scholarly journals REPLICATION OF HIV-1 SUBTYPE A6 IN THE PRESENCE OF HORMONES INCLUDED IN THE MODERN HORMONAL CONTRACEPTIVES

2019 ◽  
Vol 1 (1) ◽  
pp. 85-90
Author(s):  
M. N. Nosik ◽  
K. A. Ryzhov ◽  
A. V. Potapova
Keyword(s):  
Viral Replication ◽  
Mononuclear Cells ◽  
Virus Production ◽  
Antiretroviral Drugs ◽  
Hiv Treatment ◽  
Hormonal Contraceptives ◽  
Peripheral Blood Mononuclear ◽  
High Concentrations ◽  
Hiv 1

Aim. To study how female hormones included in oral contraceptives (β-estradiol and progesteron) affect HIV-1 replication and efficacy of antiviral drugs. Material and methods. Peripheral blood mononuclear cells (PBMC) and cell lines MT-4, Jurkat were infected with HIV-1 (subtype A6). Afterwards the cells were cultured for 6 days in the presence of β-estradiol/progesteron with or without the presence of antiretroviral drugs Lamivudin (3TC), Etravirin(ETR) and Indinavir (IDV), which are widely used for HIV treatment. Virus production was monitored by p24 levels in culture supernatants on day 6. The experemints were performed in eight repetitions. Results. There was a 1,3-1,8-fold increase of virus replication in the presence of high concentrations of both hormones (26,136 μg/ml). Incomplete suppression of viral replication was observed when infected cells were co-cultivated in the presence of hormones (26 μg, 136 μg) and antiretroviral drugs. The mean suppression rate of viral replication for β-estradiol was 77.3% and 69.8% for progesterone. However, in the absence of hormones the virus production was completely suppressed by those drugs. Conclusion. The high concentrations of steroid hormones induce HIV-1 replication and as a result reduce the efficacy of antiretroviral drugs NVP and IDV in vitro. Thus it is advisable for women at high risk of HIV infection to monitor hormone levels that change during the menstrual cycle and pregnancy before prescribing hormonal contraception.

scholarly journals Reciprocal Modulation of Antiretroviral Drug and Steroid Receptor Function In Vitro

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
Sigcinile Dlamini ◽  
Michael Kuipa ◽  
Kim Enfield ◽  
Salndave Skosana ◽  
John G. Woodland ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Line ◽  
Biological Effects ◽  
Steroid Receptor ◽  
Antiretroviral Drugs ◽  
Hormonal Contraceptives ◽  
Peripheral Blood Mononuclear ◽  
A Cell ◽  
Hiv 1

ABSTRACT Millions of women are exposed simultaneously to antiretroviral drugs (ARVs) and progestin-based hormonal contraceptives. Yet the reciprocal modulation by ARVs and progestins of their intracellular functions is relatively unexplored. We investigated the effects of tenofovir disoproxil fumarate (TDF) and dapivirine (DPV), alone and in the presence of select steroids and progestins, on cell viability, steroid-regulated immunomodulatory gene expression, activation of steroid receptors, and anti-HIV-1 activity in vitro. Both TDF and DPV modulated the transcriptional efficacy of a glucocorticoid agonist via the glucocorticoid receptor (GR) in the U2OS cell line. In TZM-bl cells, DPV induced the expression of the proinflammatory interleukin 8 (IL-8) gene while TDF significantly increased medroxyprogesterone acetate (MPA)-induced expression of the anti-inflammatory glucocorticoid-induced leucine zipper (GILZ) gene. However, peripheral blood mononuclear cell (PBMC) and ectocervical explant tissue viability and gene expression results, along with TZM-bl HIV-1 infection data, are reassuring and suggest that TDF and DPV, in combination with dexamethasone (DEX) or MPA, do not reciprocally modulate key biological effects in primary cells and tissue. We show for the first time that TDF induces progestogen-independent activation of the progesterone receptor (PR) in a cell line. The ability of TDF and DPV to influence GR and PR activity suggests that their use may be associated with steroid receptor-mediated off-target effects. This, together with cell line and individual donor gene expression responses in the primary models, raises concerns that reciprocal modulation may cause side effects in a cell- and donor-specific manner in vivo.

scholarly journals An Enhanced Emtricitabine-Loaded Long-Acting Nanoformulation for Prevention or Treatment of HIV Infection

