PKR-like ER kinase (PERK) Haplotypes Are Associated with Depressive Symptoms in People with HIV.

Background: Depression is a debilitating and difficult-to-treat condition in people with HIV (PWH) despite viral suppression on antiretroviral therapy (ART). Depression is associated with activation of the PKR-like ER kinase (PERK) pathway, which regulates protein synthesis in response to metabolic stress. We evaluated common PERK haplotypes that influence PERK expression in relation to depressed mood in PWH. Methods: PWH from 6 research centers were enrolled in the study. Genotyping was conducted using targeted sequencing with TaqMan. The major PERK haplotypes A, B, and D were identified. Depressive symptom severity was assessed using the Beck Depression Inventory-II (BDI-II). Covariates including genetically-defined ancestry, demographics, HIV disease/treatment parameters and antidepressant treatments were assessed. Data were analyzed using multivariable regression models. Results: A total of 287 PWH with a mean (SD) age of 57.1±7.8 years were enrolled. Although the largest ethnic group was non-Hispanic white (n=129, 45.3%), African-American (n=124, 43.5%) and Hispanic (n=30, 10.5%) made up over half the sample. 20.3% were female and 96.5% were virally suppressed. Mean BDI-II was 9.6±9.5, and 28.9% scored above the cutoff for mild depression (BDI-II>13). PERK haplotype frequencies were AA57.8%, AB25.8%, AD 10.1%, and BB4.88%. PERK haplotypes were differentially represented according to genetic ancestry (p=6.84e-6). BDI-II scores were significantly higher in participants with the AB haplotype (F=4.45, p=0.0007).This finding was robust to consideration of potential confounds. Conclusion: PERK haplotypes were associated with depressed mood in PWH.Consequently, pharmacological targeting of PERK-related pathways might amelioratedepression in PWH.

Apolipoprotein E4 genotype does not increase risk of HIV-associated neurocognitive disorders.

This is a cross-sectional, observational study to evaluate the hypothesis that HIV-seropositive (HIV+) apolipoprotein E4 (APOE4) carriers are at increased risk for HIV-associated neurocognitive disorders (HAND) compared to APOE4 noncarriers with HIV in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) Group sample. APOE genotype was determined in 466 CHARTER participants with varying disease stages and histories of antiretroviral treatment who did not have severe psychiatric or medical comorbid conditions that preclude diagnosis of HAND. HAND diagnoses were based on results of comprehensive neurobehavioral evaluation and use of current neuroAIDS diagnostic criteria. HAND status consists of two levels: neuropsychologically normal status (i.e., no HAND) and any HAND diagnosis (i.e., asymptomatic neurocognitive impairment, minor neurocognitive disorder, HIV-associated dementia). Logistic regression analyses revealed no association between APOE4 carrier status and HAND, and there were no interactions between APOE4 carrier status and ethnicity, age, substance use disorders, duration of infection, or nadir CD4. Results did not differ when analysis was restricted to symptomatic HAND, and no APOE4 gene dose-dependent relationship to HAND emerged. APOE4 status was not associated with concurrent HAND in this large, well-characterized sample. This does not preclude emergence of an association between APOE4 status and HAND as this population ages. Prospective, longitudinal studies are needed to examine APOE4 as a risk factor for neurocognitive decline, incident HAND at older ages, and potential associations with cerebrospinal fluid amyloid.

Role of obesity, metabolic variables, and diabetes in HIV-associated neurocognitive disorder.

OBJECTIVE: To evaluate relationships between HIV-associated neurocognitive disorder and metabolic variables in a subgroup of HIV+ participants examined in a prospective, observational, multicenter cohort study. METHODS: In a cross-sectional substudy of the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort, 130 HIV+ participants provided fasting blood samples. Neurocognitive impairment (NCI) was defined by performance on neuropsychological tests adjusting for age, education, gender, and race/ethnicity. Global ratings and global deficit scores were determined. Demographics, biomarkers of HIV disease, metabolic variables, combination antiretroviral therapy (CART) history, other drug exposures, and self-reported diabetes were examined in multivariate models predicting NCI. Separate models were used for body mass index (BMI) alone (n = 90) and BMI and waist circumference (WC) together (n = 55). RESULTS: NCI (global impairment rating ≥5) was diagnosed in 40%. In univariate analyses, age, longer duration of HIV infection, obesity, and WC, but not BMI, were associated with NCI. Self-reported diabetes was associated with NCI in the substudy and in those >55 in the entire CHARTER cohort. Multivariate logistic regression analyses demonstrated that central obesity (as measured by WC) increased the risk of NCI and that greater body mass may be protective if the deleterious effect of central obesity is accounted for. CONCLUSIONS: As in HIV-uninfected persons, central obesity, but not more generalized increases in body mass (BMI), was associated with a higher prevalence of NCI in HIV+ persons. Diabetes appeared to be associated with NCI only in older patients. Avoidance of antiretroviral drugs that induce central obesity might protect from or help to reverse neurocognitive impairment in HIV-infected persons.

HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study.

OBJECTIVES: This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals in the era of combination antiretroviral therapy (CART). METHODS: A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment). RESULTS: Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm(3) (30% vs 47% in remaining subgroups). CONCLUSIONS: The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.

