Abstract Body


>50% of people with HIV (PWH) do not achieve CD4/CD8 T-cell ratio normalization (ratio>1.0) on antiretroviral therapy (ART). Recent findings from RV254/SEARCH 010, a longitudinal investigation of acute HIV infection (AHI) and long-term response to ART, identified a combination of immune and behavioral factors (e.g., mental health) that predicted CD4/CD8 T-cell ratio inversion at week 144 of ART. This study examined a larger array of potential predictors of CD4/CD8 T-cell inversion, including multimodal indices of brain structure/function quantified using 3T MRI before ART initiation.


Archival data from RV254/SEARCH 010 were examined for individuals who completed neuroimaging (volumetrics, diffusion tensor imaging (DTI), and resting state connectivity) at enrollment followed by 144 weeks of sustained ART. Gradient boosted multivariate (GBM) regression with repeated cross validation was utilized to identify predictors for persistent CD4/CD8 T-cell ratio inversion at week 144 from baseline neuroimaging, demographic, immune, viral, cognitive, and mental/behavioral health indices.


74 Thai males with an average duration of HIV infection of 19.5 (7.2) days were included in the analysis. Study participants were of 27.4 (6.0) years of age and had a median viral load (log10) of 6.01 (IQR 5.43-6.79) copies/mL, CD4+ T-cell count of 330, CD8+ T-cell count of 526, and a CD4/CD8 T-cell ratio of 0.64. After 144 weeks of ART, all study participants were virally suppressed. 34 individuals had a CD4/CD8 T-cell ratio <1.0. The GBM analysis identified 10 baseline features that predicted CD4/CD8 T-cell ratio inversion at 144 weeks (average model performance of .72). The algorithm included larger volumes in 6 brain regions (medial superior frontal gyrus, superior temporal gyrus, rectus gyrus, nucleus accumbens, cerebellar lobes IV-V, pallidum), lower connectivity between the salience and visuospatial network, lower high-density lipoprotein (HDL) levels, lower radial diffusivity in the external capsule, and higher IL-1⍺.


Perturbations in brain structure and function, possibly reflecting early inflammatory mechanisms, dyslipidemia, and inflammation prior to ART commenced in acute infection stratify individual risk for persistent CD4/CD8 T-cell inversion following sustained use of ART. Further investigation of potential causal pathways is needed to establish mechanisms and therapeutic opportunities.