scholarly journals Trimeric heptad repeat synthetic peptides HR1 and HR2 efficiently inhibit HIV-1 entry

2019 ◽  
Vol 39 (9) ◽  
Author(s):  
Olfa Mzoughi ◽  
Meritxell Teixido ◽  
Rémi Planès ◽  
Manutea Serrero ◽  
Ibtissem Hamimed ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Heptad Repeat ◽  
Fusion Activity ◽  
Helical Structures ◽  
Fusion Inhibitors ◽  
Immunodeficiency Virus ◽  
Antiviral Activities ◽  
Physical Interactions ◽  
Kinetics Of ◽  
Hiv 1

Abstract The trimeric heptad repeat domains HR1 and HR2 of the human immunodeficiency virus 1 (HIV-1) gp41 play a key role in HIV-1-entry by membrane fusion. To develop efficient inhibitors against this step, the corresponding trimeric-N36 and C34 peptides were designed and synthesized. Analysis by circular dichroism of monomeric and trimeric N36 and C34 peptides showed their capacities to adopt α-helical structures and to establish physical interactions. At the virological level, while trimeric-C34 conserves the same high anti-fusion activity as monomeric-C34, trimerization of N36-peptide induced a significant increase, reaching 500-times higher in anti-fusion activity, against R5-tropic virus-mediated fusion. This result was associated with increased stability of the N36 trimer peptide with respect to the monomeric form, as demonstrated by the comparative kinetics of their antiviral activities during 6-day incubation in a physiological medium. Collectively, our findings demonstrate that while the trimerization of C34 peptide had no beneficial effect on its stability and antiviral activity, the trimerization of N36 peptide strengthened both stability and antiviral activity. This approach, promotes trimers as new promising HIV-1 inhibitors and point to future development aimed toward innovative peptide fusion inhibitors, microbicides or as immunogens.

scholarly journals Kinetics of Antiviral Activity and Intracellular Pharmacokinetics of Human Immunodeficiency Virus Type 1 Protease Inhibitors in Tissue Culture

1999 ◽  
Vol 43 (11) ◽  
pp. 2629-2634 ◽  
Author(s):  
Michelina Nascimbeni ◽  
Claire Lamotte ◽  
Gilles Peytavin ◽  
Robert Farinotti ◽  
François Clavel
Keyword(s):  
Human Immunodeficiency Virus ◽  
Tissue Culture ◽  
Antiviral Activity ◽  
Protease Inhibitors ◽  
Hela Cells ◽  
Immunodeficiency Virus ◽  
Antiviral Activities ◽  
Kinetics Of ◽  
Hiv 1

ABSTRACT We have examined the kinetics of the inhibition of human immunodeficiency virus type 1 (HIV-1) particle infectivity by protease inhibitors (PIs) in cell culture, using either transfected HeLa cells or infected peripheral blood mononuclear cells (PBMCs) as producers of infectious virions. Both the kinetics of the initiation of antiviral activity after addition of the PIs to these cultures and the kinetics of restoration of virion infectivity after removal of the PIs from the treated cultures were examined. We found that the kinetics of initiation of particle infectivity inhibition produced by a high extracellular concentration (5 μM) of the inhibitors were similar for all five inhibitors tested: loss of particle infectivity was perceptible as early as 1 h after the initiation of PI treatment and increased gradually thereafter. By contrast, the durability of this antiviral effect following removal of the drug from the culture varied dramatically according to the drug studied. In transfected HeLa cells, saquinavir and nelfinavir exerted the most prolonged inhibition, with the half-lives of their antiviral activities being greater than 24 h, while ritonavir exerted an intermediate length of inhibition (18 h) and indinavir and amprenavir exerted a reproducibly shorter length of inhibition (5 h). For all five tested PIs, these kinetics were significantly faster in PBMCs than in HeLa cells. The striking differences in antiviral kinetics observed among the different PIs appear mostly due to differences in their intracellular concentrations and/or rates of cellular clearance. Our observations, although limited to tissue culture conditions, may help delineate the cellular parameters of the antiviral activities of HIV-1 PIs and further optimize the efficiencies of these antiretrovirals in vivo.

scholarly journals Therapeutic Efficacy and Resistance Selection of a Lipopeptide Fusion Inhibitor in Simian Immunodeficiency Virus-Infected Rhesus Macaques

