Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine

ABSTRACT Our goal is to develop a pediatric combination vaccine to protect the vulnerable infant population against human immunodeficiency virus type 1 (HIV-1) and tuberculosis (TB) infections. The vaccine consists of an auxotroph Mycobacterium tuberculosis strain that coexpresses HIV antigens. Utilizing an infant rhesus macaque model, we have previously shown that this attenuated M. tuberculosis (AMtb)-simian immunodeficiency virus (SIV) vaccine is immunogenic, and although the vaccine did not prevent oral SIV infection, a subset of vaccinated animals was able to partially control virus replication. However, unexpectedly, vaccinated infants required fewer SIV exposures to become infected compared to naive controls. Considering that the current TB vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), can induce potent innate immune responses and confer pathogen-unspecific trained immunity, we hypothesized that an imbalance between enhanced myeloid cell function and immune activation might have influenced the outcome of oral SIV challenge in AMtb-SIV-vaccinated infants. To address this question, we used archived samples from unchallenged animals from our previous AMtb-SIV vaccine studies and vaccinated additional infant macaques with BCG or AMtb only. Our results show that vaccinated infants, regardless of vaccine strain or regimen, had enhanced myeloid cell responses. However, CD4+ T cells were concurrently activated, and the persistence of these activated target cells in oral and/or gastrointestinal tissues may have facilitated oral SIV infection. Immune activation was more pronounced in BCG-vaccinated infant macaques than in AMtb-vaccinated infant macaques, indicating a role for vaccine attenuation. These findings underline the importance of understanding the interplay of vaccine-induced immunity and immune activation and its effect on HIV acquisition risk and outcome in infants.

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Intrinsic Susceptibility of Rhesus Macaque Peripheral CD4+ T Cells to Simian Immunodeficiency Virus In Vitro Is Predictive of In Vivo Viral Replication

Journal of Virology ◽

10.1128/jvi.74.20.9388-9395.2000 ◽

2000 ◽

Vol 74 (20) ◽

pp. 9388-9395 ◽

Cited By ~ 42

Author(s):

Simoy Goldstein ◽

Charles R. Brown ◽

Houman Dehghani ◽

Jeffrey D. Lifson ◽

Vanessa M. Hirsch

Keyword(s):

T Cell ◽

Simian Immunodeficiency Virus ◽

Rank Order ◽

Rhesus Macaques ◽

Target Cells ◽

Plasma Viremia ◽

Immunodeficiency Virus ◽

Siv Infection

ABSTRACT Previous studies with simian immunodeficiency virus (SIV) infection of rhesus macaques suggested that the intrinsic susceptibility of peripheral blood mononuclear cells (PBMC) to infection with SIV in vitro was predictive of relative viremia after SIV challenge. The present study was conducted to evaluate this parameter in a well-characterized cohort of six rhesus macaques selected for marked differences in susceptibility to SIV infection in vitro. Rank order relative susceptibility of PBMC to SIVsmE543-3-infection in vitro was maintained over a 1-year period of evaluation. Differential susceptibility of different donors was maintained in CD8+T-cell-depleted PBMC, macrophages, and CD4+ T-cell lines derived by transformation of PBMC with herpesvirus saimiri, suggesting that this phenomenon is an intrinsic property of CD4+target cells. Following intravenous infection of these macaques with SIVsmE543-3, we observed a wide range in plasma viremia which followed the same rank order as the relative susceptibility established by in vitro studies. A significant correlation was observed between plasma viremia at 2 and 8 weeks postinoculation and in vitro susceptibility (P < 0.05). The observation that the two most susceptible macaques were seropositive for simian T-lymphotropic virus type 1 may suggests a role for this viral infection in enhancing susceptibility to SIV infection in vitro and in vivo. In summary, intrinsic susceptibility of CD4+ target cells appears to be an important factor influencing early virus replication patterns in vivo that should be considered in the design and interpretation of vaccine studies using the SIV/macaque model.

