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Heliyon Jul 2022While combination antiretroviral therapy (cART) has successfully increased the lifespan of individuals infected with HIV, a significant portion of this population... (Review)
Review
While combination antiretroviral therapy (cART) has successfully increased the lifespan of individuals infected with HIV, a significant portion of this population remains affected by HIV-associated neurocognitive disorder (HAND). C-C chemokine receptor 5 (CCR5) has been well studied in immune response and as a co-receptor for HIV infection. HIV-infected (HIV) patients experienced mild to significant amelioration of cognitive function when treated with different CCR5 antagonists, including maraviroc and cenicriviroc. Consistent with clinical results, knockout or knockdown rescued cognitive deficits in HIV animal models, with mechanisms of reduced microgliosis and neuroinflammation. Pharmacologic inhibition of CCR5 directly improved cerebral and hippocampal neuronal plasticity and cognitive function. By summarizing the animal and human studies of CCR5 in HIV-associated cognitive deficits, this review aims to provide an overview of the mechanistic role of CCR5 in HAND pathophysiology. This review also discusses the addition of CCR5 antagonists, such as maraviroc, to cART for targeted prevention and treatment of cognitive impairments in patients infected with HIV.
PubMed: 35865985
DOI: 10.1016/j.heliyon.2022.e09950 -
Journal of Environmental Management Oct 2022In this study photochemical transformation of the antiretroviral pharmaceutical maraviroc under the simulated UV-Vis radiation was presented. The drug was shown to be...
Efficient removal of anti-HIV drug - maraviroc from natural water by peroxymonosulfate and TiO photocatalytic oxidation: Kinetic studies and identification of transformation products.
In this study photochemical transformation of the antiretroviral pharmaceutical maraviroc under the simulated UV-Vis radiation was presented. The drug was shown to be extremely photo-resistant, with a half-life over 250 h, which is particularly significant, considering its presence in the aquatic environments. Addition of the natural river water matrix substantially increased the degradation rate, albeit the process led to formation of numerous phototransformation products. Due to high photostability and presumable environmental persistence of maraviroc, a photocatalytic method of its elimination was proposed. Although titanium dioxide alone presented acceptable results, its combination with peroxymonosulfate enormously accelerated the degradation process, increasing it over 67 000 times in comparison with the direct photolysis. Substitution of ultrapure water with river water resulted in inhibition of the PMS-driven processes, however the decomposition efficiency was still very high. Noteworthy, majority of the identified photoproducts were still present after termination of irradiation in all the experiments, which may indicate necessity of ecotoxicological assessment of those compounds.
Topics: Anti-HIV Agents; Catalysis; Kinetics; Maraviroc; Peroxides; Photolysis; Titanium; Water; Water Pollutants, Chemical
PubMed: 35863307
DOI: 10.1016/j.jenvman.2022.115735 -
Journal of Virology Jul 2022A rare but natural polymorphism in the HIV-1 envelope (Env) glycoprotein, lysine at position 425 was selected as a mutation conferring resistance to maraviroc (MVC) ....
A rare but natural polymorphism in the HIV-1 envelope (Env) glycoprotein, lysine at position 425 was selected as a mutation conferring resistance to maraviroc (MVC) . N425K has not been identified in HIV-infected individuals failing an MVC-based treatment. This study reports that the rare K425 polymorphism in an HIV-1 subtype A Env has increased affinity for CD4, resulting in faster host cell entry kinetics and the ability to scavenge for low cell surface expression of CD4 to mediate entry. Whereas the subtype A wild-type isolate-74 Env (N425) is inhibited by soluble (s) CD4, HIV-1 with K425 A74 Env shows enhanced infection and the ability to infect CCR5+ cells when pretreated with sCD4. Upon adding K425 or N425 HIV-1 to CD4/CCR5+ cells along with RANTES/CCL3, only K425 HIV-1 was able to infect cells when CCR5 recycled/returned to the cell surface at 12 h post-treatment. These findings suggest that upon binding to CD4, K425 Env may maintain a stable State 2 "open" conformation capable of engaging CCR5 for entry. Only K425 was significantly more sensitivity than wild-type N425 A74 to inhibition by the CD4 binding site (bs) compound, BMS-806, the CD4bs antibody, VRC01 and N6, and the single-chain CD4i antibody, SCm9. K425 A74 was also capable of activating B cells expressing the VRC01 surface immunoglobulin. In summary, despite increased replicative fitness, we propose that K425 HIV-1 may be counterselected within infected individuals if K425 HIV-1 is rapidly eliminated by CD4bs-neutralizing antibodies. Typically, a natural amino acid polymorphism is found as the wild-type sequence in the HIV-1 population if it provides a selective advantage to the virus. The natural K425 polymorphism in HIV-1 Env results in higher host cell entry efficiency and greater replicative fitness by virtue of its high binding affinity to CD4. The studies presented herein suggest that the rare K425 HIV-1, compared to the common N425 HIV-1, may be more sensitive to inhibition by CD4bs-neutralizing antibodies (i.e., antibodies that bind to the CD4 binding pocket on the HIV-1 envelope glycoprotein). If CD4bs antibodies did emerge in an infected individual, the K425 HIV-1 may be hypersensitive to inhibition, and thus this K425 virus variant may be removed from the HIV-1 swarm despite its higher replication fitness. Studies are now underway to determine whether addition of the K425 polymorphism into the Envelope-based HIV-1 vaccines could enhance protective immunity.
