phytosterols and HIV-Infections

It has been widely accepted that HIV-1 enters into and buds out from microdomains known as lipid rafts/caveolae of plasma membranes of infected cells. Since lipid rafts are recognized sites for budding and entry of HIV-1, and since lipids in rafts (including composition/dynamic structure) play a crucial role in modulating the functions of raft-associated signaling proteins and receptors, it has been consistently shown that modulating the composition/structure of lipid rafts have influenced the life cycle of HIV-1 inhibiting its replication. Since anti-retroviral multi-drugs treatment has severe side effects, one of the strategies could be to block the HIV-1 entry and its replication using natural compounds that can target lipid rafts. Dietary and plant-derived compounds have advantage over synthetic drugs exhibiting minimum side effects and are available in cost effective manner. Studies exploring the effects of dietary and plant-derived compounds targeting lipid rafts could be an evolving strategy to control the progression of AIDS. This article is intended to review: (i) composition/structure and conditions for the formation of lipid rafts in plasma membranes, (ii) interaction of HIV-1 with lipid rafts and (iii) to introduce a novel concept that dietary and plant-derived compounds, which can target lipid rafts, could have potential preventive/therapeutic values against the progression of AIDS. More emphasis has been given to the roles of omega-3 fatty acids and plant-derived various triterpenes, especially euphane-types of triterpenes extracted from Neem tree, targeting lipid rafts and its major component cholesterol.

Topics: Anti-HIV Agents; Caveolae; Cholesterol; HIV Infections; HIV-1; Humans; Membrane Microdomains; Phytosterols; Plant Preparations; Sphingolipids; Triterpenes; Virus Replication

Although plant sterols (phytosterols) were chemically described in 1922, their biological role in human and animal health has been underestimated. Their ability to control cholesterol plasma levels in hypercholesterolimic patients was first described in 1983 when the structure of phytosterols implied that they could, by steric hindrance, inhibit the absorption of cholesterol from our diets. This has led to the development of functional foods containing high contents of these plant molecules or their esters as cholesterol controlling foods. Over the last 15 years, however, several reports have appeared in the literature indicating that phytosterols have some immunological activity as highlighted in animal models of inflammation or even in in-vitro and in-vivo models of cancer (colorectal and breast cancer). These findings were paralleled by epidemiological studies correlating the reduced risk of numerous diseases and the dietary intake of phytosterols. It is only in the last 10 years, however, that their direct immune modulatory activity on human lymphocytes has been proven and the mechanism of action in cancer cells has been elucidated. The use of phytosterols as supportive therapies in certain chronic conditions has been tested under clinical trial conditions. This review presents a summary of the in-vitro and in-vivo studies published to date.

Topics: Adjuvants, Immunologic; Animals; Cholesterol; Disease Models, Animal; HIV Infections; Humans; Hypercholesterolemia; Immune Tolerance; Intestinal Absorption; Neoplasms; Phytosterols; Phytotherapy; Sitosterols; Tuberculosis, Pulmonary; Tumor Cells, Cultured

To determine the effects of 40 mg of pravastatin, 2 g of phytosterols, and combination therapy on lipid profiles and to compare the reduction of LDL cholesterol between combination therapy and monotherapy.. Thirty-six HIV-infected patients treated with ARVs who had high LDL cholesterol levels but no current usage of any lipid-lowering agents were enrolled into the open-labelled, randomized, cross-over study. All patients were assigned randomly into one of four intervention groups: (1) pravastatin 40 mg cross-over to the combination of pravastatin 40 mg and phytosterols 2 g (combination group), (2) the combination group cross-over to pravastatin 40 mg, (3) phytosterols 2 g cross-over to the combination group, and (4) the combination group cross-over to phytosterols 2 g. Each active treatment lasted 4 weeks with a wash-out period of 4 weeks.. The baseline mean TC, TG, HDL-c, and LDL-c levels in 36 HIV patients were 248.09 ± 34.73, 172.36 ± 125.44, 54.92 ± 16.67, and 175.13 ± 29.00 mg/dl, respectively. Pravastatin, phytosterols, and combination therapy reduced TC and LDL-c but TG and HDL-c were not significantly different from the baselines. The mean LDL-c reductions in the pravastatin, phytosterols, and the combination groups were 28.76 ± 9.32, 9.12 ± 7.84, and 27.08 ± 15.58%, respectively. The LDL-c levels in the pravastatin and combination groups were reduced more than in the phytosterols group (p < 0.01). There was no difference in the LDL-c reduction between the combination and pravastatin monotherapy groups (-25.61 ± 10.43 vs. -28.12 ± 14.07%, p = 0.555).. Pravastatin had moderate potency on LDL-c lowering in HIV patients but could not bring LDL-c to goal. Adding phytosterols to pravastatin for a 4-week duration could not demonstrate any additional lipid-lowering effect. Thai Clinical Trial Registry: TCTR20150126002 date: January 23, 2015.

