Although antiretroviral therapy effectively controls human immunodeficiency virus (HIV) replication, a residual chronic immune activation/inflammation persists throughout the disease. This aberrant immune activation and inflammation are considered an accelerator of non-AIDS-related events and one of the driving forces of CD4+ T cell depletion. Unfortunately, HIV-associated immune activation is driven by various factors, while the mechanism of excessive inflammation has not been formally clarified. To date, several clinical interventions or treatment candidates undergoing clinical trials have been proposed to combat this systemic immune activation/inflammation. However, these strategies revealed limited results, or their nonspecific anti-inflammatory properties are similar to previous interventions. Here, we reviewed recent learnings of immune activation and persisting inflammation associated with HIV infection, as well as the current directions to overcome it. Of note, a more profound understanding of the specific mechanisms for aberrant inflammation is still imperative for identifying an effective clinical intervention strategy.

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HIV-Related Immune Activation and Inflammation: Current Understanding and Strategies.

Low health literacy is associated with challenges for those living with HIV including medication non-adherence and poorer health outcomes. The aim of this study was to systematically review the literature on health literacy and health outcomes in persons living with HIV. The extended guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, as well as A Measurement Tool to Assess Systematic Reviews (AMSTAR) checklist were utilized to guide the approach to the review. A variety of electronic databases including PubMed, CINAHL, PsychInfo, and Cochrane Library were searched. Additional literature available on U.S. government websites was also included in the search. Search terms were used in a variety of combinations and included HIV, health literacy, adherence, and health outcomes. Forty-eight studies were identified that addressed health literacy and health outcomes in HIV. Although several studies in this review did not provide robust results of statistical significance linking health literacy with health outcomes, all of the studies addressed the key significance of health literacy within the scope of living with HIV disease. The relationship between health literacy and the identified health outcomes requires further research and explication.

Health Literacy and Health Outcomes in Persons Living with HIV Disease: A Systematic Review.

HIV infection and drug use intersect epidemiologically, and their combination can result in complex effects on brain and behavior. The extent to which drugs affect the health of persons with HIV (PWH) depends on many factors including drug characteristics, use patterns, stage of HIV disease and its treatment, comorbid factors, and age. To consider the range of drug effects, we have selected two that are in common use by PWH: methamphetamine and cannabis. We compare the effects of methamphetamine with those of cannabis, to illustrate how substances may potentiate, worsen, or even buffer the effects of HIV on the CNS. Data from human, animal, and ex vivo studies provide insights into how these drugs have differing effects on the persistent inflammatory state that characterizes HIV infection, including effects on viral replication, immune activation, mitochondrial function, gut permeability, blood brain barrier integrity, glia and neuronal signaling. Moving forward, we consider how these mechanistic insights may inform interventions to improve brain outcomes in PWH. This review summarizes literature from clinical and preclinical studies demonstrating the adverse effects of METH, as well as the potentially beneficial effects of cannabis, on the interacting systemic (e.g., gut barrier leakage/microbial translocation, immune activation, inflammation) and CNS-specific (e.g., glial activation/neuroinflammation, neural injury, mitochondrial toxicity/oxidative stress) mechanisms underlying HIV-associated neurocognitive disorders.

Methamphetamine and Cannabis: A Tale of Two Drugs and their Effects on HIV, Brain, and Behavior.

Objective: Recent cannabis exposure has been associated with lower rates of neurocognitive impairment in people with HIV (PWH). Cannabis’s anti-inflammatory properties may underlie this relationship by reducing chronic neuroinflammation in PWH. This study examined relations between cannabis use and inflammatory biomarkers in cerebrospinal fluid (CSF) and plasma, and cognitive correlates of these biomarkers within a community-based sample of PWH. Methods:
 263 individuals were categorized into four groups: HIV− non-cannabis users (n = 65), HIV+ non-cannabis users (n = 105), HIV+ moderate cannabis users (n = 62), and HIV+ daily cannabis users (n = 31). Differences in pro-inflammatory biomarkers (IL-6, MCP-1/CCL2, IP-10/CXCL10, sCD14, sTNFR-II, TNF-α) by study group were determined by Kruskal–Wallis tests. Multivariable linear regressions examined relationships between biomarkers and seven cognitive domains, adjusting for age, sex/gender, race, education, and current CD4 count. Results:
 HIV+ daily cannabis users showed lower MCP-1 and IP-10 levels in CSF compared to HIV+ non-cannabis users (p = .015; p = .039) and were similar to HIV− non-cannabis users. Plasma biomarkers showed no differences by cannabis use. Among PWH, lower CSF MCP-1 and lower CSF IP-10 were associated with better learning performance (all ps < .05). Conclusions:
 Current daily cannabis use was associated with lower levels of pro-inflammatory chemokines implicated in HIV pathogenesis and these chemokines were linked to the cognitive domain of learning which is commonly impaired in PWH. Cannabinoid-related reductions of MCP-1 and IP-10, if confirmed, suggest a role for medicinal cannabis in the mitigation of persistent inflammation and cognitive impacts of HIV.

