Viral evolution in a pediatric rhesus macaque model of HIV therapy and rebound
Abstract
In 2017, approximately 180,000 infants were infected with HIV and 1.8 million children
were living with HIV globally. While lifelong combination antiretroviral therapy (ART)
can effectively suppress virus replication, ART is not curative due to the establishment
of stable latent viral reservoirs immediately after infection. A functional cure able
to achieve sustained viral remission will be required to attain an ART-free life.
Our study goal was to characterize the kinetics of Simian-Human Immunodeficiency Virus
(SHIV) evolution and viral rebound in infant and adult preclinical models of HIV reservoir
on ART. In this study, 6 infant and adult rhesus macaques (RMs) were infected with
Simian-Human Immunodeficiency Virus (SHIV).C.CH0505.375H.dCT virus via oral and intravenous
challenge, respectively. Twelve weeks post infection (wpi), infant and adult RMs were
placed on ART for 8 and 12 weeks, respectively. ART was then interrupted and kinetics
of viral rebound was measured using qRT-PCR. Viral diversity was measured pre- and
post-ART using single genome amplification and sequencing of the HIV env gene. Plasma
viral RNA (vRNA) in infants and adults displayed similar kinetics until ART initiation,
peaking at 2 wpi. Upon ART initiation, plasma vRNA load was suppressed in infants
and adults to undetectable levels within 2-4 weeks. Post-ART, 5/6 infant and 3/6 adult
RMs rebounded to >150 vRNA copies/ml of plasma within 1-3 weeks. Pre-ART and post-ART,
HIV env sequence diversity was greater in adult plasma viruses than in infant plasma
viruses, with average pairwise distance values of 0.007 and 0.005, respectively. Post-ART,
infant plasma viruses are more closely related to pre-ART viruses than are adult plasma
viruses, perhaps due to less immune pressure in infants. These findings further delineate
the clinically relevant differences in HIV env genetic diversity between infants and
adults and emphasize the clear need for highly relevant, preclinical models for the
development of pediatric-specific therapeutic and curative strategies to achieve an
HIV-free generation.
Type
Honors thesisDepartment
BiologyPermalink
https://hdl.handle.net/10161/18533Citation
Mangold, Jesse (2019). Viral evolution in a pediatric rhesus macaque model of HIV therapy and rebound. Honors thesis, Duke University. Retrieved from https://hdl.handle.net/10161/18533.Collections
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