Background
In the current study, we test whether low level HIV replication is important in the pathogenesis of neurocognitive and neuroimaging biotypes, and independent of comorbidity and legacy effects.
Methods
43 virally-suppressed clinically stable men with HIV (age 53±14 years, plasma and CSF <20-50 cp/mL) were included. Neurocognition, CSF neopterin, plasma and CSF HIV RNA were measured (HIV RNA by single copy assay- SCA detection limit <0.3 cp/mL, RNA thereafter) at baseline, 6-, 12-, 18 and 24-month. Magnetic resonance spectroscopy (MRS) was conducted at baseline and 24month. Non-HIV medical, psychiatric, disability, and lifestyle history was integrated into a comorbidity score. Legacy effects were defined as historical HIV-associated neurocognitive disorder (HAND) and nadir CD4 <200. Our previous analyses had shown four neurobiotypes by neurocognitive and MRS changes. In this dataset the neurobiotypes’ prevalenc and profile were: stable=30% (mild inflammation, bioenergy abnormalities), incident decline=16.5% (increasing inflammatory activity), progressive=11.5% (axonal and neuronal injury), and cognitively-normal=42% (subclinical bioenergy abnormalities). Mixed effect models tested main effect and time-association between the neurobiotypes and the CSF biomarkers with comorbidity or legacy as covariate.
Results
A pattern of intermittent RNA or lack of detectable RNA was most common (Plasma: 81%, CSF: 87%). Plasma and CSF RNA showed a transient dissociation at 6-month (p<.005). Unlike plasma, CSF RNA was significantly increased in the progressive neurobiotype, and slightly in the stable neurobiotype (Fig 1a). The inclusion of comorbidities or legacy effects did not alter these results. Relative to cognitively-normal cases (50%), nadir CD4<200 was less frequent in incident decline (14%, p=.005). Historical HAND was more frequent in progressing (60%, p<.04) and stable cases (61%, p=.02) versus cognitively-normal cases (11%). There were no nadir CD4 differences. Comorbidities correlated modestly with baseline neurocognition (Rho=-.23; p<.08) but not with the neurobiotypes, although progressing cases had the greatest burden. CSF RNA was associated with CSF neopterin with time variations (Fig 1b). Only CSF neopterin was associated MRS abnormalities (axonal injury and neuroinflammation).
Conclusions
Partially compartmentalized CSF HIVRNA as measured by SCA links to neurobiotypes independently and despite comorbidities and legacy effects. Replication in larger and more diverse samples is needed.