2020 ◽  
Vol 94 (15) ◽  
Author(s):  
Danwei Yu ◽  
Jing Xue ◽  
Huamian Wei ◽  
Zhe Cong ◽  
Ting Chen ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Therapeutic Efficacy ◽  
Rhesus Macaques ◽  
Heptad Repeat ◽  
Fusion Inhibitor ◽  
Resistance Mutations ◽  
Fusion Inhibitors ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We recently reported a group of lipopeptide-based membrane fusion inhibitors with potent antiviral activities against human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV). In this study, the in vivo therapeutic efficacy of such a lipopeptide, LP-52, was evaluated in rhesus macaques chronically infected with pathogenic SIVmac239. In a pilot study with one monkey, monotherapy with low-dose LP-52 rapidly reduced the plasma viral loads to below the limit of detection and maintained viral suppression during three rounds of structurally interrupted treatment. The therapeutic efficacy of LP-52 was further verified in four infected monkeys; however, three out of the monkeys had viral rebounds under the LP-52 therapy. We next focused on characterizing SIV mutants responsible for the in vivo resistance. Sequence analyses revealed that a V562A or V562M mutation in the N-terminal heptad repeat (NHR) and a E657G mutation in the C-terminal heptad repeat (CHR) of SIV gp41 conferred high resistance to LP-52 and cross-resistance to the peptide drug T20 and two newly designed lipopeptides (LP-80 and LP-83). Moreover, we showed that the resistance mutations greatly reduced the stability of diverse fusion inhibitors with the NHR site, and V562A or V562M in combination with E657G could significantly impair the functionality of viral envelopes (Envs) to mediate SIVmac239 infection and decrease the thermostability of viral six-helical bundle (6-HB) core structure. In conclusion, the present data have not only facilitated the development of novel anti-HIV drugs that target the membrane fusion step, but also help our understanding of the mechanism of viral evolution to develop drug resistance. IMPORTANCE The anti-HIV peptide drug T20 (enfuvirtide) is the only membrane fusion inhibitor available for treatment of viral infection; however, it exhibits relatively weak antiviral activity, short half-life, and a low genetic barrier to inducing drug resistance. Design of lipopeptide-based fusion inhibitors with extremely potent and broad antiviral activities against divergent HIV-1, HIV-2, and SIV isolates have provided drug candidates for clinical development. Here, we have verified a high therapeutic efficacy for the lipopeptide LP-52 in SIVmac239-infected rhesus monkeys. The resistance mutations selected in vivo have also been characterized, providing insights into the mechanism of action of newly designed fusion inhibitors with a membrane-anchoring property. For the first time, the data show that HIV-1 and SIV can share a similar genetic pathway to develop resistance, and that a lipopeptide fusion inhibitor could have a same resistance profile as its template peptide.

scholarly journals Identification of a Critical Motif for the Human Immunodeficiency Virus Type 1 (HIV-1) gp41 Core Structure: Implications for Designing Novel Anti-HIV Fusion Inhibitors

2008 ◽  
Vol 82 (13) ◽  
pp. 6349-6358 ◽  
Author(s):  
Yuxian He ◽  
Jianwei Cheng ◽  
Jingjing Li ◽  
Zhi Qi ◽  
Hong Lu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Core Structure ◽  
Heptad Repeat ◽  
Fusion Inhibitors ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) entry into the host cell involves a cascade of events and currently represents one of most attractive targets in the search for new antiviral drugs. The fusion-active gp41 core structure is a stable six-helix bundle (6-HB) folded by its trimeric N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR). Peptides derived from the CHR region of HIV-1 gp41 are potent fusion inhibitors that target the NHR to block viral and cellular membrane fusion in a dominant negative fashion. However, all CHR peptides reported to date are derived primarily from residues 628 to 673 of gp41; little attention has been paid to the upstream sequence of the pocket binding domain (PBD) in the CHR. Here, we have identified a motif (621QIWNNMT627) located at the upstream region of the gp41 CHR, immediately adjacent to the PBD (628WMEWEREI635). Biophysical characterization demonstrated that this motif is critical for the stabilization of the gp41 6-HB core. The peptide CP621-652, containing the 621QIWNNMT627 motif, was able to interact with T21, a counterpart peptide derived from the NHR, to form a typical 6-HB structure with a high thermostability (thermal unfolding transition [T m ] value of 82°C). In contrast, the 6-HB formed by the peptides N36 and C34, which has been considered to be a core structure of the fusion-active gp41, had a T m of 64°C. Different from T-20 (brand name Fuseon), which is the first and only HIV-1 fusion inhibitor approved for clinical use, CP621-652 could efficiently block 6-HB formation in a dose-dependent manner. Significantly, CP621-652 had potent inhibitory activity against HIV-1-mediated cell-cell fusion and infection, especially against T-20- and C34-resistant virus. Therefore, our works provide important information for understanding the core structure of the fusion-active gp41 and for designing novel anti-HIV peptides.

