HIV-associated Inflammation Research Articles

The impacts of tobacco and nicotine on HIV-1 infection, inflammation, and the blood-brain barrier in the central nervous system.

Human immunodeficiency virus (HIV-1) remains a persistent global health crisis. Even while successfully virologically suppressed, people with HIV (PWH) experience a higher risk for inflammatory disorders such as HIV-associated neurocognitive disorder (HAND). Tobacco use puts PWH at higher risk for neurocognitive symptoms resulting from HIV-associated neuroinflammation. The NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome has been implicated as a driver of HIV-associated inflammation, including HAND. Nicotine, the psychoactive component of tobacco smoke, has also been shown to signal through the NLRP3 inflammasome and modulate inflammatory signaling in the CNS. Here, we explore the impacts of nicotine and tobacco on the complex neurobiology of HAND, including effects on cognition, inflammation, viral latency, and blood-brain barrier integrity. We outline nicotine's role in the establishment of active and latent infection in the brain and posit the NLRP3 inflammasome as a common pathway by which HIV-1 and nicotine promote neuroinflammation in PWH.

Deciphering HIV-associated inflammation: microbiome's influence and experimental insights.

To review novel experimental approaches for studying host:microbe interactions and their role in intestinal and systemic inflammation in people living with HIV (PLWH). Inflammation in PLWH is impacted by interactions between the microbiome, the intestinal epithelium, and immune cells. This complex interplay is not fully understood and requires a variety of analytical techniques to study. Using a multiomic systems biology approach provides hypothesis generating data on host:microbe interactions that can be used to guide further investigation. The direct interactions between host cells and microbes can be elucidated using peripheral blood mononuclear cells (PBMCs), lamina propria mononuclear cells (LPMC's) or human intestinal organoids (HIO). Additionally, the broader relationship between the host and the microbiome can be explored using animal models such as nonhuman primates and germ-free and double humanized mice. To explore complex host:microbe relationships, hypotheses are generated and investigations are guided by multiomic data, while causal components are identified using in-vitro and in-vivo assays.

Impaired gut microbiota-mediated short-chain fatty acid production precedes morbidity and mortality in people with HIV

Antiretroviral therapy (ART) has dramatically lengthened lifespan among people with HIV (PWH), but this population experiences heightened rates of inflammation-related comorbidities. HIV-associated inflammation is linked with an altered microbiome; whether such alterations precede inflammation-related comorbidities or occur as their consequence remains unknown. We find that ART-treated PWH exhibit depletion of gut-resident bacteria that produce short-chain fatty acids (SCFAs)-crucial microbial metabolites with anti-inflammatory properties. Prior reports establish that fecal SCFA concentrations are not depleted in PWH. We find that gut-microbiota-mediated SCFA production capacity is better reflected in serum than in feces and that PWH exhibit reduced serum SCFA, which associates with inflammatory markers. Leveraging stool and serum samples collected prior to comorbidity onset, we find that HIV-specific microbiome alterations precede morbidity and mortality in ART-treated PWH. Among these microbiome alterations, reduced microbiome-mediated conversion of lactate to propionate precedes mortality in PWH. Thus, gut microbial fiber/lactate conversion to SCFAs may modulate HIV-associated comorbidity risk.

Initiation of combined antiretroviral therapy confers suboptimal beneficial effects on neurovascular function in people with HIV.

Due to advances in combined anti-retroviral treatment (cART), there is an increased burden of age-related cerebrovascular disease (CBVD), in people living with HIV (PWH). The underlying CNS injury can be assessed by measuring cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). 35 treatment-naïve PWH and 53 HIV negative controls (HC) were enrolled in this study. Study participants underwent T1-weighted anatomical, pseudo-continuous arterial spin labeling, and resting-state functional MRI to obtain measures of CBF and CVR prior to starting cART treatment and at two-time points (12 weeks and 2 years) post-cART initiation. Controls were scanned at the baseline and 2-year visits. We also measured plasma levels of microparticles of endothelial and glial origin and well-known endothelial inflammation markers, ICAM-1 and VCAM-1, to assess HIV-associated endothelial inflammation and the interaction of these peripheral markers with brain neurovascular function. HIV infection was found to be associated with reduced CVR and increased levels of endothelial and glial microparticles (MPs) prior to initiation of cART. Further, CVR correlated negatively with peripheral MP levels in PWH. Our results suggest that while cART treatment has a beneficial effect on the neurovascular function after initiation, these benefits are suboptimal over time.

