HIV, Vascular Risk Factors, and Cognition in the Combination Antiretroviral Therapy Era: A Systematic Review and Meta-Analysis.

OBJECTIVES: Mounting evidence indicates that vascular risk factors (VRFs) are elevated in HIV and play a significant role in the development and persistence of HIV-associated neurocognitive disorder. Given the increased longevity of people living with HIV (PLWH), there is a great need to better elucidate vascular contributions to neurocognitive impairment in HIV. This systematic review and meta-analysis examine relationships between traditional VRFs, cardiovascular disease (CVD), and cognition in PLWH in the combination antiretroviral therapy era. METHODS: For the systematic review, 44 studies met inclusion criteria and included data from 14,376 PLWH and 6,043 HIV-seronegative controls. To better quantify the contribution of VRFs to cognitive impairment in HIV, a robust variance estimation meta-analysis (N = 11 studies) was performed and included data from 2139 PLWH. RESULTS: In the systematic review, cross-sectional and longitudinal studies supported relationships between VRFs, cognitive dysfunction, and decline, particularly in the domains of attention/processing speed, executive functioning, and fine motor skills. The meta-analysis demonstrated VRFs were associated with increased odds of global neurocognitive impairment (odds ratio [OR ]= 2.059, p = .010), which remained significant after adjustment for clinical HIV variables (p = .017). Analyses of individual VRFs demonstrated type 2 diabetes (p = .004), hyperlipidemia (p = .043), current smoking (p = .037), and previous CVD (p = .0005) were significantly associated with global neurocognitive impairment. CONCLUSIONS: VRFs and CVD are associated with worse cognitive performance and decline, and neurocognitive impairment in PLWH. Future studies are needed to examine these relationships in older adults with HIV, and investigate how race/ethnicity, gender, medical comorbidities, and psychosocial factors contribute to VRF-associated cognitive dysfunction in HIV.

Differential relationships between cannabis consumption and sleep health as a function of HIV status.

BACKGROUND: There is evidence that regular cannabis use has negative effects on sleep health. Relative to HIV- populations, HIV + individuals consistently report greater sleep impairments. The number of HIV + individuals reporting frequent cannabis use, often to treat sleep issues, has significantly increased recently. It is unknown, however, if HIV status moderates the association between cannabis use and sleep health. The current study, therefore, examines these associations in a sample of HIV + and HIV- adults. METHODS: HIV + and HIV- (N = 107) individuals completed one laboratory visit. Participants completed a 30-day drug use history questionnaire quantifying consumption of cannabis, cigarettes, and alcohol, and a sleep health questionnaire. To verify substance use and HIV status, participants completed a urine toxicology screening and serology testing. RESULTS: HIV + individuals demonstrated lower sleep health than HIV- individuals. Linear regressions indicated that HIV status moderated the association between total 30-day cannabis consumption and sleep health; cannabis consumption was negatively associated with sleep health in HIV-, but not HIV + individuals. This interactive effect was significant after examining cigarette/alcohol use, depression symptoms, and demographic variables as covariates. CONCLUSIONS: These results corroborate studies demonstrating an inverse relationship between sleep health and cannabis consumption. This study also suggests that factors other than cannabis may be associated with lower sleep health in HIV + individuals. Emerging studies suggest that inflammation may mediate effects of cannabis on HIV infection. Future studies examining this mechanism are warranted to understand cannabis further and sleep in HIV + individuals.

Marijuana effects on changes in brain structure and cognitive function among HIV+ and HIV- adults.

BACKGROUND: The current study examined the independent and interactive effects of HIV and marijuana (MJ) use on brain structure and cognitive function among a sample of HIV-positive (HIV+) and HIV-negative (HIV-) individuals. METHODS: Participants (HIV+, n=48; HIV-, n=29) individuals underwent cognitive testing, questionnaires about substance use, and brain MRI. The HIV+ group was clinically stable based upon current plasma CD4 count, 50% had undetectable viral load (i.e.,<20 copies/mL), and all were on a stable regimen of cART. RESULTS: For HIV+ and HIV- participants, higher levels of MJ use were associated with smaller volumes in the entorhinal cortex and fusiform gyrus. HIV status (but not MJ use) was associated with cingulate thickness, such that HIV+ participants evidenced smaller thickness of the cingulate, as compared to HIV- controls. Regarding neurocognitive functioning, there was a HIV*MJ interactive effect on global cognition, such that when the amount of MJ use was less than 1.43g per week, the HIV- group displayed significantly better neurocognitive performance than the HIV+ group (t=3.14, p=0.002). However, when MJ use reached 1.43g per week, there were no significant HIV group differences in global cognitive performance (t=1.39, p=0.168). CONCLUSIONS: Our results show independent and interactive effects of HIV and MJ on brain structure and cognition. However, our results do not support that HIV+ MJ users are at greater risk for adverse brain or cognitive outcomes compared to HIV- MJ users.