scholarly journals Design and Characterization of Cholesterylated Peptide HIV-1/2 Fusion Inhibitors with Extremely Potent and Long-Lasting Antiviral Activity

2019 ◽  
Vol 93 (11) ◽  
Author(s):  
Yuanmei Zhu ◽  
Huihui Chong ◽  
Danwei Yu ◽  
Yan Guo ◽  
Yusen Zhou ◽  
...  
Keyword(s):  
Human Serum Albumin ◽  
Antiviral Activity ◽  
Serum Albumin ◽  
Human Serum ◽  
Rhesus Monkeys ◽  
Fusion Inhibitors ◽  
Immunodeficiency Virus ◽  
Low Cytotoxicity ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT HIV infection requires lifelong treatment with multiple antiretroviral drugs in a combination, which ultimately causes cumulative toxicities and drug resistance, thus necessitating the development of novel antiviral agents. We recently found that enfuvirtide (T-20)-based lipopeptides conjugated with fatty acids have dramatically increased in vitro and in vivo anti-HIV activities. Herein, a group of cholesterol-modified fusion inhibitors were characterized with significant findings. First, novel cholesterylated inhibitors, such as LP-83 and LP-86, showed the most potent activity in inhibiting divergent human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV). Second, the cholesterylated inhibitors were highly active to inhibit T-20-resistant mutants that still conferred high resistance to the fatty acid derivatives. Third, the cholesterylated inhibitors had extremely potent activity to block HIV envelope (Env)-mediated cell-cell fusion, especially a truncated minimum lipopeptide (LP-95), showing a greatly increased potency relative to its inhibition on virus infection. Fourth, the cholesterylated inhibitors efficiently bound to both the cellular and viral membranes to exert their antiviral activities. Fifth, the cholesterylated inhibitors displayed low cytotoxicity and binding capacity with human serum albumin. Sixth, we further demonstrated that LP-83 exhibited extremely potent and long-lasting anti-HIV activity in rhesus monkeys. Taken together, the present results help our understanding on the mechanism of action of lipopeptide-based viral fusion inhibitors and facilitate the development of novel anti-HIV drugs. IMPORTANCE The peptide drug enfuvirtide (T-20) remains the only membrane fusion inhibitor available for treatment of viral infection, which is used in combination therapy of HIV-1 infection; however, it exhibits relatively low antiviral activity and a genetic barrier to inducing resistance, calling for the continuous development for novel anti-HIV agents. In this study, we report cholesterylated fusion inhibitors showing the most potent and broad anti-HIV activities to date. The new inhibitors have been comprehensively characterized for their modes of action and druggability, including small size, low cytotoxicity, binding ability to human serum albumin (HSA), and, especially, extremely potent and long-lasting antiviral activity in rhesus monkeys. Therefore, the present studies have provided new drug candidates for clinical development, which can also be used as tools to probe the mechanisms of viral entry and inhibition.

scholarly journals Circulating Metabolites of the Human Immunodeficiency Virus Protease Inhibitor Nelfinavir in Humans: Structural Identification, Levels in Plasma, and Antiviral Activities

2001 ◽  
Vol 45 (4) ◽  
pp. 1086-1093 ◽  
Author(s):  
Kanyin E. Zhang ◽  
Ellen Wu ◽  
Amy K. Patick ◽  
Bradley Kerr ◽  
Mark Zorbas ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Protease Inhibitor ◽  
Active Metabolite ◽  
Parent Drug ◽  
Hiv Reverse Transcriptase ◽  
Immunodeficiency Virus ◽  
Antiviral Activities ◽  
Hiv 1

ABSTRACT Nelfinavir mesylate (Viracept, formally AG1343) is a potent and orally bioavailable human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor (K i = 2 nM) and is being widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection. The current studies evaluated the presence of metabolites circulating in plasma following the oral administration of nelfinavir to healthy volunteers and HIV-infected patients, as well as the levels in plasma and antiviral activities of these metabolites. The results showed that the parent drug was the major circulating chemical species, followed in decreasing abundance by its hydroxy-t-butylamide metabolite (M8) and 3′-methoxy-4′-hydroxynelfinavir (M1). Antiviral assays with HIV-1 strain RF-infected CEM-SS cells showed that the 50% effective concentrations (EC50) of nelfinavir, M8, and M1 were 30, 34, and 151 nM, respectively, and that the corresponding EC50 against another HIV-1 strain, IIIB, in MT-2 cells were 60, 86, and 653 nM. Therefore, apparently similar in vitro antiviral activities were demonstrated for nelfinavir and M8, whereas an approximately 5- to 11-fold-lower level of antiviral activity was observed for M1. The active metabolite, M8, showed a degree of binding to human plasma proteins similar to that of nelfinavir (ca. 98%). Concentrations in plasma of nelfinavir and its metabolites in 10 HIV-positive patients receiving nelfinavir therapy (750 mg three times per day) were determined by a liquid chromatography tandem mass spectrometry assay. At steady state (day 28), the mean plasma nelfinavir concentrations ranged from 1.73 to 4.96 μM and the M8 concentrations ranged from 0.55 to 1.96 μM, whereas the M1 concentrations were low and ranged from 0.09 to 0.19 μM. In conclusion, the findings from the current studies suggest that, in humans, nelfinavir forms an active metabolite circulating at appreciable levels in plasma. The active metabolite M8 may account for some of the antiviral activity associated with nelfinavir in the treatment of HIV disease.