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Estimating the Effectiveness of Simian Immunodeficiency Virus-Specific CD8+ T Cells from the Dynamics of Viral Immune Escape

Journal of Virology ◽

10.1128/jvi.00946-07 ◽

2007 ◽

Vol 81 (21) ◽

pp. 11982-11991 ◽

Cited By ~ 36

Author(s):

Judith N. Mandl ◽

Roland R. Regoes ◽

David A. Garber ◽

Mark B. Feinberg

Keyword(s):

T Cells ◽

Simian Immunodeficiency Virus ◽

Viral Escape ◽

Target Cells ◽

Data Set ◽

Ctl Response ◽

Specific Ctls ◽

Immunodeficiency Virus ◽

Siv Infection

ABSTRACT Antiviral CD8+ T cells are thought to play a significant role in limiting the viremia of human and simian immunodeficiency virus (HIV and SIV, respectively) infections. However, it has not been possible to measure the in vivo effectiveness of cytotoxic T cells (CTLs), and hence their contribution to the death rate of CD4+ T cells is unknown. Here, we estimated the ability of a prototypic antigen-specific CTL response against a well-characterized epitope to recognize and kill infected target cells by monitoring the immunodominant Mamu-A*01-restricted Tat SL8 epitope for escape from Tat-specific CTLs in SIVmac239-infected macaques. Fitting a mathematical model that incorporates the temporal kinetics of specific CTLs to the frequency of Tat SL8 escape mutants during acute SIV infection allowed us to estimate the in vivo killing rate constant per Tat SL8-specific CTL. Using this unique data set, we show that at least during acute SIV infection, certain antiviral CD8+ T cells can have a significant impact on shortening the longevity of infected CD4+ T cells and hence on suppressing virus replication. Unfortunately, due to viral escape from immune pressure and a dependency of the effectiveness of antiviral CD8+ T-cell responses on the availability of sufficient CD4+ T cells, the impressive early potency of the CTL response may wane in the transition to the chronic stage of the infection.

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Trained Immunity and Susceptibility to HIV

Clinical and Vaccine Immunology ◽

10.1128/cvi.00509-16 ◽

2016 ◽

Vol 24 (1) ◽

Cited By ~ 2

Author(s):

Steven C. Derrick

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Mycobacterium Tuberculosis ◽

Cd4 T Cell ◽

Dual Purpose ◽

Content Type ◽

Trained Immunity ◽

Cell Responses ◽

Immunodeficiency Virus ◽

Increased Susceptibility

ABSTRACT In this issue of Clinical and Vaccine Immunology, K. Jensen et al. (Clin Vaccine Immunol 24:e00360-16, 2017, https://doi.org/10.1128/CVI.00360-16 ) describe a dual-purpose attenuated Mycobacterium tuberculosis-simian immunodeficiency virus vaccine (AMTB-SIV). Interestingly, immunized infant macaques required fewer oral exposures to SIV to become infected relative to nonimmunized animals. The authors hypothesized that augmented susceptibility to SIV was due to activation of CD4+ T cells through trained immunity. This commentary explores the possible relationship between trained immunity, enhanced CD4 T cell responses, and increased susceptibility to human immunodeficiency virus (HIV).

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Elite Control, Gut CD4 T Cell Sparing, and Enhanced Mucosal T Cell Responses in Macaca nemestrina Infected by a Simian Immunodeficiency Virus Lacking a gp41 Trafficking Motif

Journal of Virology ◽

10.1128/jvi.01134-15 ◽

2015 ◽

Vol 89 (20) ◽

pp. 10156-10175 ◽

Cited By ~ 9

Author(s):

Matthew W. Breed ◽

Samra E. Elser ◽

Workineh Torben ◽

Andrea P. O. Jordan ◽

Pyone P. Aye ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Viral Replication ◽