Topics: Antibodies, Neutralizing; Binding Sites; CD4 Antigens; Drug Resistance, Viral; HIV Antibodies; HIV Envelope Protein gp120; HIV-1; Humans; Maraviroc; Polymorphism, Genetic; Protein Binding; Virus Internalization
PubMed: 35862673
DOI: 10.1128/jvi.01851-21 -
Antimicrobial Agents and Chemotherapy Aug 2022Although current antiretroviral therapy (ART) has increased life expectancy, a cure for human immunodeficiency virus (HIV) remains elusive due to the persistence of the...
Quantitative Imaging Analysis of the Spatial Relationship between Antiretrovirals, Reverse Transcriptase Simian-Human Immunodeficiency Virus RNA, and Fibrosis in the Spleens of Nonhuman Primates.
Although current antiretroviral therapy (ART) has increased life expectancy, a cure for human immunodeficiency virus (HIV) remains elusive due to the persistence of the virus in tissue reservoirs. In the present study, we sought to elucidate the relationship between antiretrovirals (ARVs) and viral expression in the spleen. We performed mass spectrometry imaging (MSI) of 6 different ARVs, RNAscope hybridization of viral RNA, and immunohistochemistry of three different fibrosis markers in the spleens of 8 uninfected and 10 reverse transcriptase simian-human immunodeficiency virus (RT-SHIV)-infected rhesus macaques (infected for 6 weeks) that had been dosed for 10 days with combination ART. Using MATLAB, computational quantitative imaging analysis was performed to evaluate the spatial and pharmacological relationships between the 6 ARVs, viral RNA, and fibrotic deposition. In these spleens, >50% of the spleen tissue area was not covered by any detectable ARV response (any concentration above the limits of detection for individual ARVs). The median spatial ARV coverage across all tissues was driven by maraviroc followed by efavirenz. Yet >50% of RNA-positive cells were not exposed to any detectable ARV. Quantifiable maraviroc and efavirenz colocalization with RNA-positive cells was usually greater than the concentration inhibiting 50% replication (IC). Fibrosis markers covered more than 50% of the spleen tissue area and had negative relationships with cumulative ARV coverages. Our findings suggest that a heterogeneous ARV spatial distribution must be considered when evaluating viral persistence in lymphoid tissue reservoirs.
Topics: Animals; Anti-Retroviral Agents; Fibrosis; HIV; HIV Infections; HIV Reverse Transcriptase; Humans; Macaca mulatta; Maraviroc; RNA, Viral; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Spleen; Viral Load
PubMed: 35856680
DOI: 10.1128/aac.00609-22 -
Neural Regeneration Research Jan 2023Neuroinflammation and the NACHT, LRR, and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in...
Neuroinflammation and the NACHT, LRR, and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury (TBI). Maraviroc, a C-C chemokine receptor type 5 antagonist, has been viewed as a new therapeutic strategy for many neuroinflammatory diseases. We studied the effect of maraviroc on TBI-induced neuroinflammation. A moderate-TBI mouse model was subjected to a controlled cortical impact device. Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days. Western blot, immunohistochemistry, and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI. Our results suggest that maraviroc administration reduced NACHT, LRR, and PYD domains-containing protein 3 inflammasome activation, modulated microglial polarization from M1 to M2, decreased neutrophil and macrophage infiltration, and inhibited the release of inflammatory factors after TBI. Moreover, maraviroc treatment decreased the activation of neurotoxic reactive astrocytes, which, in turn, exacerbated neuronal cell death. Additionally, we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score, rotarod test, Morris water maze test, and lesion volume measurements. In summary, our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI, and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.
PubMed: 35799534
DOI: 10.4103/1673-5374.344829 -
Clinical Infectious Diseases : An... Feb 2023Efavirenz (EFV)- and dolutegravir (DTG)-based antiretroviral therapy (ART) is the former and current recommended regimen for treatment-naive individuals with human...
