Neurovirological correlation with HIV-associated neurocognitive disorders and encephalitis in a HAART-era cohort

Abstract

Objective: Replicating HIV-1 in the brain is present in HIV encephalitis (HIVE) and microglial nodule encephalitis (MGNE) and is putatively linked with HIV-associated neurocognitive disorders (HAND). A cliniconeurovirological correlation was conducted to elucidate the relationship between brain viral load and clinical phenotype. SUBJECTS AND ASSAYS: HIV gag/pol RNA and DNA copies were quantified with reverse transcriptase-polymerase chain reaction or polymerase chain reaction in 148 HAART-era brain specimens. Comparison with HAND, HIVE, and MGNE and correlation with neuropsychological (NP) test scores were done using one-way ANOVA with Tukey-Kramer and Spearman tests, respectively.

Results: Brain HIV RNA was higher in subjects with HAND plus HIVE versus without HAND (delta = 2.48 log10 units, n = 27 versus 36, P < 0.001). In HAND without HIVE or MGNE, brain HIV RNA was not significantly different versus without HAND (P = 0.314). Worse NP scores correlated significantly with higher HIV RNA and interferon responses in brain specimens (P < 0.001) but not with HIV RNA levels in premortem blood plasma (n = 114) or cerebrospinal fluid (n = 104). In subjects with MGNE, brain HIV RNA was slightly higher versus without MGNE (P < 0.01) and much lower versus with HIVE (P < 0.001).

Conclusions: Brain HIV RNA and to a lesser extent HIV DNA are correlated with worse NP performance in the 6 months before death. Linkage occurs primarily in patients with HIVE and MGNE, and these patients could obtain added NP improvement by further reducing brain HIV while on HAART. Patients not in those groups are less certain to obtain added NP benefit.

Figure 1

Brain HIV RNA (A) and DNA (B) expressed as copies per gram of brain tissue in the neuropsychologically-focused cohort. One-way analysis of variance showed a significant group effect (p < 0.0001). P-values for the post-hoc Tukey-Kramer tests are shown. Brain HIV RNA and DNA both were significantly higher in subjects with HAND plus HIVE. Brain HIV RNA was marginally higher in HAND with MGNE. Brain HIV RNA and DNA were not significantly higher in HAND without HIVE or MGNE. The number of subjects without HAND shown here differs from Table 1 because four subjects with HIVE did not have HAND and could not be assigned to a group (see Methods). HAND, HIV associated neurocognitive disorder; MGNE, microglial nodule encephalitis; HIVE, HIV encephalitis; N, number of subjects in each group.

Figure 2

Brain HIV RNA and DNA expressed as copies per gram of brain tissue in the larger neuropathologically-focused cohort. One-way analysis of variance showed a significant group effect (p < 0.0001). P-values for the post-hoc Tukey-Kramer tests are shown. Brain HIV RNA was higher in the subjects with MGNE and HIVE versus neither (panel A). The group with MGNE had significantly lower HIV RNA than the group with HIVE (panel A). Results using HIV DNA (panel B) are similar with smaller effect sizes. MGNE, microglial nodule encephalitis; HIVE, HIV encephalitis; N, number of subjects in each group.

Figure 3

Composite performance on neuropsychological testing (ordinate) was plotted with neurovirological and neuroimmunological measurements in the brain specimens (abscissa) of 119 HIV-infected subjects. High brain HIV RNA load was significantly correlated with lower composite neuropsychological T scores (A). High brain HIV DNA load had a similar but weaker pattern that was not significant statistically (B). High levels of ISG15 and MX1 mRNAs were significantly correlated with low T scores (C,D). The levels of IRF1 mRNA had a weaker correlation that was marginal statistically (E). High expression of DRD2L mRNA, which is a dopamine receptor transcript expressed primarily in neurons, was correlated with worse impairment (F). Relative expression of mRNAs was normalized to GAPDH mRNA. Correlations used Spearman’s test and were log transformed on both axes to achieve a uniformly-scaled comparison panel.