Simian Immunodeficiency Virus ◽

Immune Activation ◽

Rhesus Macaques ◽

Macaca Nemestrina ◽

Viral Control ◽

Content Type ◽

Immunodeficiency Virus

ABSTRACTDeletion of Gly-720 and Tyr-721 from a highly conserved GYxxØ trafficking signal in the SIVmac239 envelope glycoprotein cytoplasmic domain, producing a virus termed ΔGY, leads to a striking perturbation in pathogenesis in rhesus macaques (Macaca mulatta). Infected macaques develop immune activation and progress to AIDS, but with only limited and transient infection of intestinal CD4+T cells and an absence of microbial translocation. Here we evaluated ΔGY in pig-tailed macaques (Macaca nemestrina), a species in which SIVmac239 infection typically leads to increased immune activation and more rapid progression to AIDS than in rhesus macaques. In pig-tailed macaques, ΔGY also replicated acutely to high peak plasma RNA levels identical to those for SIVmac239 and caused only transient infection of CD4+T cells in the gut lamina propria and no microbial translocation. However, in marked contrast to rhesus macaques, 19 of 21 pig-tailed macaques controlled ΔGY replication with plasma viral loads of <15 to 50 RNA copies/ml. CD4+T cells were preserved in blood and gut for up to 100 weeks with no immune activation or disease progression. Robust antiviral CD4+T cell responses were seen, particularly in the gut. Anti-CD8 antibody depletion demonstrated CD8+cellular control of viral replication. Two pig-tailed macaques progressed to disease with persisting viremia and possible compensatory mutations in the cytoplasmic tail. These studies demonstrate a marked perturbation in pathogenesis caused by ΔGY's ablation of the GYxxØ trafficking motif and reveal, paradoxically, that viral control is enhanced in a macaque species typically predisposed to more pathogenic manifestations of simian immunodeficiency virus (SIV) infection.IMPORTANCEThe pathogenesis of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) reflects a balance between viral replication, host innate and adaptive antiviral immune responses, and sustained immune activation that in humans and Asian macaques is associated with persistent viremia, immune escape, and AIDS. Among nonhuman primates, pig-tailed macaques following SIV infection are predisposed to more rapid disease progression than are rhesus macaques. Here, we show that disruption of a conserved tyrosine-based cellular trafficking motif in the viral transmembrane envelope glycoprotein cytoplasmic tail leads in pig-tailed macaques to a unique phenotype in which high levels of acute viral replication are followed by elite control, robust cellular responses in mucosal tissues, and no disease. Paradoxically, control of this virus in rhesus macaques is only partial, and progression to AIDS occurs. This novel model should provide a powerful tool to help identify host-specific determinants for viral control with potential relevance for vaccine development.

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A Recombinant Attenuated Mycobacterium tuberculosis Vaccine Strain Is Safe in Immunosuppressed Simian Immunodeficiency Virus-Infected Infant Macaques

Clinical and Vaccine Immunology ◽

10.1128/cvi.00184-12 ◽

2012 ◽

Vol 19 (8) ◽

pp. 1170-1181 ◽

Cited By ~ 31

Author(s):

Kara Jensen ◽

Uma Devi K. Ranganathan ◽

Koen K. A. Van Rompay ◽

Don R. Canfield ◽

Imran Khan ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Simian Immunodeficiency Virus ◽

Clinical Symptoms ◽

Pediatric Population ◽

Vaccine Safety ◽

Hiv Vaccine ◽

Safe Alternative ◽

Content Type ◽

Infected Infant ◽

Immunodeficiency Virus

ABSTRACTMany resource-poor countries are faced with concurrent epidemics of AIDS and tuberculosis (TB) caused by human immunodeficiency virus (HIV) andMycobacterium tuberculosis, respectively. Dual infections with HIV andM. tuberculosisare especially severe in infants. There is, however, no effective HIV vaccine, and the only licensed TB vaccine, theMycobacterium bovisbacillus Calmette-Guérin (BCG) vaccine, can cause disseminated mycobacterial disease in HIV-infected children. Thus, a pediatric vaccine to prevent HIV andM. tuberculosisinfections is urgently needed. We hypothesized that a highly attenuatedM. tuberculosisstrain containing HIV antigens could be safely administered at birth and induce mucosal and systemic immune responses to protect against HIV and TB infections, and we rationalized that vaccine safety could be most rigorously assessed in immunocompromised hosts. Of three vaccine candidates tested, the recombinant attenuatedM. tuberculosisstrain mc26435 carrying a simian immunodeficiency virus (SIV) Gag expression plasmid and harboring attenuations of genes critical for replication (panCDandleuCD) and immune evasion (secA2), was found to be safe for oral or intradermal administration to non-SIV-infected and SIV-infected infant macaques. Safety was defined as the absence of clinical symptoms, a lack of histopathological changes indicative ofM. tuberculosisinfection, and a lack of mycobacterial dissemination. These data represent an important step in the development of novel TB vaccines and suggest that a combination recombinant attenuatedM. tuberculosis-HIV vaccine could be a safe alternative to BCG for the pediatric population as a whole and, more importantly, for the extreme at-risk group of HIV-infected infants.