scholarly journals The Heptad Repeat 2 Domain Is a Major Determinant for Enhanced Human Immunodeficiency Virus Type 1 (HIV-1) Fusion and Pathogenicity of a Highly Pathogenic HIV-1 Env

2009 ◽  
Vol 83 (22) ◽  
pp. 11715-11725 ◽  
Author(s):  
Vijay Sivaraman ◽  
Liguo Zhang ◽  
Eric G. Meissner ◽  
Jerry L. Jeffrey ◽  
Lishan Su
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Cd4 T Cell ◽  
Heptad Repeat ◽  
Fusion Activity ◽  
Highly Pathogenic ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-mediated depletion of CD4+ lymphocytes in an infected individual is the hallmark of progression to AIDS. However, the mechanism for this depletion remains unclear. To identify mechanisms of HIV-1-mediated CD4 T-cell death, two similar viral isolates obtained from a rapid progressor patient with significantly different pathogenic phenotypes were studied. One isolate (R3A) demonstrates enhanced pathogenesis in both in vivo models and relevant ex vivo lymphoid organ model systems compared to another isolate, R3B. The pathogenic determinants were previously mapped to the V5-gp41 envelope region, correlating functionally with enhanced fusion activity and elevated CXCR4 binding affinity. To further elucidate specific differences between R3A and R3B within the V5-gp41 domains that enhance CD4 depletion, R3A-R3B chimeras to study the V5-gp41 region were developed. Our data demonstrate that six residues in the ectodomain of R3A provide the major determinant for both enhanced Env-cell fusion and pathogenicity. Furthermore, three amino acid differences in the heptad repeat 2 (HR-2) domain of R3A determined its fusion activity and significantly elevated its pathogenic activity. The chimeric viruses with enhanced fusion activity, but not elevated CXCR4 affinity, correlated with high pathogenicity in the thymus organ. We conclude that the functional domain of a highly pathogenic HIV-1 Env is determined by mutations in the HR-2 region that contribute to enhanced fusion and CD4 T-cell depletion.

scholarly journals Conserved Salt Bridge between the N- and C-Terminal Heptad Repeat Regions of the Human Immunodeficiency Virus Type 1 gp41 Core Structure Is Critical for Virus Entry and Inhibition

2008 ◽  
Vol 82 (22) ◽  
pp. 11129-11139 ◽  
Author(s):  
Yuxian He ◽  
Shuwen Liu ◽  
Jingjing Li ◽  
Hong Lu ◽  
Zhi Qi ◽  
...  
Keyword(s):  
Viral Entry ◽  
Salt Bridge ◽  
Core Structure ◽  
Heptad Repeat ◽  
Helix Bundle ◽  
Fusion Inhibitors ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Positively Charged

ABSTRACT The fusogenic human immunodeficiency virus type 1 (HIV-1) gp41 core structure is a stable six-helix bundle formed by its N- and C-terminal heptad repeat sequences. Notably, the negatively charged residue Asp632 located at the pocket-binding motif in the C-terminal heptad repeat interacts with the positively charged residue Lys574 in the pocket formation region of the N-terminal heptad repeat to form a salt bridge. We previously demonstrated that the residue Lys574 plays an essential role in six-helix bundle formation and virus infectivity and is a key determinant of the target for anti-HIV fusion inhibitors. In this study, the functionality of residue Asp632 has been specifically characterized by mutational analysis and biophysical approaches. We show that Asp632 substitutions with positively charged residues (D632K and D632R) or a hydrophobic residue (D632V) could completely abolish Env-mediated viral entry, while a protein with a conserved substitution (D632E) retained its activity. Similar to the Lys574 mutations, nonconserved substitutions of Asp632 also severely impaired the α-helicity, stability, and conformation of six-helix bundles as shown by N36 and C34 peptides as a model system. Furthermore, nonconserved substitutions of Asp632 significantly reduced the potency of C34 to sequestrate six-helix bundle formation and to inhibit HIV-1-mediated cell-cell fusion and infection, suggesting its importance for designing antiviral fusion inhibitors. Taken together, these data suggest that the salt bridge between the N- and C-terminal heptad repeat regions of the fusion-active HIV-1 gp41 core structure is critical for viral entry and inhibition.