Immunological, Cognitive, and Psychiatric Outcomes After Initiating Efavirenz- and Dolutegravir-based Antiretroviral Therapy During Acute Human Immunodeficiency Virus Infection.
BACKGROUND
Efavirenz (EFV)- and dolutegravir (DTG)-based antiretroviral therapy (ART) is the former and current recommended regimen for treatment-naive individuals with human immunodeficiency virus type 1 (HIV-1). Whether they impact the immunological and neuropsychiatric profile differentially remains unclear.
METHODS
This retrospective analysis included 258 participants enrolled during acute HIV-1 infection (AHI). Participants initiated 1 of 3 ART regimens during AHI: EFV-based (n = 131), DTG-based (n = 92), or DTG intensified with maraviroc (DTG/MVC, n = 35). All regimens included 2 nucleoside reverse-transcriptase inhibitors and were maintained for 96 weeks. CD4+ and CD8+ T-cell counts, mood symptoms, and composite score on a 4-test neuropsychological battery (NPZ-4) were compared.
RESULTS
At baseline, the median age was 26 years, 99% were male, and 36% were enrolled during Fiebig stage I-II. Plasma viral suppression at weeks 24 and 96 was similar between the groups. Compared with the EFV group, the DTG group showed greater increments of CD4+ (P < .001) and CD8+ (P = .015) T-cell counts but a similar increment of CD4/CD8 ratio at week 96. NPZ-4 improvement was similar between the 2 groups at week 24 but greater in the DTG group at week 96 (P = .005). Depressive mood and distress symptoms based on the Patient Health Questionnaire and distress thermometer were similar between the 2 groups at follow-up. Findings for the DTG/MVC group were comparable to those for the DTG group vs the EFV group.
CONCLUSIONS
Among individuals with AHI, 96 weeks of DTG-based ART was associated with greater increments of CD4+ and CD8+ T-cell counts and improvement in cognitive performance.
Topics: Humans; Male; Adult; Female; Retrospective Studies; HIV Infections; Benzoxazines; Heterocyclic Compounds, 3-Ring; Cognition; Anti-HIV Agents
PubMed: 35687498
DOI: 10.1093/cid/ciac466 -
AIDS and Behavior Dec 2022HPTN 069/ACTG 5305 was designed to evaluate potential new PrEP regimens that included maraviroc, tenofovir disoproxil fumarate, and/or emtricitabine. The current...
Sexual behavior and medication adherence in men who have sex with men participating in a pre-exposure prophylaxis study of combinations of Maraviroc, Tenofovir Disoproxil Fumarate and/or Emtricitabine (HPTN 069/ACTG 5305).
HPTN 069/ACTG 5305 was designed to evaluate potential new PrEP regimens that included maraviroc, tenofovir disoproxil fumarate, and/or emtricitabine. The current analyses assessed antiretroviral (ARV) plasma concentrations in relation to sexual behavior in 224 cisgender men who have sex with men and 2 transgender women at risk for HIV. Poisson generalized estimating equations (GEE) regression were used to test for associations between self-reported sexual behavior, sociodemographic, behavioral variables, and study drug levels The median (IQR) age was 30 [25, 37] years old; 48.2% had completed college; 27.4% were Black and 21.7% Latino. At weeks 24 and 48, one third of participants reported condomless anal sex (CAS) in the prior month with more than one partner. CAS was associated with daily ARV drug use (χ = 12.64, p = 0.002). Older individuals and those with greater education were more likely to ingest ARV drugs daily (χ = 9.36, p = 0.009 and χ = 8.63, p = 0.013, respectively), while neither race nor ethnicity was associated with daily ARV drug use. Participants who reported recent condomless anal sex and/or advanced education had higher rates of daily ARV drug use. These data support the need for ongoing adherence counseling in clinical trials of new PrEP modalities.
Topics: Male; Female; Humans; Pre-Exposure Prophylaxis; Emtricitabine; Tenofovir; Maraviroc; Homosexuality, Male; Anti-HIV Agents; HIV Infections; Sexual and Gender Minorities; Medication Adherence; Sexual Behavior; Anti-Retroviral Agents
PubMed: 35687192
DOI: 10.1007/s10461-022-03736-z -
IScience Jun 2022Non-human primates (NHP) are widely used for the pre-clinical assessment of antiretrovirals (ARVs) for HIV treatment and prevention. However, the utility of these models...
