scholarly journals Spontaneous control of SIV replication does not prevent immune dysregulation and bacterial dissemination in animals co-infected with M. tuberculosis

2021 ◽  
Author(s):  
Ryan V. Moriarty ◽  
Mark Rodgers ◽  
Amy Ellis-Connell ◽  
Alexis J. Balgeman ◽  
Erica C Larson ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Cynomolgus Macaque ◽  
Viral Control ◽  
Infection Group ◽  
Bacterial Dissemination ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
The Relationship

Individuals infected with both HIV and Mycobacterium tuberculosis (Mtb) are more likely to develop severe Tuberculosis (TB) disease than HIV-naïve individuals. To understand how a chronic pre-existing Simian immunodeficiency virus (SIV) infection impairs the early immune response to Mtb, we used the Mauritian cynomolgus macaque (MCM) model of SIV/Mtb co-infection. We examined the relationship between peripheral viral control and Mtb burden, Mtb dissemination, and immunological function between SIV+ spontaneous controllers, SIV+ non-controllers, and SIV-naïve MCM who were challenged with a barcoded Mtb Erdman strain and necropsied six weeks post infection. Mycobacterial burden was highest in the SIV+ non-controllers in all assessed tissues. In lung granulomas, we found the frequency of CD4+ T cells producing TNFa was reduced in all SIV+ MCM, but CD4+ T cells producing IFNg were only lower in the SIV+ non-controllers. Further, while all SIV+ MCM had more PD1+ and TIGIT+ T cells in the lung granulomas relative to SIV-naïve MCM, SIV+ controllers exhibited the highest frequency of cells expressing these markers. To measure the effect of SIV infection on within-host bacterial dissemination, we sequenced the molecular barcodes of Mtb present in each tissue and characterized the complexity of the Mtb populations. While Mtb population complexity was not associated with infection group, lymph nodes had increased complexity when compared to lung granulomas across all groups. These results provide evidence SIV+ animals, independent of viral control, exhibit dysregulated immune responses and enhanced dissemination of Mtb, likely contributing to the poor TB disease course across all SIV/Mtb co-infected animals.

Adoptive transfer of simian immunodeficiency virus (SIV) naı̈ve autologous CD4+ cells to macaques chronically infected with SIV is sufficient to induce long-term nonprogressor status

Blood ◽  
2002 ◽  
Vol 99 (2) ◽  
pp. 590-599 ◽  
Author(s):  
Francois Villinger ◽  
Gary T. Brice ◽  
Ann E. Mayne ◽  
Pavel Bostik ◽  
Kazuyasu Mori ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Adoptive Transfer ◽  
Cd4 T Cells ◽  
Short Term ◽  
Cell Compartment ◽  
Immunodeficiency Virus ◽  
Siv Infection

Abstract Adoptive transfer of autologous preinfection-collected peripheral blood mononuclear cells (PBMCs) or activated CD4+ T cells was performed in simian immunodeficiency virus (SIVmac239)–infected monkeys following short-term antiviral therapy with PMPA (9-R-[2-phosphonylmethoxypropyl] adenine). Short-term chemotherapy alone led to a transient decrease in plasma and cellular proviral DNA loads and transient rescue of gag/pol and env cytotoxic T-lymphocyte precursors (pCTLs). However, cessation of therapy allowed for SIV infection to resume its clinical course. PMPA chemotherapy coupled with infusions of either autologous pre-SIV infection–collected PBMCs or activated CD4+ T cells led to extended control of plasma and cellular proviral DNA loads after infusion, in spite of the fact that the transfused cells were not primed against SIV. However, qualitatively different antiviral defenses were induced by infusion of unfractionated and unmanipulated PBMCs versus purified and activated CD4+ T cells: PBMC infusions significantly favored development of SIVenv-specific pCTLs, neutralizing antibodies, and secretion of soluble noncytotoxic suppressor factors of SIV replication. In contrast, activated CD4+ T cells predominantly promoted CTL responses to SIVgag/pol and SIVenv. In addition, infusion of influenza-primed activated CD4+ T cells markedly enhanced influenza-specific pCTL responses, whereas infusion of similarly influenza-primed unfractionated PBMCs enhanced such pCTL responses only modestly, suggesting that the predominant immune defect after SIV infection lies in the T helper cell compartment rather than the effector cell compartment. Thus, adoptive immunotherapy with autologous “SIV naı̈ve” CD4+ lymphocytes was sufficient to rescue cell-mediated immune responses and induce long-term anti-SIV control and immune responses in the absence of continued antiviral chemotherapy.

scholarly journals SIV and Mycobacterium tuberculosis synergy within the granuloma accelerates the reactivation pattern of latent tuberculosis