Impact of long-term treatment with neurotoxic dideoxynucleoside antiretrovirals: implications for clinical care in resource-limited settings.

OBJECTIVES: A minority of HIV-infected patients taking an antiretroviral (ARV) regimen containing dideoxynucleosides (d-drugs) such as stavudine (d4T) and didanosine (DDI) experiences dose-limiting neuropathic pain and paraesthesias, usually within weeks of starting these drugs. Because d-drugs are among the few affordable options available in developing countries, continuing d-drug therapy would be a desirable strategy for many HIV-infected individuals. Therefore, we evaluated the safety of continuing d-drug therapy. METHODS: In a US cohort, we compared the rates of worsening neuropathic symptoms and signs in HIV-infected individuals on stable ARV regimens that did (n=252) or did not (n=250) include d-drugs. Rates of worsening were compared using proportional hazards model and the log-rank test. RESULTS: The risk ratios (RR) were not significantly larger for worsening neuropathy signs [0.94; 95% confidence interval (CI) 0.84-1.07] or symptoms (0.99; 95% CI 0.88-1.14) in patients taking d-drugs continuously compared to those not taking d-drugs. CONCLUSIONS: Continued d-drug exposure among patients tolerating an initial trial did not increase the risk of worsening neuropathy compared to non-d-drug-containing regimens. If applicable in developing countries, these findings suggest that in most patients d-drugs can be continued safely in the long term without increasing the risk of worsening neuropathy.

Changing patterns in the neuropathogenesis of HIV during the HAART era.

Rapid progress in the development of highly active antiretroviral therapy has changed the observed patterns in HIV encephalitis and AIDS-related CNS opportunistic infections. Early in the AIDS epidemic, autopsy studies pointed to a high prevalence of these conditions. With the advent of nucleoside reverse transcriptase inhibitors, the prevalence at autopsy of opportunistic infections, such as toxoplasmosis and progressive multifocal leukoencephalopathy, declined while that of HIV encephalitis increased. After the introduction of protease inhibitors, a decline in both HIV encephalitis and CNS opportunistic infections was observed. However, with the increasing resistance of HIV strains to antiretrovirals, there has been a resurgence in the frequency of HIV encephalitis and HIV leukoencephalopathy. HIV leukoencephalopathy in AIDS patients failing highly active antiretroviral therapy is characterized by massive infiltration of HIV infected monocytes/macrophages into the brain and extensive white matter destruction. This condition may be attributable to interactions of anti-retrovirals with cerebrovascular endothelium, astroglial cells and white matter of the brain. These interactions may lead to cerebral ischemia, increased blood-brain barrier permeability and demyelination. Potential mechanisms of such interactions include alterations in host cell signaling that may result in trophic factor dysregulation and mitochondrial injury. We conclude that despite the initial success of combined anti-retroviral therapy, more severe forms of HIV encephalitis appear to be emerging as the epidemic matures. Factors that may contribute to this worsening include the prolonged survival of HIV-infected patients, thereby prolonging the brain's exposure to HIV virions and proteins, the use of increasingly toxic combinations of poorly penetrating drugs in highly antiretroviral-experienced AIDS patients, and selection of more virulent HIV strains with higher replication rates and greater virulence in neural tissues.

Indinavir population pharmacokinetics in plasma and cerebrospinal fluid. The HIV Neurobehavioral Research Center Group.

Plasma and cerebrospinal fluid (CSF) indinavir concentrations were measured by high-performance liquid chromatography. The median concentration in plasma exceeded that in CSF 10-fold. The modeled CSF curve was flat at 155 nM, and the estimated ratio of the areas under the CSF and plasma concentration-time curves was 6%. We conclude that CSF indinavir concentrations are lower than levels in plasma but exceed the clinical 95% inhibitory concentration range.

Cerebrospinal fluid beta chemokine concentrations in neurocognitively impaired individuals infected with human immunodeficiency virus type 1.

Macrophages express the chemokine receptor CCR-5, a coreceptor for human immunodeficiency virus (HIV) entry. This receptor is ligated by beta chemokines, which influence HIV type 1 (HIV-1) replication in CCR-5-bearing cells in vitro and could influence the course of infection in the central nervous system. Cerebrospinal fluid (CSF) samples from 73 HIV-infected men were assayed for macrophage inflammatory protein-1 alpha (MIP-1alpha), MIP-1beta, and regulated upon activation, normal T cell expressed and secreted (RANTES). Distributions of all three were positively skewed. CSF chemokine concentrations were correlated with each other and were higher in demented patients. In a multivariate analysis, demented subjects were more likely to have detectable CSF MIP-1alpha, elevated CSF HIV RNA levels, and lower CD4+ cell counts. However, among those with detectable CSF MIP-1alpha, levels were lower in demented patients. CSF beta chemokine elevation is consistent with the macrophage activation known to occur in dementia and with studies of beta chemokine mRNA expression in the brain. Low, but detectable, levels of CSF MIP-1alpha were strongly associated with dementia, suggesting that higher levels may have neuroprotective effects.