Daily Cannabis Use is Associated With Lower CNS Inflammation in People With HIV.

Background While social distancing is a key public health response during viral pandemics, psychosocial stressors, such as social isolation, have been implicated in adverse health outcomes in general (1) and in the context of infectious disease, such as HIV (2,3). A comprehensive understanding of the direct pathophysiologic effects of psychosocial stress on viral pathogenesis is needed to provide strategic and comprehensive care to patients with viral infection. Methods To determine the effect of psychosocial stress on HIV pathogenesis during acute viral infection without sociobehavioral confounders inherent in human cohorts, we compared commonly measured parameters of HIV progression between singly (n=35) and socially (n=41) housed SIV-infected pigtailed macaques (Macaca nemestrina). Results Singly housed macaques had a higher viral load in the plasma and cerebrospinal fluid and demonstrated greater CD4 T cell declines and more CD4 and CD8 T cell activation compared to socially housed macaques throughout acute SIV infection. Conclusions These data demonstrate that psychosocial stress directly impacts the pathogenesis of acute SIV infection and imply that it may act as an integral variable in the progression of HIV infection and potentially of other viral infections.

Psychosocial Stress Alters the Immune Response and Results in Higher Viral Load During Acute SIV Infection in a Pigtailed Macaque Model of HIV.

Objective To determine whether cannabis may reduce HIV-related persistent inflammation, we evaluated the relationship of cannabis use in people with HIV (PWH) to inflammatory cytokines in CSF and blood plasma Methods We measured a panel of proinflammatory cytokines (interleukin [IL]-16, C-reactive protein [CRP], IL-6, interferon gamma-induced protein [IP]-10, soluble CD14, and soluble tumor necrosis factor receptor type II [sTNFRII]) in CSF and blood plasma in PWH and HIV− individuals who did or did not use cannabis at various levels of exposure Participants in this observational cohort were recruited from community sources and underwent lumbar puncture and phlebotomy Cannabis use parameters were characterized by self-report based on a semistructured timeline follow-back interview Cytokines were measured using commercially available immunoassays Data were analyzed using factor analysis Results Participants were 35 PWH and 21 HIV− individuals, mean (SD) age 454 (145) years, 41 cannabis ever users, and 15 never users PWH and HIV− were not different in recency, cumulative months, grams, or density of cannabis use A factor analysis using CSF biomarkers yielded a factor loading on CRP, IL-16, and sTNFRII that was significantly associated with recency of cannabis use (more recent use associated with lower factor 1 values, reflecting less inflammation; r = 0331 [95% CI 00175, 0586]) In particular, more recent cannabis use was related to lower IL-16 levels (r = 0549 [0282, 0737]) Plasma biomarkers yielded a factor loading on sTNFRII and IP-10 that was associated with more recent cannabis use (more recent use related to less inflammation; r = 0374 [00660, 0617]) Conclusions Recent cannabis use was associated with lower levels of inflammatory biomarkers, both in CSF and blood, but in different patterns These results are consistent with compartmentalization of immune effects of cannabis The principal active components of cannabis are highly lipid soluble and sequestered in brain tissue; thus, our findings are consistent with specific anti-neuroinflammatory effects that may benefit HIV neurologic dysfunction

https://nn.neurology.org/content/nnn/7/5/e809.full.pdf

Recent cannabis use in HIV is associated with reduced inflammatory markers in CSF and blood

BACKGROUND Human immunodeficiency virus (HIV) infection leads to blood-brain barrier (BBB) dysfunction that does not resolve despite viral suppression on antiretroviral therapy (ART) and is associated with adverse clinical outcomes. In preclinical models, cannabis restores BBB integrity. METHODS We studied persons with HIV (PWH) and HIV-negative (HIV-) individuals who had used cannabis recently. We assessed 2 biomarkers of BBB permeability: the cerebrospinal fluid (CSF) to serum albumin ratio (CSAR) and CSF levels of soluble urokinase plasminogen activator receptor (suPAR), a receptor for uPA, a matrix-degrading proteolytic enzyme that disrupts the BBB. A composite index of the BBB markers was created using principal components analysis. Neural injury was assessed using neurofilament light (NFL) in CSF by immunoassay. RESULTS Participants were 45 PWH and 30 HIV- individuals of similar age and ethnicity. Among PWH, higher CSF suPAR levels correlated with higher CSAR values (r = 0.47, P < .001). PWH had higher (more abnormal) BBB index values than HIV- individuals (mean ± SD, 0.361 ± 1.20 vs -0.501 ± 1.11; P = .0214). HIV serostatus interacted with cannabis use frequency, such that more frequent use of cannabis was associated with lower BBB index values in PWH but not in HIV- individuals. Worse BBB index values were associated with higher NFL in CSF (r = 0.380, P = .0169). CONCLUSIONS Cannabis may have a beneficial impact on HIV-associated BBB injury. Since BBB disruption may permit increased entry of toxins such as microbial antigens and inflammatory mediators, with consequent CNS injury, these results support a potential therapeutic role of cannabis among PWH and may have important treatment implications for ART effectiveness and toxicity.