HIV-1-Host Interaction in Gut-Associated Lymphoid Tissue (GALT): Effects on Local Environment and Comorbidities.

HIV-1 replication in the gastrointestinal (GI) tract causes severe CD4+ T-cell depletion and disruption of the protective epithelial barrier in the intestinal mucosa, causing microbial translocation, the main driver of inflammation and immune activation, even in people living with HIV (PLWH) taking antiretroviral drug therapy. The higher levels of HIV DNA in the gut compared to the blood highlight the importance of the gut as a viral reservoir. CD4+ T-cell subsets in the gut differ in phenotypic characteristics and differentiation status from the ones in other tissues or in peripheral blood, and little is still known about the mechanisms by which the persistence of HIV is maintained at this anatomical site. This review aims to describe the interaction with key subsets of CD4+ T cells in the intestinal mucosa targeted by HIV-1 and the role of gut microbiome and its metabolites in HIV-associated systemic inflammation and immune activation that are crucial in the pathogenesis of HIV infection and related comorbidities.

Coronary heart disease in patients with human immunodeficiency virus infection

According to the World Health Organization, more than 38 million people are carriers of the human immunodeficiency virus (HIV). The relative risk of cardiovascular events in patients with HIV infection is 1.52 times higher than those without it. An HIV-positive status is associated with a 50% increased risk of acute myocardial infarction. The mechanisms of CVD development caused by HIV activity are not fully understood, and the contribution of traditional risk factors cannot fully explain such a high potential for coronary heart disease (CHD) in patients with HIV infection. Data suggest that HIV-associated chronic inflammation and immune system activation may lead to progressive endothelial dysfunction and vascular damage. The pathogenesis of atherosclerosis and, consequently, CHD in HIV infection is extremely versatile and poorly studied. The key mechanisms in HIV-associated CHD include the effect of HIV proteins on immunocompetent cells and vascular endothelium, immunodeficiency, translocation of microorganisms from the gut, and chronic inflammation with platelet activation. Despite considerable progress in understanding HIV-associated cardiovascular disease, many unresolved questions remain. Even with effective viral suppression, inflammation and immune dysregulation appear to increase the risk of cardiovascular complications. The lack of large-scale clinical studies on the prevention and treatment of cardiovascular disease in HIV is very important. Nevertheless, some important features should be considered in the management of patients with HIV infection.

Cardiovascular Disease Among Persons Living With HIV: New Insights Into Pathogenesis and Clinical Manifestations in a Global Context

Widespread use of contemporary antiretroviral therapy globally has transformed HIV disease into a chronic illness associated with excess risk for disorders of the heart and circulatory system. Current clinical care and research has focused on improving HIV-related cardiovascular disease outcomes, survival, and quality of life. In high-income countries, emphasis on prevention of atherosclerotic coronary artery disease over the past decade, including aggressive management of traditional risk factors and earlier initiation of antiretroviral therapy, has reduced risk for myocardial infarction among persons living with human immunodeficiency virus-1 infection. Still, across the globe, persons living with human immunodeficiency virus-1 infection on effective antiretroviral therapy treatment remain at increased risk for ischemic outcomes such as myocardial infarction and stroke relative to the persons without HIV. Unique features of HIV-related cardiovascular disease, in part, include the pathogenesis of coronary disease characterized by remodeling ectasia and unusual plaque morphology, the relative high proportion of type 2 myocardial infarction events, abnormalities of the aorta such as aneurysms and diffuse aortic inflammation, and HIV cerebrovasculopathy as a contributor to stroke risk. Literature over the past decade has also reflected a shift in the profile and prevalence of HIV-associated heart failure, with a reduced but persistent risk of heart failure with reduced ejection fraction and a growing risk of heart failure with preserved ejection fraction. Cardiac magnetic resonance imaging and autopsy data have emphasized the central importance of intramyocardial fibrosis for the pathogenesis of both heart failure with preserved ejection fraction and the increase in risk of sudden cardiac death. Still, more research is needed to better characterize the underlying mechanisms and clinical phenotype of HIV-associated myocardial disease in the current era. Across the different cardiovascular disease manifestations, a common pathogenic feature is that HIV-associated inflammation working through different mechanisms may amplify underlying pathology because of traditional risk and other host factors. The prevalence and phenotype of individual cardiovascular disease manifestations is ultimately influenced by the degree of injury from HIV disease combined with the profile of underlying cardiometabolic factors, both of which may differ substantially by region globally.