2020 ◽  
Author(s):  
Collin R Diedrich ◽  
Tara Rutledge ◽  
Pauline Maiello ◽  
Tonilynn M Baranowski ◽  
Alexander G White ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Risk Factor ◽  
T Cell ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Bacterial Burden ◽  
Common Risk Factor ◽  
Immunodeficiency Virus

AbstractHuman immunodeficiency virus infection is the most common risk factor for severe forms of tuberculosis (TB), regardless of CD4 T cell count. Using a well-characterized cynomolgus macaque model of human TB, we compared radiographic, immunologic and microbiologic characteristics of early (subclinical) reactivation of latent M. tuberculosis (Mtb) infection among animals subsequently infected with simian immunodeficiency virus (SIV) or who underwent anti-CD4 depletion by a depletion antibody. CD4 depleted animals had significantly fewer CD4 T cells within granulomas compared to Mtb/SIV co-infected and Mtb-only control animals. After 2 months of treatment, subclinical reactivation occurred at similar rates among CD4 depleted (5 of 7 animals) and SIV infected animals (4 of 8 animals). However, SIV-induced reactivation was associated with more dissemination of lung granulomas that were permissive to Mtb growth resulting in greater bacterial burden within granulomas compared to CD4 depleted reactivators. Granulomas from Mtb/SIV animals displayed a more robust T cell activation profile (IFN-α, IFN-γ, TNF, IL-17, IL-2, IL-10, IL-4 and granzyme B) compared to Mtb/αCD4 animals and controls though these effectors did not protect against reactivation or dissemination, but instead may be related to increased viral and/or Mtb antigens. SIV replication within the granuloma was associated with reactivation, greater overall Mtb growth and Mtb killing resulting in greater overall Mtb burden. These data support that SIV disrupts protective immune responses against latent Mtb infection beyond the loss of CD4 T cells, and that synergy between SIV and Mtb occurs within granulomas.Author SummaryMost humans are able to control infection with Mycobacterium tuberculosis (Mtb), the bacteria that causes tuberculosis (TB). Controlled, asymptomatic infection (latent infection) can develop into symptomatic, severe TB (reactivation TB) when the immune system is impaired, and HIV is the most common risk factor. Chronic HIV infection is associated with low CD4 T cells but there are likely other factors involved. Using macaques with latent Mtb infection, we could induce reactivation from either CD4 T cell depletion or SIV infection. We found that SIV induced reactivation was more dramatic with more bacterial dissemination and bacterial growth compared to those with CD4 depletion. While SIV-infected animals had more activated immune responses in the lung granulomas (a collection of immune cells that functions to combat Mtb), they could not prevent bacterial spread of Mtb resulting in more TB pathology, higher bacterial burden and disease throughout the body. These data suggest that the HIV-induced reactivation TB is not solely from the loss of CD4 T cells. Furthermore, our data suggest that SIV and Mtb have a synergistic relationship within granulomas that impairs the ability to kill Mtb and that this relationship exacerbates TB disease.

scholarly journals Paucity of CD4+CCR5+ T cells is a typical feature of natural SIV hosts

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1069-1076 ◽  
Author(s):  
Ivona Pandrea ◽  
Cristian Apetrei ◽  
Shari Gordon ◽  
Joseph Barbercheck ◽  
Jason Dufour ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Replication ◽  
Cd4 T Cells ◽  
Typical Feature ◽  
Target Cells ◽  
Beneficial Effects ◽  
Mucosal Tissues ◽  
Immunodeficiency Virus ◽  
Natural Hosts ◽  
Siv Infection

AbstractIn contrast to lentiviral infections of humans and macaques, simian immunodeficiency virus (SIV) infection of natural hosts is nonpathogenic despite high levels of viral replication. However, the mechanisms underlying this absence of disease are unknown. Here we report that natural hosts for SIV infection express remarkably low levels of CCR5 on CD4+ T cells isolated from blood, lymph nodes, and mucosal tissues. Given that this immunologic feature is found in 5 different species of natural SIV hosts (sooty mangabeys, African green monkeys, mandrills, sun-tailed monkeys, and chimpanzees) but is absent in 5 nonnatural/recent hosts (humans, rhesus, pigtail, cynomolgus macaques, and baboons), it may represent a key feature of the coevolution between the virus and its natural hosts that led to a nonpathogenic infection. Beneficial effects of low CCR5 expression on CD4+ T cells may include the reduction of target cells for viral replication and a decreased homing of activated CD4+ T cells to inflamed tissue.

scholarly journals Intestinal double-positive CD4+CD8+ T cells of neonatal rhesus macaques are proliferating, activated memory cells and primary targets for SIVMAC251 infection

