Neurocognitive Dysfunction in HIV+ Youth: Investigating

Neurocognitive Dysfunction in HIV+ Youth: Investigating the Relationship to Immune Activation
POSTER
469
Julia C. Rosebush1, Ann Chahroudi1, S. Thera Lee1, Mary Ann O’Riordan2, Chanda Graves1, Anita Grover3,
Bridget Wynn1, Ashley Alexander4, Grace A. McComsey2, Allison Ross Eckard1,5
1Emory
University School of Medicine, Atlanta, GA, USA; 2Case Western Reserve University and Rainbow Babies & Children’s Hospital,
Cleveland, OH, USA; 3Georgia State University, Atlanta, GA, USA; 4Children’s Healthcare of Atlanta, GA, USA;
5Medical University of South Carolina, Charleston, SC, USA
Abstract
Background
Background: HIV+ individuals are at increased
risk of developing neurocognitive impairment
compared to the general population. It is
postulated that ongoing viral replication causes
immune activation that results in neural damage.
Few studies have investigated this phenomenon
in the pediatric and young adult HIV+ population.
Ø  HIV+ individuals are at an increased risk of developing HIVassociated neurocognitive disorders (HAND)
Ø  While cART has reduced the incidence of severe HAND, the
prevalence of milder forms of neurocognitive dysfunction has
increased in the post-ART era
Ø  HAND is proposed to be due, in part, to immune activation
from viral replication which causes neural damage despite ART
Ø  Monocyte activation (evidenced by the CD14+ and/or CD16+
phenotype) as well as increased plasma levels of sCD14 and
sCD16 are associated with impaired neurocognitive test
performance in adults
Ø  Few studies have assessed neurocognitive impairment and
immune activation in HIV+ youth
Methods: This was a pilot, cross-sectional study
evaluating the association of neurocognitive
impairment in virologically-suppressed HIV-1infected youth ages 8-26 years with immune
activation compared to matched healthy controls.
Neurocognitive performance was assessed by
age-appropriate Wechsler intelligence scales
and markers of lymphocyte and monocyte
immune activation by ELISA and flow cytometry
in plasma and PBMC samples. Analyses used
non-parametric tests, Spearman coefficients, and
multivariable linear regression.
Results: 68 subjects (47 HIV+: 57% male, 89%
black, mean age 19 years) were enrolled. Mean
scores were low-average for 4 of 5 testing
domains for the HIV+ subjects and average for
all 5 in the controls. Working memory was
statistically lower in the controls compared to the
HIV group (89 vs. 99; P=0.04). Markers of CD4+
and CD8+ T-cell activation and monocyte
activation were higher in the HIV+ subjects
compared to the controls, but proportions of
inflammatory (CD14+CD16+) and patrolling
monocytes (CD14dimCD16+) were similar
between groups. In the HIV+ group, plasma
levels of soluble CD14 and %CD4+CD38+HLADR+ activated T-lymphocytes were negatively
correlated with verbal comprehension, and HIV
duration was negatively associated with verbal
comprehension, working memory and full-scale
intelligence quotient. Marijuana use was
positively associated with working memory and
processing speed. In multivariable regression
evaluating associations with working memory,
HIV duration was the only statistically significant
factor (P = 0.038).
Conclusions: HIV+ youth have evidence of
neurocognitive impairment and increased
immune activation compared to matched healthy
controls. While there may be a relationship
between neurocognitive impairment and immune
activation in HIV+ youth as evidenced by
significant bivariate relationships, HIV duration
appears to be the most important factor in this
study.
Julia Rosebush, D.O.
