Abstract
Although HIV has been shown to impact brain connectivity in adults and youth, it is not yet known to what extent long-term early antiretroviral therapy (ART) may alter these effects, especially during rapid brain development in early childhood. Using both independent component analysis (ICA) and seed-based correlation analysis (SCA), we examine the effects of HIV infection in conjunction with early ART on resting state functional connectivity (FC) in 7 year old children. HIV infected (HIV+) children were from the Children with HIV Early Antiretroviral Therapy (CHER) trial and all initiated ART before 18 months; uninfected children were recruited from an interlinking vaccine trial. To better understand the effects of current and early immune health on the developing brain, we also investigated among HIV+ children the association of FC at 7 years with CD4 count and CD4%, both in infancy (6–8 weeks) and at scan. Although we found no differences within any ICA-generated resting state networks (RSNs) between HIV+ and uninfected children (27 HIV+, 18 uninfected), whole brain connectivity to seeds located at RSN connectivity peaks revealed several loci of FC differences, predominantly from seeds in midline regions (posterior cingulate cortex, paracentral lobule, cuneus, and anterior cingulate). Reduced long-range connectivity and increased short-range connectivity suggest developmental delay. Within the HIV+ children, clinical measures at age 7 years were not associated with FC values in any of the RSNs; however, poor immune health during infancy was associated with localized FC increases in the somatosensory, salience and basal ganglia networks. Together these findings suggest that HIV may affect brain development from its earliest stages and persist into childhood, despite early ART.
Highlights
Increased access to antiretroviral therapy (ART) has transformed human immunodeficiency virus (HIV) infection from a fatal to a chronic illness
For example, that alterations in brain white matter (WM) and basal ganglia metabolism are evident at age 5 years in children from the Children with HIV Early Antiretroviral Therapy (CHER) cohort despite starting ART before 75 weeks of age and viral load (VL) suppression (Ackermann et al, 2016; Mbugua et al, 2016)
This study investigated HIV-associated functional connectivity (FC) changes in 7 year old children on two levels: firstly, comparing FC between HIV+ and uninfected cohorts, and secondly, examining relations of FC and HIV clinical measures within the infected group
Summary
Increased access to antiretroviral therapy (ART) has transformed human immunodeficiency virus (HIV) infection from a fatal to a chronic illness. Since HIV penetrates the CNS during the first 3 weeks of life of perinatally HIV+ children (GonzálezScarano and Martín-García, 2005), which corresponds to a critical period in development, markers of early immune health, or virologic status may play an integral part in determining later neurological outcomes (Bilbo, 2013) Children in these earlier studies initiated ART at different ages, mostly after 2 years of age, and often with limited viral load (VL) suppression. Since brain activity is measured when subjects are not performing a specific task, it greatly reduces the potentially confounding influences of attention, task performance, and language comprehension and is ideally suited to pediatric studies It is a sensitive marker of alterations in brain development (Superkar et al, 2010; Thomason et al, 2011; de Bie et al, 2012) and disease (Greicius, 2008). We postulated that improved immune health, measured by CD4 count and percentage in infancy and at scan, would be related to greater functional connectivity in these networks
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