Analytical treatment interruption after short-term anti-retroviral therapy in a postnatally SHIV infected infant rhesus macaque model

ABSTRACTTo achieve long-term viral remission in HIV-infected children, novel strategies beyond early anti-retroviral therapy (ART) will be necessary. Identifying clinical predictors of time to viral rebound upon ART interruption will streamline the development of novel therapeutic strategies and accelerate their evaluation in clinical trials. However, identification of these biomarkers is logistically challenging in infants, due to sampling limitations and potential risks of treatment interruption. To facilitate identification of biomarkers predicting viral rebound, we have developed an infant rhesus macaque (RM) model of oral SHIV.CH505.375H.dCT challenge and analytical treatment interruption (ATI) after short-term ART. We used this model to characterize SHIV replication kinetics and virus-specific immune responses during short-term ART or post-ATI and demonstrated plasma viral rebound in 5 out of 6 (83%) infants. We observed a decline in humoral immune responses and partial dampening of systemic immune activation upon initiation of ART in these infants. Furthermore, we documented that infant and adult macaques have similar SHIV replication and rebound kinetics and equally potent virus-specific humoral immune responses. Finally, we validated our models by confirming a well-established correlate of time to viral rebound, namely pre-ART plasma viral load, as well as identified additional potential humoral immune correlates. Thus, this model of infant ART and viral rebound can be used and further optimized to define biomarkers of viral rebound following long-term ART as well as to pre-clinically assess novel therapies to achieve a pediatric HIV functional cure.IMPORTANCENovel interventions that do not rely on daily adherence to ART are needed to achieve sustained viral remission for perinatally infected children who currently rely on lifelong ART. Considering the risks and expense associated with ART-interruption trials, identification of biomarkers of viral rebound will prioritize promising therapeutic intervention strategies, including anti-HIV Env protein therapeutics. However, comprehensive studies to identify those biomarkers are logistically challenging in human infants, demanding the need for relevant non-human primate models of HIV rebound. In this study, we developed an infant RM model of oral Simian/Human Immunodeficiency virus infection expressing clade C HIV Env, and short-term ART followed by ATI, longitudinally characterizing immune responses to viral infection during ART and post-ATI. Additionally, we compared this infant RM model to an analogous adult RM rebound model and identified virologic and immunologic correlates of time to viral rebound post-ATI.

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Analytical Treatment Interruption after Short-Term Antiretroviral Therapy in a Postnatally Simian-Human Immunodeficiency Virus-Infected Infant Rhesus Macaque Model

mBio ◽

10.1128/mbio.01971-19 ◽

2019 ◽

Vol 10 (4) ◽

Cited By ~ 5

Author(s):

Ria Goswami ◽

Ashley N. Nelson ◽

Joshua J. Tu ◽

Maria Dennis ◽

Liqi Feng ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Immune Responses ◽

Treatment Interruption ◽

Viral Rebound ◽

Short Term ◽

Analytical Treatment ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Immunodeficiency Virus

ABSTRACT To achieve long-term viral remission in human immunodeficiency virus (HIV)-infected children, novel strategies beyond early antiretroviral therapy (ART) will be necessary. Identifying clinical predictors of the time to viral rebound upon ART interruption will streamline the development of novel therapeutic strategies and accelerate their evaluation in clinical trials. However, identification of these biomarkers is logistically challenging in infants, due to sampling limitations and the potential risks of treatment interruption. To facilitate the identification of biomarkers predicting viral rebound, we have developed an infant rhesus macaque (RM) model of oral simian-human immunodeficiency virus (SHIV) SHIV.CH505.375H.dCT challenge and analytical treatment interruption (ATI) after short-term ART. We used this model to characterize SHIV replication kinetics and virus-specific immune responses during short-term ART or after ATI and demonstrated plasma viral rebound in 5 out of 6 (83%) infants. We observed a decline in humoral immune responses and partial dampening of systemic immune activation upon initiation of ART in these infants. Furthermore, we monitored SHIV replication and rebound kinetics in infant and adult RMs and found that both infants and adults demonstrated equally potent virus-specific humoral immune responses. Finally, we validated our models by confirming a well-established correlate of the time to viral rebound, namely, the pre-ART plasma viral load, as well as identified additional potential humoral immune correlates. Thus, this model of infant ART and viral rebound can be used and further optimized to define biomarkers of viral rebound following long-term ART as well as to preclinically assess novel therapies to achieve a pediatric HIV functional cure. IMPORTANCE Novel interventions that do not rely on daily adherence to ART are needed to achieve sustained viral remission for perinatally infected children, who currently rely on lifelong ART. Considering the risks and expense associated with ART interruption trials, the identification of biomarkers of viral rebound will prioritize promising therapeutic intervention strategies, including anti-HIV Env protein therapeutics. However, comprehensive studies to identify those biomarkers are logistically challenging in human infants, demanding the need for relevant nonhuman primate models of HIV rebound. In this study, we developed an infant RM model of oral infection with simian-human immunodeficiency virus expressing clade C HIV Env and short-term ART followed by ATI, longitudinally characterizing the immune responses to viral infection during ART and after ATI. Additionally, we compared this infant RM model to an analogous adult RM rebound model and identified virologic and immunologic correlates of the time to viral rebound after ATI.