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Subhra Mandal ◽  
Michael Belshan ◽  
Ashley Holec ◽  
You Zhou ◽  
Christopher J. Destache
Keyword(s):  
Hiv Infection ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Antiretroviral Drugs ◽  
Volume Distribution ◽  
Major Drawback ◽  
Peripheral Blood Mononuclear ◽  
Long Acting ◽  
Hiv 1

ABSTRACT Among various FDA-approved combination antiretroviral drugs (cARVs), emtricitabine (FTC) has been a very effective nucleoside reverse transcriptase inhibitor. Thus far, FTC is the only deoxycytidine nucleoside analog. However, a major drawback of FTC is its large volume distribution (averaging 1.4 liters/kg) and short plasma half-life (8 to 10 h), necessitating a high daily dosage. Thus, we propose an innovative fabrication method of loading FTC in poly(lactic-co-glycolic acid) polymeric nanoparticles (FTC-NPs), potentially overcoming these drawbacks. Our nanoformulation demonstrated enhanced FTC loading (size of <200 nm and surface charge of −23 mV) and no to low cytotoxicity with improved biocompatibility compared to those with FTC solution. An ex vivo endosomal release assay illustrated that NP entrapment prolongs FTC release over a month. Intracellular retention studies demonstrate sustained FTC retention over time, with approximately 8% (24 h) to 68% (96 h) release with a mean retention of ∼0.74 μg of FTC/105 cells after 4 days. An in vitro HIV-1 inhibition study demonstrated that FTC-NP treatment results in a 50% inhibitory concentration (IC50) ∼43 times lower in TZM-bl cells (0.00043 μg/ml) and ∼3.7 times lower (0.009 μg/ml) in peripheral blood mononuclear cells (PBMCs) than with FTC solution (TZM-bl cells, 0.01861, and PBMCs, 0.033 μg/ml). Further, on primary PBMCs, FTC-NPs also illustrate an HIV-1 infection blocking efficacy comparable to that of FTC solution. All the above-described studies substantiate that FTC nanoformulation prolongs intracellular FTC concentration and inhibition of HIV infection. Therefore, FTC-NPs potentially could be a long-acting, stable formulation to ensure once-biweekly dosing to prevent or treat HIV infection.

scholarly journals High Levels of TRIM5a Are Associated with Xenophagy in HIV-1-Infected Long-Term Nonprogressors

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1207
Author(s):  
Fabiola Ciccosanti ◽  
Marco Corazzari ◽  
Rita Casetti ◽  
Alessandra Amendola ◽  
Diletta Collalto ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Protective Role ◽  
Antiretroviral Drugs ◽  
Peripheral Blood Mononuclear ◽  
Successful Control ◽  
Special Subset ◽  
Hiv 1

Autophagy is a lysosomal-dependent degradative mechanism essential in maintaining cellular homeostasis, but it is also considered an ancient form of innate eukaryotic fighting against invading microorganisms. Mounting evidence has shown that HIV-1 is a critical target of autophagy that plays a role in HIV-1 replication and disease progression. In a special subset of HIV-1-infected patients that spontaneously and durably maintain extremely low viral replication, namely, long-term nonprogressors (LTNP), the resistance to HIV-1-induced pathogenesis is accompanied, in vivo, by a significant increase in the autophagic activity in peripheral blood mononuclear cells. Recently, a new player in the battle of autophagy against HIV-1 has been identified, namely, tripartite motif protein 5α (TRIM5α). In vitro data demonstrated that TRIM5α directly recognizes HIV-1 and targets it for autophagic destruction, thus protecting cells against HIV-1 infection. In this paper, we analyzed the involvement of this factor in the control of HIV-1 infection through autophagy, in vivo, in LTNP. The results obtained showed significantly higher levels of TRIM5α expression in cells from LTNP with respect to HIV-1-infected normal progressor patients. Interestingly, the colocalization of TRIM5α and HIV-1 proteins in autophagic vacuoles in LTNP cells suggested the participation of TRIM5α in the autophagy containment of HIV-1 in LTNP. Altogether, our results point to a protective role of TRIM5α in the successful control of the chronic viral infection in HIV-1-controllers through the autophagy mechanism. In our opinion, these findings could be relevant in fighting against HIV-1 disease, because autophagy inducers might be employed in combination with antiretroviral drugs.

scholarly journals Identification and Characterization of BMS-955176, a Second-Generation HIV-1 Maturation Inhibitor with Improved Potency, Antiviral Spectrum, and Gag Polymorphic Coverage