The Effect of HIV on the Heart and HAART on the Heart

HIV/AIDS is a disease characterized by immune dysfunction with superimposed severe opportunistic liability. The past few years has seen a significant rise to 75% of HIV patients compliant on ART. Delving into specific complications reveal significant associations between HIV and HAART in the heart. The purpose of this article is to throw more light on the key role players in cardiac dysfunction among HIV patients on HAART. In this article, we discuss the effects of HIV-associated chronic inflammation, immune dysfunction, high-risk medications, and their effects on the cardiovascular, and metabolic systems which further hastens the progression of cardiac dysfunction in individuals. Complications such as heart failure, coronary artery disease, pericardial effusion, and pulmonary hypertension are also discussed to appreciate the pathophysiology and outcomes. We believe that if more studies into cardiac complications of HIV patients on HAART are conducted, many patients will benefit from the evidenced-based outcomes which will influence clinical decision-making.

HIV-associated vaginal microbiome and inflammation predict spontaneous preterm birth in Zambia

A Lactobacillus-deficient, anaerobe-rich vaginal microbiome has been associated with local inflammation and spontaneous preterm birth (sPTB), but few studies have assessed this association in the setting of HIV. We performed metagenomic sequencing and inflammatory marker assays on vaginal swabs collected in pregnancy. We grouped samples into 7 metagenomic clusters (mgClust) using the non-redundant VIRGO catalogue, and derived inflammatory scores by factor analysis. Of 221 participants, median Shannon diversity index (SDI) was highest in HIV+ with detectable viral load (1.31, IQR: 0.85–1.66; p < 0.001) and HIV+ with undetectable virus (1.17, IQR: 0.51–1.66; p = 0.01) compared to HIV− (0.74, IQR: 0.35–1.26). Inflammatory scores positively correlated with SDI (+ 0.66, 95%CI 0.28, 1.03; p = 0.001), highest among anaerobe-rich mgClust2–mgClust6. HIV was associated with predominance of anaerobe-rich mgClust5 (17% vs. 6%; p = 0.02) and mgClust6 (27% vs. 11%; p = 0.002). Relative abundance of a novel Gardnerella metagenomic subspecies > 50% predicted sPTB (RR 2.6; 95%CI: 1.1, 6.4) and was higher in HIV+ (23% vs. 10%; p = 0.001). A novel Gardnerella metagenomic subspecies more abundant in women with HIV predicted sPTB. The risk of sPTB among women with HIV may be mediated by the vaginal microbiome and inflammation, suggesting potential targets for prevention.

Deprenyl reduces inflammation during acute SIV infection

SummaryIn the era of antiretroviral therapy, inflammation is a central factor in numerous HIV-associated comorbidities, such as cardiovascular disease, cognitive impairment, and neuropsychiatric disorders. This highlights the value of developing therapeutics that both reduce HIV-associated inflammation and treat associated comorbidities. Previous research on monoamine oxidase inhibitors (MAOIs) suggests this class of drugs has anti-inflammatory properties in addition to neuropsychiatric effects. Therefore, we examined the impact of deprenyl, an MAOI, on SIV-associated inflammation during acute SIV infection using the rhesus macaque model of HIV infection. Our results show deprenyl decreased both peripheral and CNS inflammation but had no effect on viral load in either the periphery or CNS. These data show that the MAOI deprenyl may have broad anti-inflammatory effects when given during the acute stage of SIV infection, suggesting more research into the anti-inflammatory effects of this drug could result in a beneficial adjuvant for antiretroviral therapy.