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4981-4990 ◽  
Author(s):  
Xiaolei Wang ◽  
Arpita Das ◽  
Andrew A. Lackner ◽  
Ronald S. Veazey ◽  
Bapi Pahar
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Rhesus Macaques ◽  
Memory Cells ◽  
Double Positive ◽  
Immunodeficiency Virus ◽  
Single Positive ◽  
Siv Infection ◽  
Different Tissues

AbstractPeripheral blood and thymic double-positive (DP) CD4+CD8+ T cells from neonates have been described earlier, but the function and immunophenotypic characteristics of other tissue-derived DP T cells are not clearly understood. Here, we demonstrate the functional and immunophenotypic characteristics of DP cells in 6 different tissues, including thymus from normal neonatal rhesus macaques (Macaca mulatta) between 0 and 21 days of age. In general, intestinal DP T cells of neonates have higher percentages of memory markers (CD28+CD95+CD45RAlowCD62Llow) and proliferation compared with single-positive (SP) CD4+ and CD8+ T cells. In addition, percentages of DP T cells increase and CD62L expression decreases as animals mature, suggesting that DP cells mature and proliferate with maturity and/or antigen exposure. Consistent with this, intestinal DP T cells in neonates express higher levels of CCR5 and are the primary targets in simian immunodeficiency virus (SIV) infection. Finally, DP T cells produce higher levels of cytokine in response to mitogen stimulation compared with SP CD4+ or CD8+ T cells. Collectively, these findings demonstrate that intestinal DP T cells of neonates are proliferating, activated memory cells and are likely involved in regulating immune responses, in contrast to immature DP T cells in the thymus.

scholarly journals Association of HLA Genotype With T-Cell Activation in Human Immunodeficiency Virus (HIV) and HIV/Hepatitis C Virus–Coinfected Women

2019 ◽  
Vol 221 (7) ◽  
pp. 1156-1166
Author(s):  
Andrea A Z Kovacs ◽  
Naoko Kono ◽  
Chia-Hao Wang ◽  
Daidong Wang ◽  
Toni Frederick ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Immunodeficiency Virus ◽  
The Relationship

Abstract Background Global immune activation and HLA alleles are each associated with the pathogenesis of human immunodeficiency virus (HIV) and hepatitis C virus . Methods We evaluated the relationship between 44 HLA class I and 28 class II alleles and percentages of activated CD8 (CD8+CD38+DR+) and CD4 (CD4+CD38+DR+) T cells in 586 women who were naive to highly active antiretroviral therapy. We used linear generalized estimating equation regression models, adjusting for race/ethnicity, age, HIV load, and hepatitis C virus infection and controlling for multiplicity using a false discovery rate threshold of 0.10. Results Ten HLA alleles were associated with CD8 and/or CD4 T-cell activation. Lower percentages of activated CD8 and/or CD4 T cells were associated with protective alleles B*57:03 (CD8 T cells, −6.6% [P = .002]; CD4 T cells, −2.7% [P = .007]), C*18:01 (CD8 T cells, −6.6%; P < .0008) and DRB1*13:01 (CD4 T cells, −2.7%; P < .0004), and higher percentages were found with B*18:01 (CD8 T cells, 6.2%; P < .0003), a detrimental allele. Other alleles/allele groups associated with activation included C*12:03, group DQA1*01:00, DQB1*03:01, DQB1*03:02, DQB1*06:02, and DQB1*06:03. Conclusion These findings suggest that a person’s HLA type may play a role in modulating T-cell activation independent of viral load and sheds light on the relationship between HLA, T-cell activation, immune control, and HIV pathogenesis.

scholarly journals Massive infection and loss of CD4+ T cells occurs in the intestinal tract of neonatal rhesus macaques in acute SIV infection

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1174-1181 ◽  
Author(s):  
Xiaolei Wang ◽  
Terri Rasmussen ◽  
Bapi Pahar ◽  
Bhawna Poonia ◽  
Xavier Alvarez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Intestinal Tract ◽  
Rhesus Macaques ◽  
Central Memory ◽  
T Cell Subsets ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Memory Cd4 T Cells

Abstract Rapid, profound, and selective depletion of memory CD4+ T cells has now been confirmed to occur in simian immunodeficiency virus (SIV)–infected adult macaques and human immunodeficiency virus (HIV)–infected humans. Within days of infection, marked depletion of memory CD4+ T cells occurs primarily in mucosal tissues, the major reservoir for memory CD4+ T cells in adults. However, HIV infection in neonates often results in higher viral loads and rapid disease progression, despite the paucity of memory CD4+ T cells in the peripheral blood. Here, we examined the immunophenotype of CD4+ T cells in normal and SIV-infected neonatal macaques to determine the distribution of naive and memory T-cell subsets in tissues. We demonstrate that, similar to adults, neonates have abundant memory CD4+ T cells in the intestinal tract and spleen and that these are selectively infected and depleted in primary SIV infection. Within 12 days of SIV infection, activated (CD69+), central memory (CD95+CD28+) CD4+ T cells are marked and persistently depleted in the intestine and other tissues of neonates compared with controls. The results in dicate that “activated” central memory CD4+ T cells are the major target for early SIV infection and CD4+ T cell depletion in neonatal macaques.