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Cellular and humoral immune responses to adenoviral vectors containing factor IX gene: tolerization of factor IX and vector antigens allows for long-term expression.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.92.5.1401 ◽

1995 ◽

Vol 92 (5) ◽

pp. 1401-1405 ◽

Cited By ~ 436

Author(s):

Y. Dai ◽

E. M. Schwarz ◽

D. Gu ◽

W. W. Zhang ◽

N. Sarvetnick ◽

...

Keyword(s):

Immune Responses ◽

Adenoviral Vectors ◽

Factor Ix ◽

Humoral Immune ◽

Humoral Immune Responses

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Viral Dynamics during Structured Treatment Interruptions of Chronic Human Immunodeficiency Virus Type 1 Infection

Journal of Virology ◽

10.1128/jvi.76.3.968-979.2002 ◽

2002 ◽

Vol 76 (3) ◽

pp. 968-979 ◽

Cited By ~ 39

Author(s):

Simon D. W. Frost ◽

Javier Martinez-Picado ◽

Lidia Ruiz ◽

Bonaventura Clotet ◽

Andrew J. Leigh Brown

Keyword(s):

Human Immunodeficiency Virus ◽

Viral Load ◽

Immune Responses ◽

Treatment Interruption ◽

Viral Rebound ◽

Viral Dynamics ◽

Viral Loads ◽

Treatment Interruptions ◽

Immunodeficiency Virus

ABSTRACT Although antiviral agents which block human immunodeficiency virus (HIV) replication can result in long-term suppression of viral loads to undetectable levels in plasma, long-term therapy fails to eradicate virus, which generally rebounds after a single treatment interruption. Multiple structured treatment interruptions (STIs) have been suggested as a possible strategy that may boost HIV-specific immune responses and control viral replication. We analyze viral dynamics during four consecutive STI cycles in 12 chronically infected patients with a history (>2 years) of viral suppression under highly active antiretroviral therapy. We fitted a simple model of viral rebound to the viral load data from each patient by using a novel statistical approach that allows us to overcome problems of estimating viral dynamics parameters when there are many viral load measurements below the limit of detection. There is an approximate halving of the average viral growth rate between the first and fourth STI cycles, yet the average time between treatment interruption and detection of viral loads in the plasma is approximately the same in the first and fourth interruptions. We hypothesize that reseeding of viral reservoirs during treatment interruptions can account for this discrepancy, although factors such as stochastic effects and the strength of HIV-specific immune responses may also affect the time to viral rebound. We also demonstrate spontaneous drops in viral load in later STIs, which reflect fluctuations in the rates of viral production and/or clearance that may be caused by a complex interaction between virus and target cells and/or immune responses.

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Long-term exposure to arsenic affects head kidney and impairs humoral immune responses of Clarias batrachus

Aquatic Toxicology ◽

10.1016/j.aquatox.2006.11.004 ◽

2007 ◽

Vol 81 (1) ◽

pp. 79-89 ◽

Cited By ~ 42

Author(s):

Debabrata Ghosh ◽

Soma Datta ◽

Shelley Bhattacharya ◽

Shibnath Mazumder

Keyword(s):

Immune Responses ◽

Head Kidney ◽

Clarias Batrachus ◽

Humoral Immune ◽

Humoral Immune Responses

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Induction of humoral immunity in response to immunization with recombinantMycobacterium bovisBCG expressing the S1 subunit ofBordetella pertussistoxin

Canadian Journal of Microbiology ◽

10.1139/w05-095 ◽

2005 ◽

Vol 51 (12) ◽

pp. 1015-1020 ◽

Cited By ~ 11

Author(s):

Marco A Medeiros ◽

Geraldo R.G Armôa ◽

Odir A Dellagostin ◽

Douglas McIntosh

Keyword(s):

Immune Responses ◽

Pertussis Toxin ◽

Whooping Cough ◽

Low Cost ◽

Long Term Memory ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Specific Igg

Two recombinant Mycobacterium bovis BCG (rBCG) vaccine strains were developed for the expression of cytoplasmically located S1 subunit of pertussis toxin, with expression driven by the hsp60 promoter of M. bovis (rBCG/pPB10) or the pAN promoter of Mycobacterium paratuberculosis (rBCG/pPB12). Both strains showed stable expression of equivalent levels of recombinant S1 in vitro and induced long-term (up to 8 months) humoral immune responses in BALB/c mice, although these responses differed quantitatively and qualitatively. Specifically, rBCG/pPB12 induced markedly higher levels of IgG1 than did rBCG/pPB10, and mice immunized with the former strain developed specific long-term memory to S1, as indicated by the production of high levels of S1-specific IgG in response to a sublethal challenge with pertussis toxin 15 months after initial immunization. When considered in combination with previous studies, our data encourage further evaluation of rBCG as a potential means of developing a low-cost whooping cough vaccine based on defined antigens.Key words: recombinant BCG, humoral immune response, B. pertussis.