Aging With Grace for People Living With HIV: Strategies to Overcome Leaky Gut and Cytomegalovirus Coinfection.

:The intestinal epithelial layer acts as a mechanical and functional barrier between the intraluminal microbiota and the immunologically active submucosa. A progressive loss of gut barrier function (leaky gut) leads to enhanced translocation of microbial products, which in turn contributes as endotoxins to inflammaging. Th17 T cell represents the main immune sentinels in the gut epithelium, preventing aggression from commensal and pathogenic microbes. As HIV infection deeply affects gut Th17 function and increases gut permeability, microbial translocation occurs at high level in people living with HIV (PLWH) and has been associated with the development of non-AIDS comorbidities. Although the inflammatory role of endotoxins like lipopolysaccharide produced by Gram-negative bacteria is well-established, fungal products such as β-D-glucan emerge as new contributors. In addition, PLWH are more frequently infected with cytomegalovirus (CMV) than the general population. CMV infection is a well-described accelerator of immune aging, through the induction of expansion of dysfunctional CD8 T-cells as well as through enhancement of gut microbial translocation. We critically review immune mechanisms related to bacterial and fungal translocation, with a focus on the contribution of CMV coinfection in PLWH. Improving gut barrier dysfunction, microbial composition, and reducing microbial translocation constitute emerging strategies for the prevention and treatment of HIV-associated inflammation and may be relevant for age-related inflammatory conditions.

Sex Differences in Non-AIDS Comorbidities Among People With Human Immunodeficiency Virus

Women are grossly underrepresented in human immunodeficiency virus (HIV) clinical and translational research. This is concerning given that people with HIV (PWH) are living longer, and thus accumulating aging-related non-AIDS comorbidities (NACMs); emerging evidence suggests that women are at higher risk of NACM development and progression compared with men. It is widely recognized that women vs men have greater immune activation in response to many viruses, including HIV-1; this likely influences sex-differential NACM development related to differences in HIV-associated chronic inflammation. Furthermore, many sociobehavioral factors that contribute to aging-related NACMs are known to differ by sex. The objectives of this review were to (1) synthesize sex-stratified data on 4 NACMs among PWH: bone disease, cardiovascular disease, metabolic dysfunction, and neurocognitive impairment; (2) evaluate the characteristics of key studies assessing sex differences in NACMs; and (3) introduce potential biological and psychosocial mechanisms contributing to emerging trends in sex-differential NACM risk and outcomes among PWH.

The Adenosine Pathway and Human Immunodeficiency Virus-Associated Inflammation.

Human immunodeficiency virus (HIV) is associated with an increased risk of age-associated comorbidities and mortality compared to people without HIV. This has been attributed to HIV-associated chronic inflammation and immune activation despite viral suppression. The adenosine pathway is an established mechanism by which the body regulates persistent inflammation to limit tissue damage associated with inflammatory conditions. However, HIV infection is associated with derangements in the adenosine pathway that limits its ability to control HIV-associated inflammation. This article reviews the function of purinergic signaling and the role of the adenosine signaling pathway in HIV-associated chronic inflammation. This review also discusses the beneficial and potential detrimental effects of pharmacotherapeutic strategies targeting this pathway among people with HIV.

Role of Brain Arterial Remodeling in HIV-Associated Cerebrovascular Outcomes.