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Preexisting Simian Immunodeficiency Virus Infection Increases Susceptibility to Tuberculosis in Mauritian Cynomolgus Macaques

Infection and Immunity ◽

10.1128/iai.00565-18 ◽

2018 ◽

Vol 86 (12) ◽

Cited By ~ 6

Author(s):

Mark A. Rodgers ◽

Cassaundra Ameel ◽

Amy L. Ellis-Connell ◽

Alexis J. Balgeman ◽

Pauline Maiello ◽

...

Keyword(s):

Simian Immunodeficiency Virus ◽

Ct Imaging ◽

Content Type ◽

Positron Emission ◽

Pet Ct ◽

Immunodeficiency Virus ◽

Cynomolgus Macaques ◽

Siv Infection ◽

Dichotomous Outcomes ◽

Humane Endpoint

ABSTRACT Tuberculosis (TB), caused by Mycobacterium tuberculosis, is the leading cause of death among human immunodeficiency virus (HIV)-positive patients. The precise mechanisms by which HIV impairs host resistance to a subsequent M. tuberculosis infection are unknown. We modeled this coinfection in Mauritian cynomolgus macaques (MCM) using simian immunodeficiency virus (SIV) as an HIV surrogate. We infected seven MCM with SIVmac239 intrarectally and 6 months later coinfected them via bronchoscope with ∼10 CFU of M. tuberculosis. Another eight MCM were infected with M. tuberculosis alone. TB progression was monitored by clinical parameters, by culturing bacilli in gastric and bronchoalveolar lavages, and by serial [18F]fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging. The eight MCM infected with M. tuberculosis alone displayed dichotomous susceptibility to TB, with four animals reaching humane endpoint within 13 weeks and four animals surviving >19 weeks after M. tuberculosis infection. In stark contrast, all seven SIV+ animals exhibited rapidly progressive TB following coinfection and all reached humane endpoint by 13 weeks. Serial PET/CT imaging confirmed dichotomous outcomes in MCM infected with M. tuberculosis alone and marked susceptibility to TB in all SIV+ MCM. Notably, imaging revealed a significant increase in TB granulomas between 4 and 8 weeks after M. tuberculosis infection in SIV+ but not in SIV-naive MCM and implies that SIV impairs the ability of animals to contain M. tuberculosis dissemination. At necropsy, animals with preexisting SIV infection had more overall pathology, increased bacterial loads, and a trend towards more extrapulmonary disease than animals infected with M. tuberculosis alone. We thus developed a tractable MCM model in which to study SIV-M. tuberculosis coinfection and demonstrate that preexisting SIV dramatically diminishes the ability to control M. tuberculosis coinfection.

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A MUC16 IgG Binding Activity Selects for a Restricted Subset of IgG Enriched for Certain Simian Immunodeficiency Virus Epitope Specificities

Journal of Virology ◽

10.1128/jvi.01246-19 ◽

2019 ◽

Vol 94 (5) ◽

Author(s):

Jeffrey R. Schneider ◽

Xiaoying Shen ◽

Chiara Orlandi ◽

Tinashe Nyanhete ◽

Sheetal Sawant ◽

...