2016 ◽  
Vol 60 (7) ◽  
pp. 3956-3969 ◽  
Author(s):  
Beata Nowicka-Sans ◽  
Tricia Protack ◽  
Zeyu Lin ◽  
Zhufang Li ◽  
Sharon Zhang ◽  
...  
Keyword(s):  
Human Serum ◽  
Second Generation ◽  
Mononuclear Cells ◽  
Integrase Inhibitor ◽  
Wild Type Virus ◽  
Peripheral Blood Mononuclear ◽  
Subtype B ◽  
Maturation Inhibitor ◽  
Hiv 1

ABSTRACTBMS-955176 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor (MI). A first-generation MI, bevirimat, showed clinical efficacy in early-phase studies, but ∼50% of subjects had viruses with reduced susceptibility associated with naturally occurring polymorphisms in Gag near the site of MI action. MI potency was optimized using a panel of engineered reporter viruses containing site-directed polymorphic changes in Gag that reduce susceptibility to bevirimat (including V362I, V370A/M/Δ, and T371A/Δ), leading incrementally to the identification of BMS-955176. BMS-955176 exhibits potent activity (50% effective concentration [EC50], 3.9 ± 3.4 nM [mean ± standard deviation]) toward a library (n= 87) ofgag/prrecombinant viruses representing 96.5% of subtype B polymorphic Gag diversity near the CA/SP1 cleavage site. BMS-955176 exhibited a median EC50of 21 nM toward a library of subtype B clinical isolates assayed in peripheral blood mononuclear cells (PBMCs). Potent activity was maintained against a panel of reverse transcriptase, protease, and integrase inhibitor-resistant viruses, with EC50s similar to those for the wild-type virus. A 5.4-fold reduction in EC50occurred in the presence of 40% human serum plus 27 mg/ml of human serum albumin (HSA), which corresponded well to anin vitromeasurement of 86% human serum binding. Time-of-addition and pseudotype reporter virus studies confirm a mechanism of action for the compound that occurs late in the virus replication cycle. BMS-955176 inhibits HIV-1 protease cleavage at the CA/SP1 junction within Gag in virus-like particles (VLPs) and in HIV-1-infected cells, and it binds reversibly and with high affinity to assembled Gag in purified HIV-1 VLPs. Finally,in vitrocombination studies showed no antagonistic interactions with representative antiretrovirals (ARVs) of other mechanistic classes. In conclusion, BMS-955176 is a second-generation MI with potentin vitroanti-HIV-1 activity and a greatly improved preclinical profile compared to that of bevirimat.

scholarly journals Design and Profiling of GS-9148, a Novel Nucleotide Analog Active against Nucleoside-Resistant Variants of Human Immunodeficiency Virus Type 1, and Its Orally Bioavailable Phosphonoamidate Prodrug, GS-9131

2007 ◽  
Vol 52 (2) ◽  
pp. 655-665 ◽  
Author(s):  
Tomas Cihlar ◽  
Adrian S. Ray ◽  
Constantine G. Boojamra ◽  
Lijun Zhang ◽  
Hon Hui ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mononuclear Cells ◽  
Biological Properties ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid] is a novel ribose-modified human immunodeficiency virus type 1 (HIV-1) nucleotide reverse transcriptase (RT) inhibitor (NRTI) selected from a series of nucleoside phosphonate analogs for its favorable in vitro biological properties including (i) a low potential for mitochondrial toxicity, (ii) a minimal cytotoxicity in renal proximal tubule cells and other cell types, (iii) synergy in combination with other antiretrovirals, and (iv) a unique resistance profile against multiple NRTI-resistant HIV-1 strains. Notably, antiviral resistance analysis indicated that neither the K65R, L74V, or M184V RT mutation nor their combinations had any effect on the antiretroviral activity of GS-9148. Viruses carrying four or more thymidine analog mutations showed a substantially smaller change in GS-9148 activity relative to that observed with most marketed NRTIs. GS-9131, an ethylalaninyl phosphonoamidate prodrug designed to maximize the intracellular delivery of GS-9148, is a potent inhibitor of multiple subtypes of HIV-1 clinical isolates, with a mean 50% effective concentration of 37 nM. Inside cells, GS-9131 is readily hydrolyzed to GS-9148, which is further phosphorylated to its active diphosphate metabolite (A. S. Ray, J. E. Vela, C. G. Boojamra, L. Zhang, H. Hui, C. Callebaut, K. Stray, K.-Y. Lin, Y. Gao, R. L. Mackman, and T. Cihlar, Antimicrob. Agents Chemother. 52:648-654, 2008). GS-9148 diphosphate acts as a competitive inhibitor of RT with respect to dATP (Ki = 0.8 μM) and exhibits low inhibitory potency against host polymerases including DNA polymerase γ. Oral administration of GS-9131 to beagle dogs at a dose of 3 mg/kg of body weight resulted in high and persistent levels of GS-9148 diphosphate in peripheral blood mononuclear cells (with a maximum intracellular concentration of >9 μM and a half-life of >24 h). This favorable preclinical profile makes GS-9131 an attractive clinical development candidate for the treatment of patients infected with NRTI-resistant HIV.

