Abstract
Background:
Huntington Disease (HD) and human immunodeficiency virus (HIV) are both associated with neurodegeneration in the cerebral cortex and striatum. The rate of striatal degeneration is a known predictor of symptom onset in HD indicating a potential neurobiological link between HD and HIV.
Objective:
To determine if the presence of pre-existing HIV infection would trigger a significantly earlier age of symptom onset (ASO) in HD-mutation carriers when compared to non-infected HD subjects.
Methods:
This was a retrospective analysis of the Enroll-HD database that included participants with a CAG repeat of at least 36. Participants with HD and a comorbidity of HIV that was diagnosed prior to their reported ASO were identified and compared to participants with HD who did not have HIV. An ANCOVA analysis was performed to investigate the differences in ASO between the HIV and non-HIV groups. Sex, drug use, and CAG repeat number were used as covariates.
Results:
The average ASO of HD subjects with previous HIV infection (n = 8) was 9.1 years earlier than non-HIV infected HD subjects (n = 3259) [F (1, 3267) =10.05, p = 0.002]. Despite low numbers of participants in the HIV group, the calculated effect size of this difference was 1.07.
Conclusion:
The known neurobiological changes caused by HIV seem to hasten the ASO in patients with HD. These results may enhance our understanding of the neuropathology of HD in a way that will help with the identification of novel targets for future therapies.
INTRODUCTION
Huntington’s Disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HTT gene [1]. This mutation leads to neuronal dysfunction and death with accompanying motor, cognitive, and functional impairments [2]. The rate of striatal degeneration predicts the timing of symptom onset in HD [3–5] and is negatively correlated with the number of CAG repeats [6]. However, the age of symptom onset (ASO) is affected by genetic and environmental factors, and not just the number of CAG repeats [7–10].
Human Immunodeficiency Virus (HIV) causes brain dysfunction with a collection of cognitive, behavioral and motor symptoms known as HIV-associated neurocognitive disorders (HAND) [11] and can trigger neurodegeneration in the cerebral cortex, caudate and other brain regions [12, 13]. Heme oxygenase-1 (HO1) deficiency has been linked to the pathogenesis of HAND [14]. Pharmacological enhancement of the HO1 pathway is beneficial in genetic and toxic models of HD [15, 16]. Due to this potential neurobiological link, we hypothesized that the presence of pre-existing HIV infection would trigger a significantly earlier ASO in HD-mutation carriers when compared to non-infected HD subjects.
MATERIALS AND METHODS
Enroll-HD is a clinical research platform to facilitate research in HD. Core data sets are collected annually on participants in this multi-center longitudinal observational study. Data are monitored for quality and accuracy using a risk-based monitoring approach. The database currently includes 8714 participants from over 150 sites across the world; participants that have pre-motor-manifest HD, motor-manifest HD, genotype-negative participants, and family controls are included.
Outcome measures of interest
This analysis was performed to quantify differences in the reported ASO between patients with HD who do not have HIV versus patients with HD with a reported diagnosis of HIV. Participants and their family members are asked to estimate the age at which the participant initially noticed symptoms of HD. The clinician conducting the interview is also asked to estimate the age at which they believe symptoms first began based on the interview. The rater is also asked to state if this estimate of the ASO was made with a high or low level of confidence. In order to decrease subjectivity, this analysis used the ASO reported by the clinical rater as the primary outcome measure. Furthermore, only estimates that were made with a high level of confidence were included.
Identifying patient with HIV
The Enroll-HD dataset contains comorbidities of participants. Twenty-one participants were found to have an HIV-related comorbidity, and 15 of those participants had the HD gene expansion. Of those participants, six had “unspecified human immunodeficiency virus disease,” six had “asymptomatic human immunodeficiency virus infection status,” one had “laboratory evidence of human immunodeficiency virus,” and one had “acute HIV infection syndrome.” One remaining participant had a comorbidity reported of “contact with and exposure to human immunodeficiency virus.” Review of this participant’s medication profile revealed continued use of antiretroviral therapy for nearly 3.5 years prior to enrollment into the study, indicating that the participant likely had confirmed HIV. Therefore, this participant was included in the analysis. The medication records of these 15 participants were reviewed to confirm the use of antiretrovirals and other medications to treat HIV-related comorbidities. All 15 participants were being treated with antiretrovirals and/or medications to treat HIV-related illnesses. Participants in the non-HIV group were confirmed to not be using antiretrovirals, as well.
Inclusion of participants with HIV prior to symptom onset
Participants were included in the HIV group only if the diagnosis of HIV was made prior to the reported ASO, to ensure the effect of HIV on ASO was being accurately evaluated. The timing of the diagnosis of the reported comorbidities is included as days relative to the baseline enrollment day in Enroll-HD. A negative value indicates that the diagnosis was made prior to enrollment. Only eight of the 15 participants with HIV were diagnosed prior to their ASO were included in this analysis. For these participants, the diagnosis of HIV was made, on average, 4.68 (s.d. 6.64) years prior to the diagnosis of HD.