Beneficial Effects of Cannabis on Blood-Brain Barrier Function in Human Immunodeficiency Virus.

Background Even in the era of suppressive antiretroviral therapy, people with HIV (PWH) suffer greater exposure to inflammation than their uninfected peers. Although poor social support and social isolation have been linked to systemic inflammation in the general population, it is not known whether this is true also among PWH. Methods People with and without HIV infection were enrolled in a community-based, single-center study. Primary predictors were the Medical Outcomes Study Social Support Survey, and outcomes were a panel of inflammatory biomarkers (ICAM-1, MCP-1, IL-6, IL-8, IP-10, C-reactive protein, D-dimer, VEGF, sCD14, and uPAR) in blood plasma and cerebrospinal fluid (CSF). Results PWH had worse positive social support (P = 0.0138) and affectionate support (P = 0.0078) than did HIV- individuals. A factor analysis was used to group the biomarkers into related categories separately for each fluid. Levels of 3 of the 4 plasma factors were significantly higher in PWH than HIV- (ps = 0.007, 0.001, and 0.0005, respectively). Levels of 1 of the 3 CSF factors also were significantly higher in PWH than HIV- (P = 0.0194). In the combined PWH and HIV- cohort, poorer social support was associated with higher levels of a factor in plasma loading on MCP-1, IL-8, and VEGF (P = 0.020) and with a CSF factor loading on MCP-1 and IL-6 (P = 0.006). Conclusion These results suggest that enhancing social support might be an intervention to reduce inflammation and its associated adverse outcomes among PWH.

Social Isolation Is Linked to Inflammation in Aging People With HIV and Uninfected Individuals.

This study sought to determine the effects of HIV-associated neurocognitive disorders (HAND) on health literacy, which encompasses the ability to access, understand, appraise, and apply health-related information. Participants included 56 HIV seropositive individuals, 24 of whom met Frascati criteria for HAND, and 24 sero- negative subjects who were comparable on age, education, ethnicity, and oral word reading. Each participant was administered a brief battery of well-validated measures of health literacy, including the Expanded Numeracy Scale (ENS), Newest Vital Sign (NVS), Rapid Estimate of Adult Literacy in Medicine (REALM), and Brief Health Literacy Screen (BHLS). Results revealed significant omnibus dif- ferences on the ENS and NVS, which were driven by poorer performance in the HAND group. There were no significant differences on the REALM or the BHLS by HAND status. Among individuals with HAND, lower scores on the NVS were associated with greater severity of neurocognitive dysfunction (e.g., working memory and verbal fluency) and self-reported dependence in activities of daily living. These preliminary findings suggest that HAND hinders both fundamental (i.e., basic knowledge, such as numeracy) and critical (i.e., comprehension and application of healthcare information) health literacy capacities, and therefore may be an important factor in the prevalence of health illiteracy. Health literacy-focused intervention may play an important role in the treatment and health trajectories among persons living with HIV infection.

Neurocognitive Impairment is Associated with Lower Health Literacy Among Persons Living with HIV Infection Erin E. MorganJennifer E. IudicelloJordan E. Cattie • Kaitlin BlackstoneIgor GrantSteven Paul Woods • The HIV Neurobehavioral Research Program (HNRP) Group

Jenny Iudicello

Papers

Recent cannabis use in HIV is associated with reduced inflammatory markers in CSF and blood

Beneficial Effects of Cannabis on Blood-Brain Barrier Function in Human Immunodeficiency Virus.

Social Isolation Is Linked to Inflammation in Aging People With HIV and Uninfected Individuals.

Neurocognitive Impairment is Associated with Lower Health Literacy Among Persons Living with HIV Infection Erin E. MorganJennifer E. IudicelloJordan E. Cattie • Kaitlin BlackstoneIgor GrantSteven Paul Woods • The HIV Neurobehavioral Research Program (HNRP) Group

Chronic methamphetamine use heightens concurrent risk of functional dependence in persons living with HIV infection