-unprotected animals had moderate tissue vRNA levels, and unvaccinated animals had high tissue vRNA levels. The long-term challenge outcome in vaccinated monkeys was correlated with the relative balance between SIV-specific IFN-γ T-cell responses and nonspecific IFN-γ-driven inflammation. Vaccinated-protected monkeys had slightly increased tissue IFN-γ mRNA levels and a high frequency of IFN-γ-secreting T cells responding to in vitro SIVgag peptide stimulation; thus, it is likely that they could develop effective anti-SIV cytotoxic T lymphocytes in vivo. In contrast, both high tissue IFN-γ mRNA levels and strong in vitro SIV-specific IFN-γ T-cell responses were detected in lymphoid tissues of vaccinated-unprotected monkeys. Unvaccinated monkeys had increased tissue IFN-γ mRNA levels but weak in vitro anti-SIV IFN-γ T-cell responses. In addition, in lymphoid tissues of vaccinated-unprotected and unvaccinated monkeys, the increased IFN-γ mRNA levels were associated with increased Mig/CXCL9, IP-10/CXCL10, and CXCR3 mRNA levels, suggesting that increased Mig/CXCL9 and IP-10/CXCL10 expression resulted in recruitment of CXCR3+ activated T cells. Thus, IFN-γ-driven inflammation promotes SIV replication in vaccinated-unprotected and unvaccinated monkeys. Unlike all unvaccinated monkeys, most monkeys vaccinated with SHIV89.6 did not develop IFN-γ-driven inflammation, but they did develop effective antiviral CD8+-T-cell responses.

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