Overview
Participants with juvenile HD (defined as a reported ASO of 20 years or less) were excluded from this study (n = 115). No participants with HIV met the criteria for JHD. IBM SPSS Statistics ® Version 24 was used to perform all statistical analyses. An independent samples T-test was used to compare the average CAG repeat length between groups, and a Chi-square test was performed to compare differences in sex distribution and frequency of drug use between groups. An ANCOVA analysis was performed to investigate the differences in ASO between the HIV and non-HIV groups. Sex, drug use, and CAG repeat number were used as covariates and all results are reported as the adjusted ASO. Drug use was included as a covariate based on our previous findings that drug use in HD was associated with a significantly earlier ASO [10]. Results were considered significant if they had a p-value of <0.05. Effect sizes were calculated for each analysis using Cohen’s effect size calculation.
RESULTS
The number of CAG repeats is the strongest predictor of the timing of symptom onset of HD. There was not a significant difference (p = 0.79) in the CAG repeat length between the HIV and non-HIV groups (43.5 and 43.81, respectively). Two (25% ) of the eight participants in the HIV group had a history of using illicit drugs compared to 316 (9.7% ) of the 3255 participants in the non-HIV group, but this difference was not statistically significant (p = 0.145). There was a significant difference in the proportion of males and females between the groups (p = 0.005). The non-HIV group included 1633 females (50.2% ) and 1622 males (49.8% ), but all participants in the HIV group were males (100% ). This discrepancy resulted in an unplanned follow-up ANCOVA analysis that included only males, in an effort to decrease confounding.
The mean-adjusted ASO of the HIV group (n = 8) was 36.69 (s.e. 2.83) years and 45.27 (s.e. 0.14) years in the non-HIV group (n = 3255) [F(1, 3263) = 9.17, p = 0.002]. The calculated effect size was d = 1.07), indicating a very large effect. For the unplanned follow-up analysis restricted to males,sex was not included as a covariate, but CAG repeat length and drug use remained. The eight male participants in the HIV group were compared to 1622 males in the non-HIV group. The mean adjusted ASO in the HIV group was 37.02 (s.e. 2.78) years compared to 45.56 (s.e. 0.20) in the non-HIV group [F(1, 1630) = 9.44, p = 0.002], and the calculated effect size was d = 1.09.
As noted previously, there were seven participants who contracted HIV after their reported ASO of HD. Of those seven participants only three had a reported ASO that was predicted by the clinician rater with a high level of confidence. The average ASO of those three participants was 49.85 (s.e. 6.67) years, which is similar to the non-HIV group.
DISCUSSION
In this study, we show that HD subjects infected with HIV have an earlier ASO than non-HIV HD subjects. Despite the relatively small number of participants in the HIV group, the association between concomitant HIV infection and an earlier ASO was significant due to a very large calculated effect size. This increases our confidence that these findings result from potential HIV-driven neurobiological changes causing synergistic neurodegeneration in HD patients. Furthermore, patients diagnosed with HIV after the onset of HD had an average ASO comparable to the non-HIV group. As a result, the rate of neurodegeneration might have been accelerated in the HIV group, hastening the timing of symptom onset in these participants.
These results further demonstrate that environmental factors can strongly influence the course of HD. We previously demonstrated that the use of illicit substances was associated with an earlier age of motor symptoms onset [10]. The identification of factors that modify the progression of HD will continue to illuminate the specific neurobiological changes that contribute to the clinical changes that are seen in HD. This will increase our understanding of the pathology of HD, enhancing our ability to identify disease modifying treatments in the future. In the case of HAND, reduced levels of the key antioxidant enzyme HO1 has been conclusively linked to disease pathogenesis. Treatment with dimethyl fumarate, which increases levels of HO1, was beneficial in two genetic models of HD [15]. In a toxic model, a small molecule that increases HO1 levels was equally beneficial [16]. While still speculative, if proven that HO1 influences the rate of neurodegeneration in HD, it would offer novel pharmacological targets to intervene in the process.
The largest limitation of this study is the small sample size of participants with HIV. However, given the relative rarity of HD, it is very difficult to identify a large number of patients with concomitant HIV infection. As the largest database of HD patients in the world, the findings from Enroll-HD likely represent the most comprehensive collection of patients with HIV and HD available for investigation. Furthermore, the very large effect sizes associated with these findings demonstrate that these results represent an association that is based on underlying biological changes.
CONFLICT OF INTEREST
The authors have no conflict of interest to report.
Footnotes
ACKNOWLEDGMENTS
Enroll-HD is a longitudinal observational study for Huntington’s disease families intended to accelerate progress towards therapeutics; it is sponsored by CHDI Foundation, a nonprofit biomedical research organization exclusively dedicated to developing therapeutics for HD. Enroll-HD would not be possible without the vital contribution of the research participants and their families.