Keyword(s):

Rhesus Macaque ◽

Simian Immunodeficiency Virus ◽

Specific Antigen ◽

Binding Activity ◽

Effector Function ◽

Target Cells ◽

Antigen Specificity ◽

Igg Binding ◽

Immunodeficiency Virus ◽

Siv Infection

ABSTRACT We have recently shown that MUC16, a component of the glycocalyx of some mucosal barriers, has elevated binding to the G0 glycoform of the Fc portion of IgG. Therefore, IgG from patients chronically infected with human immunodeficiency virus (HIV), who typically exhibit increased amounts of G0 glycoforms, showed increased MUC16 binding compared to uninfected controls. Using the rhesus macaque simian immunodeficiency virus SIVmac251 model, we can compare plasma antibodies before and after chronic infection. We find increased binding of IgG to MUC16 after chronic SIV infection. Antibodies isolated for tight association with MUC16 (MUC16-eluted antibodies) show reduced FcγR engagement and antibody-dependent cellular cytotoxicity (ADCC) activity. The glycosylation profile of these IgGs was consistent with a decrease in FcγR engagement and subsequent ADCC effector function, as they contain a decrease in afucosylated bisecting glycoforms that preferentially bind FcγRs. Testing of the SIV antigen specificity of IgG from SIV-infected macaques revealed that the MUC16-eluted antibodies were enriched for certain specific epitopes, including regions of gp41 and gp120. This enrichment of specific antigen responses for fucosylated bisecting glycoforms and the subsequent association with MUC16 suggests that the immune response has the potential to direct specific epitope responses to localize to the glycocalyx through interaction with this specific mucin. IMPORTANCE Understanding how antibodies are distributed in the mucosal environment is valuable for developing a vaccine to block HIV infection. Here, we study an IgG binding activity in MUC16, potentially representing a new IgG effector function that would concentrate certain antibodies within the glycocalyx to trap pathogens before they can reach the underlying columnar epithelial barriers. These studies reveal that rhesus macaque IgG responses during chronic SIV infection generate increased antibodies that bind MUC16, and interestingly, these MUC16-tethered antibodies are enriched for binding to certain antigens. Therefore, it may be possible to direct HIV vaccine-generated responses to associate with MUC16 and enhance the antibody’s ability to mediate immune exclusion by trapping virions within the glycocalyx and preventing the virus from reaching immune target cells within the mucosa. This concept will ultimately have to be tested in the rhesus macaque model, which is shown here to have MUC16-targeted antigen responses.

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A Five-Year Longitudinal Analysis of Sooty Mangabeys Naturally Infected with Simian Immunodeficiency Virus Reveals a Slow but Progressive Decline in CD4+ T-Cell Count Whose Magnitude Is Not Predicted by Viral Load or Immune Activation

Journal of Virology ◽

10.1128/jvi.00039-10 ◽

2010 ◽

Vol 84 (11) ◽

pp. 5476-5484 ◽

Cited By ~ 28

Author(s):

Jessica Taaffe ◽

Ann Chahroudi ◽

Jessica Engram ◽

Beth Sumpter ◽

Tracy Meeker ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Simian Immunodeficiency Virus ◽

Immune Activation ◽

Progressive Decline ◽

Cell Counts ◽

Immunodeficiency Virus ◽

Sooty Mangabeys ◽

Siv Infection ◽

Time Point

ABSTRACT Natural simian immunodeficiency virus (SIV) infection in sooty mangabeys (SMs) typically does not result in AIDS, despite high-level viremia and significant depletion of mucosal CD4+ T cells. Here, we report the results of the first longitudinal study of a large cohort of SMs naturally infected with SIV (n = 78) housed at the Yerkes National Primate Research Center from which samples were obtained three times over a 5-year period. In this study, we observed (i) no signs of simian AIDS, (ii) stable SIV loads, (iii) a slow but progressive decline in CD4+ T-cell counts (from a mean of 1,067.0 cells/mm3 at time point 1 to 764.8 cells/mm3 at time point 3) and increases in the numbers of animals with CD4+ T-cell levels below 500 and 200 cells/mm3 (from 8 to 28 of 78 and from 1 to 4 of 78, respectively), (iv) progressive declines in percentages of naïve CD4+ and CD8+ T cells (from 37.7 to 24.8% and from 21.0 to 13.0%, respectively), and (v) stably low levels of activated/proliferating T cells as well as CD4+ CCR5+ T cells. Since the level of total CD4+ T cells and the fraction of naïve T cells in SIV-uninfected SMs also declined, it is possible that some of these observations are related to aging, as the SIV-infected animals were significantly older than the uninfected animals. In contrast to the decline in CD4+ T cell counts in individuals infected with human immunodeficiency virus (HIV), the decline in CD4+ T cell counts in SMs naturally infected with SIV over a 5-year period was not predicted by either plasma viremia or levels of T-cell activation. Taken together, these results confirm that natural SIV infection is nonprogressive from a clinical, virological, and immunological point of view and that stable levels of viremia associated with persistently low-level immune activation represent key differences from the natural course of HIV infection in humans.

