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CHANGES IN BRAIN VOLUME AND COGNITION IN MICE EXPOSED IN UTERO TO ABC/ 3TC-ATV/ RTV
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Reported by Jules Levin
CROI 2018 March 4-7 Boston MAKayode Balogun1, Monica Guzman Lenis1, Lindsay Cahill2, Howard Mount3, John Sled3, Lena Serghides1
1University Health Network, Toronto, ON, Canada,2The Hospital for Sick Children, Toronto, ON, Canada,3University of Toronto, Toronto, ON, Canada
CROI: BRAIN VOLUMES CHANGES AFTER ABC/3TC + EFV OR TDF/FTC + ATV/r AS FIRST LINE ART (03/12/18)
CROI: Amyloid uptake by PET imaging in older HIV+ individuals with cognitive impairment (03/12/18)
CROI: Asymptomatic Neurocognitive Impairment With HIV Marked by Brain Atrophy - Mark Mascolini (03/12/18)
Program Abstract:
Combination antiretroviral therapy (cART) has facilitated the radical reduction of perinatal transmission of HIV. However, there are concerns about the effects of cART on fetal development and long-term health outcomes of the offspring. Studies have reported several adverse neurological outcomes in HIV-exposed uninfected children. Our objective was to investigate the impact of in utero exposure to cART on infant brain development and cognitive behavior using advanced imaging techniques and well-validated behavioral testing methods in a mouse pregnancy model.
Gravid C57BL/6 mice were exposed to human-relevant plasma concentration of Abacavir (ABC)/Lamivudine (3TC)-atazanavir (ATV)/ritonavir (RTV) or water (control) starting from gestational day (GD) 1 to delivery. At GD 16, mice were euthanized; fetal weights were recorded and fetal morphology was assessed using micro-CT. A subset of the pregnant mice was allowed to carry to term and pups were accessed for developmental milestones (motor, tactile, auditory, and olfactory reflexes) from postnatal day 1-21. Postweaning, all mice were subjected to the novel object recognition test to assess non-spatial learning and memory. Alterations in brain regional volumes were assessed by magnetic resonance imaging.
Fetuses exposed to cART were smaller than the controls [mean (SD); 0.32g (0.09) vs. 0.41g (0.06); P=0.007] and continued to remain smaller until sacrifice at 8 months after birth [mean (SD); 27.95g (1.78) vs. 30.95g (1.87) P=0.00025]. Micro-CT imaging showed significant volumetric changes in different regions of the fetal brains including a significant 7% decrease in the volume of the neocortex and amygdala (P<0.05) and a 7% increase in the hypothalamus in the cART-exposed group compared to controls (P<0.05); similar changes were observed in the adult brains by MRI at 8 months. The development of motor skills, tactile and olfactory reflexes were delayed in the cART-exposed offspring compared to controls (P<0.01). The cART-exposed mice had lower memory indices (MI) compared to controls (P<0.0001), and there was a positive correlation between MI vs. hippocampus CA1 and CA2 (r=0.68, P<0.0001), and MI vs. cingulate cortex (r=0.4, P=0.024).
Our data suggest that the in utero exposure to ABC/ 3TC-ATV/ RTV is associated with volumetric changes in key regions of the brain, developmental delays and cognitive deficits in a mouse model of pregnancy.
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