Non-human primates (NHP) are widely used for the pre-clinical assessment of antiretrovirals (ARVs) for HIV treatment and prevention. However, the utility of these models is questionable given the differences in ARV pharmacology between humans and macaques. Here, we report a model based on ARV exposure and the challenge of mucosal tissue explants to define pharmacological differences between NHPs and humans. For colorectal and cervicovaginal explants in both species, high concentrations of tenofovir (TFV) and maraviroc were predictive of anti-viral efficacy. However, their combinations resulted in increased inhibitory potency in NHP when compared to human explants. In NHPs, higher TFV concentrations were measured in colorectal versus cervicovaginal explants (p = 0.042). In humans, this relationship was inverted with lower levels in colorectal tissue (p = 0.027). TFV-resistance caused greater loss of viral fitness for HIV-1 than SIV. This, tissue explants provide an important bridge to refine and appropriately interpret NHP studies.
PubMed: 35663021
DOI: 10.1016/j.isci.2022.104409 -
Critical Care Explorations May 2022Clinical correlations suggest that systemic chemokine (C-C motif) ligand (CCL) 2 release may contribute to blood pressure regulation and the development of hemodynamic...
The Chemokine (C-C Motif) Receptor 2 Antagonist INCB3284 Reduces Fluid Requirements and Protects From Hemodynamic Decompensation During Resuscitation From Hemorrhagic Shock.
UNLABELLED
Clinical correlations suggest that systemic chemokine (C-C motif) ligand (CCL) 2 release may contribute to blood pressure regulation and the development of hemodynamic instability during the early inflammatory response to traumatic-hemorrhagic shock. Thus, we investigated whether blockade of the principal CCL2 receptor chemokine (C-C motif) receptor (CCR) 2 affects blood pressure in normal animals, and hemodynamics and resuscitation fluid requirements in hemorrhagic shock models.
DESIGN
Randomized prospective treatment study.
SETTING
University laboratory.
SUBJECTS
Male Sprague-Dawley rats.
INTERVENTIONS
First, treatment of healthy anesthetized rats with increasing doses of INCB3284 or vehicle. Second, rats were hemorrhaged for 30 minutes, followed by treatment with the CCR2 antagonist INCB3284 (1.1 and 5.5 μmol/kg), the CCR5 antagonist Maraviroc (=control, 5.5 μmol/kg) or vehicle, and subsequent fluid resuscitation to maintain blood pressure until = 90 minutes. Third, treatment of rats with 5 μmol/kg INCB3284 or vehicle after hemorrhage and fluid resuscitation until = 300 minutes.
MEASUREMENTS AND MAIN RESULTS
INCB3284 did not affect intrinsic function of isolated rat resistance arteries in pressure myography experiments. Blood pressure in anesthetized vehicle-treated animals continuously decreased by 0.09 ± 0.01 mm Hg/min ( < 0.001) but remained constant after INCB3284 injections. Systemic concentrations of the CCR2 agonists CCL2, CCL5, and CCL11 increased during hemorrhage and fluid resuscitation. INCB3284 dose-dependently reduced fluid requirements by 58% ± 11% in short-term experiments, whereas Maraviroc and vehicle-treated animals were indistinguishable. When resuscitation was performed until = 300 minutes, INCB3284 reduced fluid requirements by 62% ± 6%, prevented from hemodynamic decompensation, reduced mortality from 50% with vehicle treatment to zero, and reduced overall tissue wet-weight/dry-weight ratios.
CONCLUSIONS
Our findings suggest that CCR2 is involved in the regulation of normal cardiovascular function and during the cardiovascular stress response to hemorrhagic shock and fluid resuscitation. The present study identifies CCR2 as a drug target to reduce fluid requirements and to prevent death from hemodynamic decompensation during resuscitation from hemorrhagic shock.
PubMed: 35620770
DOI: 10.1097/CCE.0000000000000701 -
Journal of Neurovirology Apr 2022Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the CNS caused by the human polyomavirus 2 (JCV). PML predominantly occurs in...
Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the CNS caused by the human polyomavirus 2 (JCV). PML predominantly occurs in immunocompromised patients. To date, no specific antiviral treatment exists, leaving only restoration of the immune system as possible treatment. In 2019, the monoclonal antibody pembrolizumab was reported as a potential treatment option in PML in a case series. Following case reports could not thoroughly confirm a positive outcome. Pembrolizumab targets the inhibitory programmed cell death protein 1 (PD-1) receptor on lymphocytes and is associated with beneficial expansion of pre-existing virus-specific T cells. Here we describe a patient with PML who benefited from combined treatment with intravenous immunoglobulins, maraviroc, and pembrolizumab.
Topics: Antibodies, Monoclonal, Humanized; Humans; Immunoglobulins, Intravenous; JC Virus; Leukoencephalopathy, Progressive Multifocal
PubMed: 35320511
DOI: 10.1007/s13365-022-01059-2