Combined effects of HIV and marijuana use on neurocognitive functioning and immune status.

The current study examined the independent and combined effects of HIV and marijuana (MJ) use (no use, light use, and moderate-to-heavy use) on neurocognitive functioning among a convenience sample of HIV-positive (HIV+) and HIV-negative (HIV-) individuals recruited from HIV community care clinics and advertisements in the Greater Los Angeles area. MJ users consisted of individuals who reported regular use of MJ for at least 12 months, with last reported use within the past month. Participants included 89 HIV+ (n = 55) and HIV- (n = 34) individuals who were grouped into non-users, light users, and moderate-to-heavy users based on self-reported MJ use. Participants were administered a brief cognitive test battery and underwent laboratory testing for CD4 count and viral load. HIV+ individuals demonstrated lower performance on neurocognitive testing than controls, and moderate-to-heavy MJ users performed more poorly on neurocognitive testing than light users or non-users. Moderate-to-heavy HIV+ users performed significantly lower on learning/memory than HIV- moderate-to-heavy users (MD = -8.34; 95% CI: -16.11 to -0.56) as well as all other comparison groups. In the domain of verbal fluency, HIV+ light users outperformed HIV- light users (MD = 7.28; 95% CI: 1.62-12.39), but no HIV group differences were observed at other MJ use levels. HIV+ MJ users demonstrated lower viral load (MD = -0.58; 95% CI: -1.30 to 0.14) and higher CD4 count than non-users (MD = 137.67; 95% CI: 9.48-265.85). The current study findings extend the literature by demonstrating the complex relationship between HIV status and MJ use on neurocognitive and clinical outcomes.

The role of chemokine C-C motif ligand 2 genotype and cerebrospinal fluid chemokine C-C motif ligand 2 in neurocognition among HIV-infected patients.

OBJECTIVES: We examined interrelationships between chemokine C-C motif ligand 2 (CCL2) genotype and expression of inflammatory markers in the cerebrospinal fluid (CSF), plasma viral load, CD4 cell count and neurocognitive functioning among HIV-infected adults. We hypothesized that HIV-positive carriers of the 'risk' CCL2 -2578G allele, caused by a single nucleotide polymorphism (SNP) at rs1024611, would have a higher concentration of CCL2 in CSF, and that CSF CCL2 would be associated with both higher concentrations of other proinflammatory markers in CSF and worse neurocognitive functioning. DESIGN: A cross-sectional study of 145 HIV-infected individuals enrolled in the National NeuroAIDS Tissue Consortium cohort for whom genotyping, CSF and neurocognitive data were available. METHODS: Genomic DNA was extracted from peripheral blood mononuclear cells and/or frozen tissue specimens. CSF levels of CCL2, interleukin (IL)-2, IL-6, tumour necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), soluble tumor necrosis factor receptor 2, sIL-6Rα, sIL-2, sCD14 and B-cell activating factor were quantified. Neurocognitive functioning was measured using a comprehensive battery of neuropsychological tests. RESULTS: Carriers of the CCL2 -2578G allele had a significantly higher concentration of CCL2 in CSF. CSF CCL2 level was positively and significantly associated with other CSF neuroinflammatory markers and worse cognitive functioning. There was a significant association between genotype and plasma viral load, such that carriers of the CCL2 -2578G allele with high viral load expressed greater levels of CCL2 and had higher neurocognitive deficit scores than other genotype/viral load groups. CONCLUSION: Individuals with the CCL2 -2578G allele had higher levels of CCL2 in CSF, which was associated with increased pro-inflammatory markers in CSF and worse neurocognitive functioning. The results highlight the potential role of intermediate phenotypes in studies of genotype and cognition.

Viral immune surveillance: Toward a TH17/TH9 gate to the central nervous system.

