TY - JOUR
T1 - Analytical treatment interruption after short-term antiretroviral therapy in a postnatally simian-human immunodeficiency virus-infected infant rhesus macaque model
AU - Goswami, Ria
AU - Nelson, Ashley N.
AU - Tu, Joshua J.
AU - Dennis, Maria
AU - Feng, Liqi
AU - Kumar, Amit
AU - Mangold, Jesse
AU - Mangan, Riley J.
AU - Mattingly, Cameron
AU - Curtis, Alan D.
AU - Obregon-Perko, Veronica
AU - Mavigner, Maud
AU - Pollara, Justin
AU - Shaw, George M.
AU - Bar, Katharine J.
AU - Chahroudi, Ann
AU - De Paris, Kristina
AU - Chan, Cliburn
AU - Van Rompay, Koen K.A.
AU - Permara, Sallie R.
N1 - Publisher Copyright:
© 2019 Goswami et al.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85071745855
U2 - 10.1128/mBio.01971-19
DO - 10.1128/mBio.01971-19
M3 - Article
C2 - 31488511
AN - SCOPUS:85071745855
SN - 2161-2129
VL - 10
JO - mBio
JF - mBio
IS - 5
M1 - e01971-19
ER -