As the life expectancy of people living with HIV (PLWH) on combination antiretroviral therapy (cART) increases, so does morbidity from cerebrovascular disease and neurocognitive disorders. Brain arterial remodeling stands out as a novel investigational target to understand the role of HIV in cerebrovascular and neurocognitive outcomes. We therefore conducted a review of publications in PubMed, EMBASE, Web of Science and Wiley Online Library, from inception to April 2021. We included search terms such as HIV, cART, brain, neuroimmunity, arterial remodeling, cerebrovascular disease, and neurocognitive disorders. The literature shows that, in the post-cART era, PLWH continue to experience an increased risk of stroke and neurocognitive disorders (albeit milder forms) compared to uninfected populations. PLWH who are immunosuppressed have a higher proportion of hemorrhagic strokes and strokes caused by opportunistic infection and HIV vasculopathy, while PLWH on long-term cART have higher rates of ischemic strokes, compared to HIV-seronegative controls. Brain large artery atherosclerosis in PLWH is associated with lower CD4 nadir and higher CD4 count during the stroke event. HIV vasculopathy, a form of non-atherosclerotic outward remodeling, on the other hand, is associated with protracted immunosuppression. HIV vasculopathy was also linked to a thinner media layer and increased adventitial macrophages, suggestive of non-atherosclerotic degeneration of the brain arterial wall in the setting of chronic central nervous system inflammation. Cerebrovascular architecture seems to be differentially affected by HIV infection in successfully treated versus immunosuppressed PLWH. Brain large artery atherosclerosis is prevalent even with long-term immune reconstitution post-cART. HIV-associated changes in brain arterial walls may also relate to higher rates of HIV-associated neurocognitive disorders, although milder forms are more prevalent in the post-cART era. The underlying mechanisms of HIV-associated pathological arterial remodeling remain poorly understood, but a role has been proposed for chronic HIV-associated inflammation with increased burden on the vasculature. Neuroimaging may come to play a role in assessing brain arterial remodeling and stratifying cerebrovascular risk, but the data remains inconclusive. An improved understanding of the different phenotypes of brain arterial remodeling associated with HIV may reveal opportunities to reduce rates of cerebrovascular disease in the aging population of PLWH on cART.

Gut Leakage of Fungal-Related Products: Turning Up the Heat for HIV Infection.

The intestinal epithelial layer serves as a physical and functional barrier between the microbiota in the lumen and immunologically active submucosa. Th17 T-cell function protects the gut epithelium from aggression from microbes and their by-products. Loss of barrier function has been associated with enhanced translocation of microbial products which act as endotoxins, leading to local and systemic immune activation. Whereas the inflammatory role of LPS produced by Gram-negative bacteria has been extensively studied, the role of fungal products such as β-D-glucan remains only partially understood. As HIV infection is characterized by impaired gut Th17 function and increased gut permeability, we critically review mechanisms of immune activation related to fungal translocation in this viral infection. Additionally, we discuss markers of fungal translocation for diagnosis and monitoring of experimental treatment responses. Targeting gut barrier dysfunction and reducing fungal translocation are emerging strategies for the prevention and treatment of HIV-associated inflammation and may prove useful in other inflammatory chronic diseases.

Probing the Interface of HIV and Inflammaging.

Systemic inflammation increases as a consequence of aging (inflammaging) and contributes to age-related morbidities. Inflammation in people living with HIV is elevated compared with the general population even after prolonged suppression of viremia with anti-retroviral therapy. Mechanisms that contribute to inflammation during aging and in treated HIV disease are potentially interactive, leading to an exaggerated inflammatory phenotype in people with HIV. Recent studies highlight roles for anti-retroviral therapy, co-infections, immune system alterations, and microbiome perturbations as important contributors to HIV-associated inflammation. These factors likely contribute to increased risk of age-related morbidities in people living with HIV. Understanding mechanisms that exaggerate the inflammaging process in people with HIV may lead to improved intervention strategies, ultimately, extending both lifespan and healthspan.

Dysregulation of IL-17/IL-22 Effector Functions in Blood and Gut Mucosal Gamma Delta T Cells Correlates With Increase in Circulating Leaky Gut and Inflammatory Markers During cART-Treated Chronic SIV Infection in Macaques.