Topics: Adult; Anticholesteremic Agents; Cholesterol, LDL; Cross-Over Studies; Drug Therapy, Combination; Female; HIV Infections; Humans; Hypercholesterolemia; Male; Middle Aged; Phytosterols; Pravastatin

Cholesterol contributes to neuronal membrane integrity, supports membrane protein clustering and function, and facilitates proper signal transduction. Extensive evidence has shown that cholesterol imbalances in the central nervous system occur in aging and in the development of neurodegenerative diseases. In this work, we characterize cholesterol homeostasis in the inner ear of young and aged mice as a new unexplored possibility for the prevention and treatment of hearing loss. Our results show that cholesterol levels in the inner ear are reduced during aging, an effect that is associated with an increased expression of the cholesterol 24-hydroxylase (CYP46A1), the main enzyme responsible for cholesterol turnover in the brain. In addition, we show that pharmacological activation of CYP46A1 with the antiretroviral drug efavirenz reduces the cholesterol content in outer hair cells (OHCs), leading to a decrease in prestin immunolabeling and resulting in an increase in the distortion product otoacoustic emissions (DPOAEs) thresholds. Moreover, dietary supplementation with phytosterols, plant sterols with structure and function similar to cholesterol, was able to rescue the effect of efavirenz administration on the auditory function. Altogether, our findings point towards the importance of cholesterol homeostasis in the inner ear as an innovative therapeutic strategy in preventing and/or delaying hearing loss.

Topics: Animals; Cholesterol 24-Hydroxylase; Hearing Loss; HIV Infections; Mice; Phytosterols

The effects of ezetimibe on cholesterol metabolism in HIV-infected patients receiving boosted protease inhibitors have not been thoroughly assessed. The aim of this study was to assess cholesterol homeostasis in patients with PI associated dyslipidemia and its relationship with the response to treatment with the cholesterol-absorption inhibitor ezetimibe.. Fifteen patients with ritonavir-boosted PI-containig therapy and LDL-cholesterol > 3.36 mmol/L (>130 mg/dL) were assessed at baseline and after an 8-week course of ezetimibe 10 mg/d. Serum non-cholesterol sterols were measured at each visit as markers of cholesterol synthesis and absorption. Total-, LDL-, and HDL-cholesterol triglycerides, apolipoproteins A1 and B, high sensitivity C-reactive protein, CD4 cells and HIV-1 RNA were also measured.. Ezetimibe treatment was well tolerated in all patients and resulted in significant reductions in total cholesterol (-11.4%, p = .002), LDL-cholesterol (-20.4%, p = .003), non-HDL-cholesterol (-13.4%, p = .002) and apolipoprotein B (-9.1%, p = .021). Treatment with ezetimibe was associated with decreased cholesterol absorption markers (campesterol-to-cholesterol ratio -43.0%, p = .001; sitosterol-to-cholesterol ratio -41.9%, p = .001) and increased synthesis markers (lathosterol-to-cholesterol ratio 53.2%, p = .005). Baseline absorption or synthesis markers were unrelated to the response to treatment. CD4 cell count and plasma HIV-1 RNA remained unchanged.. The level of cholesterol absorption or synthesis does not appear to be a major determinant of the responsiveness to ezetimibe in patients on ritonavir-boosted PI-containing therapy.. EudraCT: 2006-006156-36.