scholarly journals Gut Mucosal FOXP3+ Regulatory CD4+ T Cells and Nonregulatory CD4+ T Cells Are Differentially Affected by Simian Immunodeficiency Virus Infection in Rhesus Macaques

2010 ◽  
Vol 84 (7) ◽  
pp. 3259-3269 ◽  
Author(s):  
Kristina Allers ◽  
Christoph Loddenkemper ◽  
Jörg Hofmann ◽  
Anett Unbehaun ◽  
Désirée Kunkel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Cd4 T Cells ◽  
Rhesus Macaques ◽  
Virus Production ◽  
Cell Pool ◽  
Immunodeficiency Virus ◽  
Gut Mucosa ◽  
Siv Infection

ABSTRACT The gastrointestinal tract represents a major site for human and simian immunodeficiency virus (HIV and SIV) replication and CD4+ T-cell depletion. Despite severe depletion of mucosal CD4+ T cells, FOXP3+ regulatory CD4+ T cells (Treg) are highly increased in the gut mucosa of chronically HIV-infected individuals and may contribute to HIV pathogenesis, either by their immunosuppressive function or as a significant target cell population for virus production. Little is known about the susceptibility of mucosal Treg to viral infection and the longitudinal effect of HIV/SIV infection on Treg dynamics. In this study, we determined the level of SIV infection in Treg and nonregulatory CD4+ T cells (non-Treg) isolated from the colon of SIV-infected rhesus macaques. The dynamics of mucosal Treg and alterations in the mucosal CD4+ T-cell pool were examined longitudinally. Our findings indicate that mucosal Treg were less susceptible to productive SIV infection than non-Treg and thus were selectively spared from SIV-mediated cell death. In addition to improved survival, local expansion of Treg by SIV-induced proliferation of the mucosal CD4+ T-cell pool facilitated the accumulation of mucosal Treg during the course of infection. High frequency of mucosal Treg in chronic SIV infection was strongly related to a reduction of perforin-expressing cells. In conclusion, this study suggests that mucosal Treg are less affected by productive SIV infection than non-Treg and therefore spared from depletion. Although SIV production is limited in mucosal Treg, Treg accumulation may indirectly contribute to viral persistence by suppressing antiviral immune responses.

scholarly journals Identification of Protein Kinases Dysregulated in CD4+ T Cells in Pathogenic versus Apathogenic Simian Immunodeficiency Virus Infection

2001 ◽  
Vol 75 (23) ◽  
pp. 11298-11306 ◽  
Author(s):  
Pavel Bostik ◽  
Peggy Wu ◽  
Geraldine L. Dodd ◽  
Francois Villinger ◽  
Ann E. Mayne ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Immune Responses ◽  
Cell Signaling ◽  
Simian Immunodeficiency Virus ◽  
Gene Transcription ◽  
T Cell Signaling ◽  
Immunodeficiency Virus ◽  
Siv Infection

ABSTRACT Human immunodeficiency virus infection in humans and simian immunodeficiency virus (SIV) infection in rhesus macaques (RM) leads to a generalized loss of immune responses involving perturbations in T-cell receptor (TCR) signaling. In contrast, naturally SIV-infected sooty mangabeys (SM) remain asymptomatic and retain immune responses despite relatively high viral loads. However, SIV infection in both RM and SM led to similar decreases in TCR-induced Lck phosphorylation. In this study, a protein tyrosine kinase (PTK) differential display method was utilized to characterize the effects of in vivo SIV infection on key signaling molecules of the CD4+ T-cell signaling pathways. The CD4+ T cells from SIV-infected RM, but not SIV-infected SM, showed chronic downregulation of baseline expression of MLK3, PRK, and GSK3, and symptomatically SIV-infected RM showed similar downregulation of MKK3. In vitro TCR stimulation with or without CD28 costimulation of CD4+ T cells did not lead to the enhancement of gene transcription of these PTKs. While the CD4+ T cells from SIV-infected RM showed a significant increase of the baseline and anti-TCR-mediated ROR2 transcription, SIV infection in SM led to substantially decreased anti-TCR-stimulated ROR2 transcription. TCR stimulation of CD4+ T cells from SIV-infected RM (but not SIV-infected SM) led to the repression of CaMKKβ and the induction of gene transcription of MLK2. Studies of the function of these molecules in T-cell signaling may lead to the identification of potential targets for specific intervention, leading to the restoration of T-cell responses.

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