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Short-term handling stress affects the humoral immune responses of juvenile Atlantic cod, Gadus morhua

Aquaculture International ◽

10.1007/s10499-013-9746-2 ◽

2014 ◽

Vol 22 (4) ◽

pp. 1283-1293 ◽

Cited By ~ 5

Author(s):

Christopher Marlowe A. Caipang ◽

Effrosyni Fatira ◽

Carlo C. Lazado ◽

Michail Pavlidis

Keyword(s):

Immune Responses ◽

Gadus Morhua ◽

Atlantic Cod ◽

Short Term ◽

Handling Stress ◽

Humoral Immune ◽

Humoral Immune Responses

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Specific Cellular and Humoral Immune Responses in Patients with Different Long-Term Courses of Alveolar Echinococcosis (Infection with Echinococcus Multilocularis)

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.1991.45.734 ◽

1991 ◽

Vol 45 (6) ◽

pp. 734-742 ◽

Cited By ~ 41

Author(s):

Bruno Gottstein ◽

Joseph F. Wilson ◽

Isabelle Tanner ◽

Anne Lanier ◽

Barbara Mesarina ◽

...

Keyword(s):

Immune Responses ◽

Echinococcus Multilocularis ◽

Alveolar Echinococcosis ◽

Humoral Immune ◽

Humoral Immune Responses

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Tolerance induction by lentiviral gene therapy with a nonmyeloablative regimen

Blood ◽

10.1182/blood-2005-03-1172 ◽

2006 ◽

Vol 107 (6) ◽

pp. 2286-2293 ◽

Cited By ~ 10

Author(s):

Noboru Mitsuhashi ◽

Jacqueline Fischer-Lougheed ◽

Irina Shulkin ◽

Annette Kleihauer ◽

Donald B. Kohn ◽

...

Keyword(s):

Immune Responses ◽

Blood Cells ◽

Lentiviral Vector ◽

Lethal Dose ◽

Tolerance Induction ◽

Xenograft Rejection ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Lentiviral Gene Therapy

AbstractAntibodies (Abs) directed at the Galα1,3Galβ1,4GlcNAc-R (αGal) carbohydrate epitope initiate xenograft rejection. Previously, we have shown that bone marrow transplantation (BMT) with lentivirus-mediated gene transfer of porcine α1,3 galactosyltransferase (GalT) is able to induce tolerance to αGal-expressing heart grafts following a lethal dose of irradiation. Here we show the first demonstration of permanent survival of αGal+ hearts following transplantation with autologous, lentivirus-transduced BM using a nonmyeloablative regimen. Autologous BM from GalT knockout (GalT–/–) mice was transduced with a lentiviral vector expressing porcine GalT and transplanted into sublethally irradiated (3 Gy) GalT–/– mice. Chimerism in the peripheral blood cells (PBCs) remained low but was higher in the BM, especially within the stromal cell population. Mice reconstituted with GalT did not produce anti-αGal Abs over time. We immunized these mice with αGal-expressing cells and assessed humoral immune responses. Anti-αGal xenoantibodies were not produced in mice reconstituted with GalT, but normal Ab responses to other xenoantigens were detected. Mice reconstituted with GalT accepted αGal+ heart grafts over 100 days. Transduction with lentiviral vectors results in chimerism at levels sufficient to induce long-term tolerance under nonmyeloablative conditions.

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Host-Pathogen Interactions in Campylobacter Infections: the Host Perspective

Clinical Microbiology Reviews ◽

10.1128/cmr.00055-07 ◽

2008 ◽

Vol 21 (3) ◽

pp. 505-518 ◽

Cited By ~ 169

Author(s):

Riny Janssen ◽

Karen A. Krogfelt ◽

Shaun A. Cawthraw ◽

Wilfrid van Pelt ◽

Jaap A. Wagenaar ◽

...

Keyword(s):

Animal Models ◽

Immune Responses ◽

Protective Immunity ◽

Relative Importance ◽

Short Term ◽

Innate And Adaptive Immunity ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Genomics And Proteomics ◽

Frequent Exposure

SUMMARY Campylobacter is a major cause of acute bacterial diarrhea in humans worldwide. This study was aimed at summarizing the current understanding of host mechanisms involved in the defense against Campylobacter by evaluating data available from three sources: (i) epidemiological observations, (ii) observations of patients, and (iii) experimental observations including observations of animal models and human volunteer studies. Analysis of available data clearly indicates that an effective immune system is crucial for the host defense against Campylobacter infection. Innate, cell-mediated, and humoral immune responses are induced during Campylobacter infection, but the relative importance of these mechanisms in conferring protective immunity against reinfection is unclear. Frequent exposure to Campylobacter does lead to the induction of short-term protection against disease but most probably not against colonization. Recent progress in the development of more suitable animal models for studying Campylobacter infection has opened up possibilities to study the importance of innate and adaptive immunity during infection and in protection against reinfection. In addition, advances in genomics and proteomics technologies will enable more detailed molecular studies. Such studies combined with better integration of host and pathogen research driven by epidemiological findings may truly advance our understanding of Campylobacter infection in humans.

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