jrosebush@uchicago.edu
Results
Participant Characteristics
Summary of Results
Neurocognitive Testing Scores by Study Group
u
u
Objectives
Ø  Primary objective: to determine the relationship between
neurocognitive performance and markers of lymphocyte and
monocyte activation among HIV+ youth
Limitations
Ø  Secondary objective: to investigate differences in associations
between immune activation and neurocognitive performance in
HIV+ youth compared to healthy, matched controls
Ø  Cross-sectional design, small sample size
Ø  Performance on neurocognitive testing in HIV+
youth may be confounded by environmental
factors but subjects were well-matched to
controls with regard to socioeconomic status
Methods
Ø  STUDY DESIGN
v  Pilot, prospective, cross-sectional evaluation of a cohort of HIV+ youth
and healthy, matched controls
Ø  SELECTION OF SUBJECTS
v  Inclusion criteria for HIV-infected group: HIV-1 infection, age
between 8-26 years, cumulative ARV duration ≥6 months, current ARV
regimen consistently for ≥12 weeks, HIV-1 RNA level ≤1,000 copies/mL
v  Inclusion criteria for controls: absence of HIV, 8-26 years of age
v  Exclusion criteria for both groups: Acute illness, inflammatory
condition, malignancy, medication use which could lead to changes in
immune activation markers, pregnancy/breastfeeding, diagnosis of
encephalopathy, cerebral palsy, or other existing neurologic deficit
v  Healthy controls were matched to the HIV+ group by sex, race, age
Ø 
STUDY ASSESSMENTS
v  Clinical/laboratory evaluations: demographics, medical/mental
health history, substance use, educational background, socioeconomic
data; chart review, HIV-1 RNA, CD4+ count
v  Neurocognitive assessment: Wechsler Intelligence Scale for
Children-4th Edition (WISC-IV) for subjects 8-16 years old and the
Wechsler Adult Intelligence Scale-4th Edition (WAIS-IV) for subjects
≥17 years old
v  Immune activation assessment: CD4+/CD8+ T-cell and monocyte
activation assessed via flow cytometry. Activation of monocyte subsets
measured by CD86 and HLA-DR expression; T-cell activation
assessed by CD38, HLA-DR. Plasma levels of soluble markers, sCD14
and sCD16 measured by ELISA
Ø  STATISTICAL ANALYSIS:
v  Correlations/associations: correlation between WISC/WAIS-IV
scores and selected biomarkers described via Spearman correlation
coefficient and association of WISC/WAIS-IV scores and categorical
variables via appropriate two-sample tests (t-tests for normally
distributed variables or Wilcoxon rank sum tests for non-normally
distributed variables)
v  Multiple regression analysis: used to explore relationships between
neurocognitive performance scores and biomarker levels while
controlling for clinical and demographic characteristics
Ø  HIV+ youth have evidence of neurocognitive
impairment and increased immune activation
compared to matched healthy controls
Ø  Mean neurocognitive scores were low-average
for 4 of 5 testing domains for HIV+ subjects
and average for all 5 in controls
Ø  Markers of CD4+ and CD8+ T-cell and
monocyte activation were higher in HIV+
subjects compared to controls, but proportions
of inflammatory and patrolling monocytes were
similar between groups
Ø  After multivariate analysis, HIV duration was
the only statistically significant factor
associated with working memory
Data are mean (interquartile range) or no. (%) of individuals.
*Statistically significant results (p<0.05).
uStatistically significant results
Scores are standardized based on the US population with mean = 100; and
standard deviation (SD) = 15.
Associations with Neurocognitive Performance by Study Group
Multivariable Regression Analysis for Working Memory
in HIV+ Subjects
Conclusions
v  HIV+ youth with virologic suppression perform
below average on neurocognitive tests and
have higher levels of peripheral immune
activation compared to controls
v  HIV duration may play a significant role in the
spectrum of neurocognitive deficits seen in
HIV+ youth in the post-ART era
v  Ramifications of unrecognized HAND could be
immense given that youth comprise the fastest
growing population of newly infected HIV+
individuals in the United States
v  Targeting this population offers an opportunity
to identify those at risk for poor outcomes and
develop strategies to mitigate damage while
neurodevelopment is still occurring
Acknowledgments
Variables chosen on the basis of clinical significance and/or bivariate
results. HIV duration was the only variable that remained statistically significant
(p=0.038).
*Statistically significant associations are boldfaced.
Variables tested but not significant include age, %CD8+CD38+HLA-DR+
T-lymphocytes, and CD14+CD16+ and CD14dimCD16+ monocytes.
This work was supported by the National Institutes of Health [R01
HD070490 to GAM; K23 HD 069199 to ARE], Emory’s Center for
AIDS Research (P30 AI050409), Clinical and Translational Science
Collaborative (CTSC) grant support (UL1TR 000439), Emory and
Children’s Pediatric Research Center Biomarkers, Flow Cytometry,
and Immunology cores.