scholarly journals F18, a Novel Small-Molecule Nonnucleoside Reverse Transcriptase Inhibitor, Inhibits HIV-1 Replication Using Distinct Binding Motifs as Demonstrated by Resistance Selection and Docking Analysis

2011 ◽  
Vol 56 (1) ◽  
pp. 341-351 ◽  
Author(s):  
Xiaofan Lu ◽  
Li Liu ◽  
Xu Zhang ◽  
Terrence Chi Kong Lau ◽  
Stephen Kwok Wing Tsui ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Small Molecule ◽  
Mononuclear Cells ◽  
Binding Motif ◽  
Drug Resistant ◽  
Peripheral Blood Mononuclear ◽  
Docking Analysis ◽  
Hiv 1 ◽  
Calanolide A

ABSTRACTNonnucleoside reverse transcriptase inhibitors (NNRTIs) are one of the key components of antiretroviral therapy drug regimen against human immunodeficiency virus type 1 (HIV-1) replication. We previously described a newly synthesized small molecule, 10-chloromethyl-11-demethyl-12-oxo-calanolide A (F18), a (+)-calanolide A analog, as a novel anti-HIV-1 NNRTI (H. Xue et al., J. Med. Chem. 53:1397–1401, 2010). Here, we further investigated its antiviral range, drug resistance profile, and underlying mechanism of action. F18 consistently displayed potent activity against primary HIV-1 isolates, including various subtypes of group M, circulating recombinant form (CRF) 01_AE, and laboratory-adapted drug-resistant viruses. Moreover, F18 displayed distinct profiles against 17 NNRTI-resistant pseudoviruses, with an excellent potency especially against one of the most prevalent strains with the Y181C mutation (50% effective concentration, 1.0 nM), which was in stark contrast to the extensively used NNRTIs nevirapine and efavirenz. Moreover, we induced F18-resistant viruses byin vitroserial passages and found that the mutation L100I appeared to be the dominant contributor to F18 resistance, further suggesting a binding motif different from that of nevirapine and efavirenz. F18 was nonantagonistic when used in combination with other antiretrovirals against both wild-type and drug-resistant viruses in infected peripheral blood mononuclear cells. Interestingly, F18 displayed a highly synergistic antiviral effect with nevirapine against nevirapine-resistant virus (Y181C). Furthermore,in silicodocking analysis suggested that F18 may bind to the HIV-1 reverse transcriptase differently from other NNRTIs. This study presents F18 as a new potential drug for clinical use and also presents a new mechanism-based design for future NNRTI.

scholarly journals Anti-phospholipid human monoclonal antibodies inhibit CCR5-tropic HIV-1 and induce β-chemokines

2010 ◽  
Vol 207 (4) ◽  
pp. 763-776 ◽  
Author(s):  
M. Anthony Moody ◽  
Hua-Xin Liao ◽  
S. Munir Alam ◽  
Richard M. Scearce ◽  
M. Kelly Plonk ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Virus Entry ◽  
Human Monoclonal Antibodies ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Hiv 1

Traditional antibody-mediated neutralization of HIV-1 infection is thought to result from the binding of antibodies to virions, thus preventing virus entry. However, antibodies that broadly neutralize HIV-1 are rare and are not induced by current vaccines. We report that four human anti-phospholipid monoclonal antibodies (mAbs) (PGN632, P1, IS4, and CL1) inhibit HIV-1 CCR5-tropic (R5) primary isolate infection of peripheral blood mononuclear cells (PBMCs) with 80% inhibitory concentrations of &lt;0.02 to ∼10 µg/ml. Anti-phospholipid mAbs inhibited PBMC HIV-1 infection in vitro by mechanisms involving binding to monocytes and triggering the release of MIP-1α and MIP-1β. The release of these β-chemokines explains both the specificity for R5 HIV-1 and the activity of these mAbs in PBMC cultures containing both primary lymphocytes and monocytes.

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