HIV-associated inflammation has been implicated in the premature aging and increased risk of age-associated comorbidities in cART-treated individuals. However, the immune mechanisms underlying the chronic inflammatory state of cART-suppressed HIV infection remain unclear. Here, we investigated the role of γδT cells, a group of innate IL-17 producing T lymphocytes, in the development of systemic inflammation and leaky gut phenotype during cART-suppressed SIV infection of macaques. Plasma levels of inflammatory mediators, intestinal epithelial barrier disruption (IEBD) and microbial translocation (MT) biomarkers, and Th1/Th17-type cytokine functions were longitudinally assessed in blood and gut mucosa of SIV-infected, cART-suppressed macaques. Among the various gut mucosal IL-17/IL-22-producing T lymphocyte subsets including Th17, γδT, CD161+ CD8+ T, and MAIT cells, a specific decline in the Vδ2 subset of γδT cells and impaired IL-17/IL-22 production in γδT cells significantly correlated with the subsequent increase in plasma IEBD/MT markers (IFABP, LPS-binding protein, and sCD14) and pro-inflammatory cytokines (IL-6, IL-1β, IP10, etc.) despite continued viral suppression during long-term cART. Further, the plasma inflammatory cytokine signature during long-term cART was distinct from acute SIV infection and resembled the inflammatory cytokine profile of uninfected aging (inflammaging) macaques. Overall, our data suggest that during cART-suppressed chronic SIV infection, dysregulation of IL-17/IL-22 cytokine effector functions and decline of Vδ2 γδT cell subsets may contribute to gut epithelial barrier disruption and development of a distinct plasma inflammatory signature characteristic of inflammaging. Our results advance the current understanding of the impact of chronic HIV/SIV infection on γδT cell functions and demonstrate that in the setting of long-term cART, the loss of epithelial barrier-protective functions of Vδ2 T cells and ensuing IEBD/MT occurs before the hallmark expansion of Vδ1 subsets and skewed Vδ2/Vδ1 ratio. Thus, our work suggests that novel therapeutic approaches toward restoring IL-17/IL-22 cytokine functions of intestinal Vδ2 T cells may be beneficial in preserving gut epithelial barrier function and reducing chronic inflammation in HIV-infected individuals.

Cannabis use is not associated with increased balance disturbances in HIV-infected individuals

BackgroundThe association between long-term cannabis use and balance disturbances has not been investigated in people living with HIV (PWH). We hypothesized that long-term cannabis use in PWH might be associated with more deleterious effects on balance than in HIV seronegative individuals due to potential neurotoxic interactions between HIV and cannabis.MethodsThree thousand six-hundred and forty-eight participants with and without HIV completed an interviewer-administered timeline follow-back assessment to assess lifetime days and quantity of cannabis use and other cannabis use characteristics. A structured clinical interview was used to collect any history of balance disturbance. Comparisons between HIV+ vs the HIV− groups and moderate-severe vs. no or minimal imbalance in participant characteristics (demographics, cannabis use, medication currently used, and neurological disease) were performed using Student t tests for continuous variables and Fisher’s exact test for binary and categorical variables. Multivariate logistic regression was applied to determine the interaction effect of total quantity of cannabis use with HIV status on balance disturbance. Age, gender, cDSPN symptoms, gait ataxia, opioid medications, and sedatives were included as covariates in the adjusted model after variable selection. The effect sizes are presented as Cohen’s d or odds ratios.ResultsOn average, participants were 45.4 years old (SD = 11 years), primarily male (77.7%), and non-Hispanic white (48.1%). A majority of participants were HIV+ (79.1%). Four hundred thirty (11.9%) of the participants reported balance disturbances within the past 10 years. PWH were more likely to have balance disturbances than demographically matched HIV-uninfected participants (odds ratio [OR] 2.66, 95% CI 1.91–3.7). Participants with moderate-severe balance disturbances did not differ from those with no or minimal imbalance in the proportion who had ever used cannabis (73.8% vs. 74.4%; p = 0.8) (OR 1.03, 95% CI 0.80–1.32) neither did they have a higher total amount of cannabis use (4871 vs. 4648; p = 0.3) (Cohen’s d 0.11, 95% CI 0.01–0.14). In the HIV− population, those with balance disturbances reported more total amount of cannabis use as compared to those with normal balance (11316 vs 4154; p = 0.007). In the HIV+ population on the other hand, there was no significant association (4379 vs 4773; p = 0.6).ConclusionsWe found unexpectedly that while long-term cannabis use in HIV− individuals was associated with more severe balance disturbances, there were no associations in HIV+ individuals. This suggests that cannabis use in HIV is safe with respect to balance disturbances. Given that HIV is related to persistent inflammation despite virologic suppression on antiretroviral therapy, future mechanistic studies are needed to determine whether HIV-associated inflammation contributes to the higher prevalence of balance disturbance in HIV+ individuals and whether cannabinoids have anti-inflammatory effects that mitigate HIV-associated balance disturbance.

