In a cohort of HIV+ subjects with nadir CD4 counts <300, we demonstrated elevated plasma sCD14, but not CCL2 or LPS, in subjects with neurocognitive test scores indicating global impairment compared to unimpaired subjects. Furthermore, plasma sCD14 level yielded higher AUROC values for predicting impaired neurocognitive testing than plasma or CSF VL in subjects with CD4 counts <300 cells/μL or plasma VL >400 copies/mL in univariate and multivariate models. Plasma sCD14 levels were higher in subjects with impaired testing in attention and learning domains and correlated inversely with global, attention, and learning T scores, suggesting these domains are the main drivers of impairment. These findings indicate that chronic inflammation, in particular monocyte activation, is associated with dysfunction of cortical and limbic pathways in HIV-infected individuals in the cART era, and argue in support of a shift in neuropathology underlying HAND in the cART era from the subcortical process characteristic of pre-CART HAND toward a mixed cortical and subcortical process.1,28–31
The explanation for the association between sCD14, indicative of monocyte activation, and dysfunction of cortical and limbic pathways is unknown, but one possible reason is the preferential recruitment of circulating activated monocytes to these brain regions. Indeed, chemokines that attract monocytes are highly expressed in the cortex and limbic system.32
Thus, therapeutic strategies to reduce chronic inflammation in HIV infection may be beneficial for prevention or treatment of HAND.
By using continuous descriptors of neurocognitive status (T scores) and evaluating relationships between plasma sCD14 and neurocognitive impairment by specific domain, our findings extend those of our previous study12
and those of Ryan, et al.14
. Ryan and colleagues found elevated plasma sCD14 in HIV+ subjects with impaired neurocognitive testing, but did not compare plasma sCD14 levels to impairment by specific domain. Because our previous study showed elevated plasma sCD14 levels in MCMD and HAD, we designed the current study to evaluate milder forms of HAND. The current cohort included more subjects with ANI (8% vs. 17%) and fewer subjects with HAD (28% vs. 11%) compared to the previous cohort12
, and plasma sCD14 levels were compared to global and domain-specific T scores. As expected, T scores were more sensitive indicators of neurocognitive impairment than categorical diagnoses. Importantly, we found that using continuous descriptors rather than categorical clinical diagnoses was important for demonstrating an association between plasma sCD14 levels and impaired neurocognitive function.
Although monocyte activation continues to play a role in HAND pathogenesis in the cART era,34–36
additional mechanisms are likely to contribute as well.33
Indeed, for virologically suppressed subjects on cART (plasma VL <400 copies/mL), we found no difference in plasma sCD14 levels between those with impaired vs. unimpaired global T scores. However, our study was underpowered for this analysis, given the sample size for virologically suppressed subjects (n=35). HAND pathogenesis in the cART era is likely to be multifactorial, with other processes distinct from monocyte activation contributing to development of neurocognitive impairment in both viremic and aviremic subjects.
Previously, we found higher levels of plasma LPS and CCL2 in HAD,12
while others reported neurocognitive impairment associated with low nadir CD4.37,38
We did not find these associations in the present study, however, most likely reflecting cohort differences. Subjects in the present study had nadir CD4 <300, making this relationship difficult to assess. Compared to the previous cohort12
, the current cohort included more subjects not currently on cART (12% vs. 21%, respectively), more with ANI, and fewer with HAD. Despite these cohort differences, however, sCD14 levels were associated with neurocognitive impairment in both studies. Together, these findings imply that the monocyte response to activating stimuli (indicated by sCD14 levels), rather than elevated LPS or other activating stimuli per se, is related more closely to underlying mechanisms involved in cART-era HAND in subjects with advanced disease.
Studies of neurocognitive function in HIV infection and illicit drug use have reported mixed results, some suggesting more severe cognitive impairment in HIV+ subjects associated with drug use and others reporting no association.39–41
We found evidence that opiate abuse adversely affects test performance on learning, memory, motor, and SIP tasks in HIV+ individuals, but no association between plasma sCD14 levels and drug use. Thus, illicit drug use is not likely to account for the association between elevated sCD14 levels and impaired global, attention, and learning T scores in the study cohort.
HCV co-infection has been associated with increased risk of impaired neurocognitive function in patients with advanced HIV disease.27,42,43
In well-controlled HIV, however, Clifford, et al
did not find any differences in neurocognitive function associated with HCV co-infection.44
Our subgroup analysis is consistent with this finding, as we found no differences in global cognitive function associated with HCV co-infection; HIV infection was better controlled in the HCV+ subgroup, based on higher CD4 counts and lower VL. Thus, the impact of HCV co-infection on neurocognition may be attenuated when HIV is well controlled.
Our study has several limitations including its cross-sectional design and small sample size, which may have limited the power to detect some associations between biomarkers and neurocognitive test scores, particularly in subgroup analyses. Also, the narrow selection criteria used to define the study cohort (CD4 nadir <300 cells/μL) limits our findings to those with advanced HIV disease. As such, we cannot reach any conclusion regarding the predictive ability of sCD14 compared with CD4 nadir. We included NPI-O subjects because many of them likely exhibit neurocognitive effects attributable to HIV. Furthermore, there was marked site-to-site variation in assigning a diagnosis of NPI-O, and HIV patients frequently have complex histories with more than one risk factor for cognitive impairment, making it difficult to ascertain relative contributions of HIV versus co-morbid conditions in contributing to cognitive impairment. No adjustment was made for multiple comparisons, as there was no a priori hypothesis regarding specific cognitive domains that would be associated with elevated levels of inflammation markers or LPS. Finally, the study cohort was from two larger cohorts — NNTC, which specifically recruits individuals with advanced disease, and CHARTER — to represent a diverse population of HIV-infected individuals with a broad range of viral loads. The results cannot be generalized to all populations of HIV-infected patients because the cohort had a high prevalence of co-morbid drug use and HCV co-infection, 26% were not on cART at the time of testing, and only 36% had undetectable VL.
Overall, our study provides evidence that inflammation continues to contribute to HAND pathogenesis in the cART era. Plasma sCD14, a marker of monocyte activation, is associated with impaired attention and learning test performance in patients with nadir CD4 counts <300 who are not well-controlled on cART. Plasma sCD14 was not clearly linked to HAND diagnoses, suggesting that additional mechanisms contribute to these clinical diagnoses. Together, these findings point toward neuroanatomical pathways involved in cART era HAND, and suggest that plasma sCD14 is a potential biomarker that may be useful to monitor HAND progression and therapeutic responses.