Topics: Adult; Aged; Anticholesteremic Agents; Azetidines; C-Reactive Protein; Cholesterol; Cholesterol, LDL; Dyslipidemias; Ezetimibe; Female; HIV Infections; Humans; Lipid Metabolism; Male; Middle Aged; Phytosterols; Protease Inhibitors

The Th1--Th2 balance plays a pivotal role in determining the outcome of an immune response to an infectious organism. It is proposed that during HIV infection, disease progression is characterized by a loss of Th1 activity, a shift to a more 'allergic' Th2-type response and hence loss of cytotoxic cell activity against infected host cells. This study was undertaken to investigate this balance in three groups of individuals: HIV-negative volunteers (n=10), a group of HIV-infected patients on no therapy (n=10) as well as a group of patients managed with a mixture of plant sterols/sterolins (n=9). In parallel, their response to mitogens and the subsequent expression of the activation antigen CD69 was measured. This study was conducted by three-colour flow cytometry in order to obviate the less sensitive cytokine secretion assays that have yielded controversial results. The results indicate that HIV-infected patients on no therapy exhibit a pre-dominant Th2 response (IL-4 secretion), whereas those on the sterol/sterolin mixture exhibit a beneficial Th1 response (IFN-gamma). Surprisingly, in both patient groups, the expression of CD69 was abnormally low when compared to the uninfected volunteers, implying that chronic activation is already present in vivo. It appears that the detrimental Th2 driven response might be swung to the more beneficial Th1 response with the immune modulatory sterols/sterolin mixture. Clinical use of this mixture in HIV infection has yielded results which corroborate the above observations in that patients using the plant sterol/sterolin mixture maintain their CD4 cell numbers over an extended period of time in the absence of any anti-retroviral therapy.

Topics: Antigens, CD; Antigens, Differentiation, T-Lymphocyte; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP-Binding Cassette Transporters; CD4-Positive T-Lymphocytes; Cells, Cultured; Cytokines; Flow Cytometry; HIV Infections; HIV Seropositivity; Humans; Interferon-gamma; Interleukin-4; Lectins, C-Type; Lipoproteins; Phytosterols; Th1 Cells; Th2 Cells; Time Factors

Sterols and sterolins, also known as phytosterols, are fats present in all plants, including fruits and vegetables. Although they are chemically similar to the animal fat, cholesterol, they have been shown to exert significant unique biochemical effects in both animals and humans. Because they are bound to the fibers of the plant, they are difficult to absorb during the transit of digested food through the gut, particularly in individuals with impaired digestive function. For this reason, and because much of the modern diet is over-processed and low in fresh plant materials, sterols and sterolins appear in the serum and tissue of healthy humans at 800-1000 times lower concentrations than that of cholesterol. Beta-sitosterol (BSS) is the major phytosterol in higher plants along with its glycoside, beta-sitosterolin (BSSG). Animal studies have demonstrated BSS and BSSG possess anti-inflammatory, antipyretic, antineoplastic, and immune-modulating properties. In other in vitro, animal, and human studies, a proprietary BSS:BSSG mixture has shown promise in normalizing T-cell function, dampening overactive antibody responses, and normalizing DHEA:cortisol ratios. Research has shown plant oils contain the highest concentration of phytosterols, nuts and seeds contain moderate amounts, and fruits and vegetables generally contain the lowest phytosterol concentrations. Because only low levels of these substances are found in humans, increased dietary intake of unprocessed fruits and vegetables or supplementation with commercial phytosterols may be of benefit in re-establishing optimal immune parameters. Restoring balance to the immune system may be of therapeutic benefit in disease processes such as chronic viral infections, stress-induced immune suppression, tuberculosis, allergies, cancer, and rheumatoid arthritis and other autoimmune conditions.

Topics: Animals; Arthritis, Rheumatoid; Diabetes Mellitus; HIV Infections; Humans; Male; Phytosterols; Prostatic Hyperplasia; Tuberculosis, Pulmonary

Topics: Adjuvants, Immunologic; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP-Binding Cassette Transporters; CD4 Lymphocyte Count; HIV Infections; Humans; Lipoproteins; Phytosterols