UNLABELLED: Viral cellular immune surveillance is a dynamic and fluid system that is driven by finely regulated cellular processes including cytokines and other factors locally in the microenvironment and systemically throughout the body. It is questionable as to what extent the central nervous system (CNS) is an immune-privileged organ protected by the blood-brain barrier (BBB). Recent evidence suggests converging pathways through which viral infection, and its associated immune surveillance processes, may alter the integrity of the blood-brain barrier, and lead to inflammation, swelling of the brain parenchyma and associated neurological syndromes. Here, we expand upon the recent "gateway theory", by which viral infection and other immune activation states may disrupt the specialized tight junctions of the BBB endothelium making it permeable to immune cells and factors. The model we outline here builds upon the proposition that this process may actually be initiated by cytokines of the IL-17 family, and recognizing the intimate balance between TH17 and TH9 cytokine profiles systemically. We argue that immune surveillance events, in response to viruses such as the Human Immunodeficiency Virus (HIV), cause a TH17/TH9 induced gateway through blood brain barrier, and thus lead to characteristic neuroimmune pathology. It is possible and even probable that the novel TH17/TH9 induced gateway, which we describe here, opens as a consequence of any state of immune activation and sustained chronic inflammation, whether associated with viral infection or any other cause of peripheral or central neuroinflammation. This view could lead to new, timely and critical patient-centered therapies for patients with neuroimmune pathologies across a variety of etiologies. ABBREVIATIONS: BBB - blood brain barrier, BDV - Borna disease virus, CARD - caspase activation and recruitment domains, CD - clusters of differentiation, CNS - central nervous system, DAMP - damage-associated molecular patterns, DENV - Dengue virus, EBOV - Ebola virus, ESCRT - endosomal sorting complex required for transport-I, HepC - Hepatitis C virus, HIV - human immunodeficiency virus, IFN - interferon, ILn - interleukin-n, IRF-n - interferon regulatory factor-n, MAVS - mitochondrial antiviral-signaling, MBGV - Marburg virus, M-CSF - macrophage colony-stimulating factor, MCP-1 - monocyte chemotactic protein 1 (aka CCL2), MHC - major histocompatibility complex, MIP-α ß - macrophage inflammatory protein-1 α ß (aka CCL3 & CCL4), MIF - macrophage migration inhibitory factor, NVE - Nipah virus encephalitis, NK - natural killer cell, NLR - NLR, NOD - like receptor, NOD - nucleotide oligomerization domain, PAMP - pathogen-associated molecular patterns, PtdIns - phosphoinositides, PV - Poliovirus, RIG-I - retinoic acid-inducible gene I, RIP - Receptor-interacting protein (RIP) kinase, RLR - RIG-I-like receptor, sICAM1 - soluble intracellular adhesion molecule 1, STAT-3 - signal tranducer and activator of transcription-3, sVCAM1 - soluble vascular cell adhesion molecule 1, TANK - TRAF family member-associated NF- . B activator, TBK1 - TANK-binding kinase 1, TLR - Toll-like receptor, TNF - tumor necrosis factor, TNFR - TNF receptor, TNFRSF21 - tumor necrosis factor receptor superfamily member 21, TRADD TNFR-SF1A - associated via death domain, TRAF TNFR - associated factor, Tregs - regulatory T cellsubpopulation (CD4/8+CD25+FoxP3+), VHF - viral hemorrhagic fever.

Viral immune evasion in dengue: toward evidence-based revisions of clinical practice guidelines.

UNLABELLED: Dengue, a leading cause of illness and death in the tropics and subtropics since the 1950׳s, is fast spreading in the Western hemisphere. Over 30% of the world׳s population is at risk for the mosquitoes that transmit any one of four related Dengue viruses (DENV). Infection induces lifetime protection to a particular serotype, but successive exposure to a different DENV increases the likelihood of severe form of dengue fever (DF), dengue hemorrhagic fever (DHF), or dengue shock syndrome (DSS). Prompt supportive treatment lowers the risk of developing the severe spectrum of Dengue-associated physiopathology. Vaccines are not available, and the most effective protective measure is to prevent mosquito bites. Here, we discuss selected aspects of the syndemic nature of Dengue, including its potential for pathologies of the central nervous system (CNS). We examine the fundamental mechanisms of cell-mediated and humoral immunity to viral infection in general, and the specific implications of these processes in the regulatory control of DENV infection, including DENV evasion from immune surveillance. In line with the emerging model of translational science in health care, which integrates translational research (viz., going from the patient to the bench and back to the patient) and translational effectiveness (viz., integrating and utilizing the best available evidence in clinical settings), we examine novel and timely evidence-based revisions of clinical practice guidelines critical in optimizing the management of DENV infection and Dengue pathologies. We examine the role of tele-medicine and stakeholder engagement in the contemporary model of patient centered, effectiveness-focused and evidence-based health care. ABBREVIATIONS: BBB - blood-brain barrier, CNS - central nervous system, DAMP - damage-associated molecular patterns, DENV - dengue virus, DF - dengue fever, DHF - dengue hemorrhagic fever, DSS - dengue shock syndrome, DALYs - isability adjusted life years, IFN-g - interferon-gamma, ILX - interleukinX, JAK/STAT - janus kinase (JAK) / Signal transducer and activator of transcription (STAT), LT - Escherichia coli heat-labile enterotoxin formulations deficient in GM1 binding by mutation (LT[G33D]), MCP-1 - monocyte chemotactic protein 1, M-CSF - macrophage colony-stimulating fact, MHC - major histocompatibility complex, MIF - macrophage migration inhibitory factor, [MIP-1]-α / -ß - macrophage inflammatory protein-1 alpha and beta, mAb - monoclonal antibody, NS1 - non-structural protein 1 of dengue virus, NK - natural killer cells, PAMP - pathogen-associated molecular patterns, PBMC - peripheral blood mononuclear cells, TBF-b - transforming growth factor-beta, TNF-α - tumor necrosis-alpha, VHFs - virus hemorrhagic fevers, WHO - World Health Organization.