Deprenyl Reduces Inflammation During Acute SIV Infection

In the era of antiretroviral therapy, inflammation is currently a central factor in a growing number of HIV-associated comorbidities, such as cardiovascular disease, cognitive impairment, and neuropsychiatric disorders. This highlights the value of developing therapeutics that both reduce HIV-associated inflammation and treat associated co-morbidities. Previous research on monoamine oxidase inhibitors (MAOIs) suggests that this class of drugs has anti-inflammatory properties in addition to neuropsychiatric effects. Therefore, we examined the impact of the deprenyl, an MAOI, on SIV-associated inflammation during acute SIV infection using the rhesus macaque model of HIV infection. Our results show that deprenyl decreased both peripheral and CNS inflammation but had no effect on viral load in either the periphery or CNS. These data show that the MAOI deprenyl has broad anti-inflammatory effects when given during the acute stage of SIV infection, suggesting that repurposing this drug could provide a beneficial adjuvant for antiretroviral therapy.

Astrocyte HIV-1 Tat Differentially Modulates Behavior and Brain MMP/TIMP Balance During Short and Prolonged Induction in Transgenic Mice

Despite effective antiretroviral therapy (ART), mild forms of HIV-associated neurocognitive disorders (HAND) continue to afflict approximately half of all people living with HIV (PLWH). As PLWH age, HIV-associated inflammation perturbs the balance between brain matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs), likely contributing to neuropathogenesis. The MMP/TIMP balance is associated with cognition, learning, and memory, with TIMPs eliciting neuroprotective effects. Dysregulation of the MMP/TIMP balance was evident in the brains of PLWH where levels of TIMP-1, the inducible family member, were significantly lower than non-infected controls, and MMPs were elevated. Here, we evaluated the MMP/TIMP levels in the doxycycline (DOX)-induced glial fibrillary acidic protein promoter-driven HIV-1 transactivator of transcription (Tat) transgenic mouse model. The HIV-1 protein Tat is constitutively expressed by most infected cells, even during ART suppression of viral replication. Many studies have demonstrated indirect and direct mechanisms of short-term Tat-associated neurodegeneration, including gliosis, blood-brain barrier disruption, elevated inflammatory mediators and neurotoxicity. However, the effects of acute vs. prolonged exposure on Tat-induced dysregulation remain to be seen. This is especially relevant for TIMP-1 as expression was previously shown to be differentially regulated in human astrocytes during acute vs. chronic inflammation. In this context, acute Tat expression was induced with DOX intraperitoneal injections over 3 weeks, while DOX-containing diet was used to achieve long-term Tat expression over 6 months. First, a series of behavior tests evaluating arousal, ambulation, anxiety, and cognition was performed to examine impairments analogous to those observed in HAND. Next, gene expression of components of the MMP/TIMP axis and known HAND-relevant inflammatory mediators were assessed. Altered anxiety-like, motor and/or cognitive behaviors were observed in Tat-induced (iTat) mice. Gene expression of MMPs and TIMPs was altered depending on the duration of Tat expression, which was independent of the HIV-associated neuroinflammation typically implicated in MMP/TIMP regulation. Collectively, we infer that HIV-1 Tat-mediated dysregulation of MMP/TIMP axis and behavioral changes are dependent on duration of exposure. Further, prolonged Tat expression demonstrates a phenotype comparable to asymptomatic to mild HAND manifestation in patients.