Analytical Treatment Interruption after Short-Term Antiretroviral Therapy in a Postnatally Simian-Human Immunodeficiency Virus-Infected Infant Rhesus Macaque Model
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 n...
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American Society for Microbiology
2019
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oai:doaj.org-article:2d07f7f1798d4cddb1ebdeee807044e82021-11-15T15:59:42ZAnalytical Treatment Interruption after Short-Term Antiretroviral Therapy in a Postnatally Simian-Human Immunodeficiency Virus-Infected Infant Rhesus Macaque Model10.1128/mBio.01971-192150-7511https://doaj.org/article/2d07f7f1798d4cddb1ebdeee807044e82019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01971-19https://doaj.org/toc/2150-7511ABSTRACT 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.Ria GoswamiAshley N. NelsonJoshua J. TuMaria DennisLiqi FengAmit KumarJesse MangoldRiley J. ManganCameron MattinglyAlan D. CurtisVeronica Obregon-PerkoMaud MavignerJustin PollaraGeorge M. ShawKatharine J. BarAnn ChahroudiKristina De ParisCliburn ChanKoen K. A. Van RompaySallie R. PermarAmerican Society for Microbiologyarticleanalytical treatment interruptionHIV reservoirpediatric HIV cureSHIVMicrobiologyQR1-502ENmBio, Vol 10, Iss 5 (2019) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
analytical treatment interruption HIV reservoir pediatric HIV cure SHIV Microbiology QR1-502 |
| spellingShingle |
analytical treatment interruption HIV reservoir pediatric HIV cure SHIV Microbiology QR1-502 Ria Goswami Ashley N. Nelson Joshua J. Tu Maria Dennis Liqi Feng Amit Kumar Jesse Mangold Riley J. Mangan Cameron Mattingly Alan D. Curtis Veronica Obregon-Perko Maud Mavigner Justin Pollara George M. Shaw Katharine J. Bar Ann Chahroudi Kristina De Paris Cliburn Chan Koen K. A. Van Rompay Sallie R. Permar Analytical Treatment Interruption after Short-Term Antiretroviral Therapy in a Postnatally Simian-Human Immunodeficiency Virus-Infected Infant Rhesus Macaque Model |
| description |
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. |
| format |
article |
| author |
Ria Goswami Ashley N. Nelson Joshua J. Tu Maria Dennis Liqi Feng Amit Kumar Jesse Mangold Riley J. Mangan Cameron Mattingly Alan D. Curtis Veronica Obregon-Perko Maud Mavigner Justin Pollara George M. Shaw Katharine J. Bar Ann Chahroudi Kristina De Paris Cliburn Chan Koen K. A. Van Rompay Sallie R. Permar |
| author_facet |
Ria Goswami Ashley N. Nelson Joshua J. Tu Maria Dennis Liqi Feng Amit Kumar Jesse Mangold Riley J. Mangan Cameron Mattingly Alan D. Curtis Veronica Obregon-Perko Maud Mavigner Justin Pollara George M. Shaw Katharine J. Bar Ann Chahroudi Kristina De Paris Cliburn Chan Koen K. A. Van Rompay Sallie R. Permar |
| author_sort |
Ria Goswami |
| title |
Analytical Treatment Interruption after Short-Term Antiretroviral Therapy in a Postnatally Simian-Human Immunodeficiency Virus-Infected Infant Rhesus Macaque Model |
| title_short |
Analytical Treatment Interruption after Short-Term Antiretroviral Therapy in a Postnatally Simian-Human Immunodeficiency Virus-Infected Infant Rhesus Macaque Model |
| title_full |
Analytical Treatment Interruption after Short-Term Antiretroviral Therapy in a Postnatally Simian-Human Immunodeficiency Virus-Infected Infant Rhesus Macaque Model |
| title_fullStr |
Analytical Treatment Interruption after Short-Term Antiretroviral Therapy in a Postnatally Simian-Human Immunodeficiency Virus-Infected Infant Rhesus Macaque Model |
| title_full_unstemmed |
Analytical Treatment Interruption after Short-Term Antiretroviral Therapy in a Postnatally Simian-Human Immunodeficiency Virus-Infected Infant Rhesus Macaque Model |
| title_sort |
analytical treatment interruption after short-term antiretroviral therapy in a postnatally simian-human immunodeficiency virus-infected infant rhesus macaque model |
| publisher |
American Society for Microbiology |
| publishDate |
2019 |
| url |
https://doaj.org/article/2d07f7f1798d4cddb1ebdeee807044e8 |
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