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Next-Generation mRNA Sequencing Reveals Pyroptosis-Induced CD4+T Cell Death in Early Simian Immunodeficiency Virus-Infected Lymphoid Tissues

Journal of Virology ◽

10.1128/jvi.02297-15 ◽

2015 ◽

Vol 90 (2) ◽

pp. 1080-1087 ◽

Cited By ~ 8

Author(s):

Wuxun Lu ◽

Andrew J. Demers ◽

Fangrui Ma ◽

Guobin Kang ◽

Zhe Yuan ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Simian Immunodeficiency Virus ◽

Immune Activation ◽

Lymphoid Tissues ◽

Host Interactions ◽

Immunodeficiency Virus ◽

Siv Infection ◽

Hiv 1

ABSTRACTLymphoid tissues (LTs) are the principal sites where human immunodeficiency virus type 1 (HIV-1) replicates and virus-host interactions take place, resulting in immunopathology in the form of inflammation, immune activation, and CD4+T cell death. The HIV-1 pathogenesis in LTs has been extensively studied; however, our understanding of the virus-host interactions in the very early stages of infection remains incomplete. We investigated virus-host interactions in the rectal draining lymph nodes (dLNs) of rhesus macaques at different times after intrarectal inoculation (days postinoculation [dpi]) with simian immunodeficiency virus (SIV). At 3 dpi, 103 differentially expressed genes (DEGs) were detected using next-generation mRNA sequencing (RNA-seq). At 6 and 10 dpi, concomitant with increased SIV replication, 366 and 1,350 DEGs were detected, respectively, including upregulation of genes encoding proteins that play a role in innate antiviral immune responses, inflammation, and immune activation. Notably, genes (IFI16, caspase-1, and interleukin 1β [IL-1β]) in the canonical pyroptosis pathway were significantly upregulated in expression. We further validated increased pyroptosis using flow cytometry and found that the number of CD4+T cells expressing activated caspase-1 protein, the hallmark of ongoing pyroptosis, were significantly increased, which is correlated with decreased CD4+T cells in dLNs. Our results demonstrated that pyroptosis contributes to the CD4+T cell deathin vivoin early SIV infection, which suggests that pyroptosis may play a pivotal role in the pathogenesis of SIV, and by extension, that of HIV-1, since pyroptosis not only induces CD4+T cell death but also amplifies inflammation and immune activation. Thus, blocking CD4+T cell pyroptosis could be a complementary treatment to antiretroviral therapy.IMPORTANCEAlthough secondary lymphoid tissues (LTs) are principal sites of human immunodeficiency virus type 1 (HIV-1) replication, inflammation, immune activation, and CD4+T cell death, immunopathogenesis in LTs during early infection remains largely unknown. Using the simian immunodeficiency virus (SIV)/rhesus monkey model of HIV rectal infection, we investigated early virus-host interactions. Our results revealed elevated potent host responses in early infection in LTs, including upregulation of genes involved in antiviral immune response, inflammation, and immune activation. Importantly, genes involved in the canonical pyroptosis pathway were significantly upregulated, and there was a strong correlation between CD4+T cell decrease and increased number of CD4+T cells expressing activated caspase-1 protein, demonstrating that pyroptosis contributes to CD4+T cell deathin vivoin very early SIV infection. Our finding suggests that blocking pyroptosis may be able to decrease CD4+T cell loss during early SIV infection.

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