scholarly journals Limonoids Containing a C1–O–C29 Moiety: Isolation, Structural Modification, and Antiviral Activity

Marine Drugs ◽  
2018 ◽  
Vol 16 (11) ◽  
pp. 434 ◽  
Author(s):  
Jing-Ling Ren ◽  
Xiao-Peng Zou ◽  
Wan-Shan Li ◽  
Li Shen ◽  
Jun Wu
Keyword(s):  
Antiviral Activity ◽  
Inhibitory Activity ◽  
Influenza A ◽  
Structural Modification ◽  
X Ray Diffraction ◽  
Ic50 Value ◽  
Immunodeficiency Virus ◽  
Antiviral Activities ◽  
Hiv 1

Five new limonoids named thaigranatins A–E (1–5), containing a C1–O–C29 moiety, were isolated from seeds of the Thai Xylocarpus granatum, collected at the mangrove swamp of Trang Province, together with the known limonoid, granatumin L (6). The structures of these compounds were established by HR-ESIMS and extensive NMR spectroscopic data. The absolute configuration of 1 was unequivocally determined by single-crystal X-ray diffraction analysis, conducted with Cu Kα radiation; whereas that of 2 or 6 was established to be the same as that of 1 by the similarity of their electronic circular dichroism (ECD) spectra. In view of the marked antiviral activity of 6, its structure was modified via hydrolysis with alkaline KOH, esterification with diazomethane and various organic acids, and oximization with hydroxyamine. Finally, 18 derivatives, viz. 7–10, 8a–8i, 9a–9b, and 10a–10c, were obtained. In vitro antiviral activities of these derivatives against human immunodeficiency virus 1 (HIV-1) and influenza A virus (IAV) were evaluated. Most notably, 8i exhibited marked inhibitory activity against HIV-1 with an IC50 value of 15.98 ± 6.87 μM and a CC50 value greater than 100.0 μM; whereas 10b showed significant inhibitory activity against IAV with an IC50 value of 14.02 ± 3.54 μM and a CC50 value greater than 100.0 μM.

scholarly journals Creating an Artificial Tail Anchor as a Novel Strategy To Enhance the Potency of Peptide-Based HIV Fusion Inhibitors

2016 ◽  
Vol 91 (1) ◽  
Author(s):  
Shan Su ◽  
Yun Zhu ◽  
Sheng Ye ◽  
Qianqian Qi ◽  
Shuai Xia ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Target ◽  
Heptad Repeat ◽  
Enveloped Viruses ◽  
Fusion Inhibitors ◽  
Simple Strategy ◽  
C Terminus ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT 20 (enfuvirtide) and other peptides derived from the human immunodeficiency virus type 1 (HIV-1) gp41 C-terminal heptad repeat (CHR) region inhibit HIV fusion by binding to the hydrophobic grooves on the N-terminal heptad repeat (NHR) trimer and blocking six-helix-bundle (6-HB) formation. Several strategies focusing on the binding grooves of the NHR trimer have been adopted to increase the antiviral activity of the CHR peptides. Here, we developed a novel and simple strategy to greatly enhance the potency of the existing peptide-based HIV fusion inhibitors. First, we identified a shallow pocket adjacent to the groove in the N-terminal region of NHR trimer as a new drug target, and then we designed several short artificial peptides to fit this target. After the addition of IDL (Ile-Asp-Leu) to the C terminus of CHR peptide WQ or MT-WQ, the conjugated peptides, WQ-IDL and MT-WQ-IDL, showed much more potent activities than WQ and T20, respectively, in inhibiting HIV-1 IIIB infection. WQ-IDL and MT-WQ-IDL were also more effective than WQ in blocking HIV-1 Env-mediated membrane fusion and had higher levels of binding affinity with NHR peptide N46. We solved the crystal structure of the 6-HB formed by MT-WQ-IDL and N46 and found that, besides the N-terminal MT hook tail, the IDL tail anchor of MT-WQ-IDL also binds with the shallow hydrophobic pocket outside the groove of the NHR trimer, resulting in enhanced inhibition of HIV-1 fusion with the target cell. It is expected that this novel approach can be widely used to improve the potency of peptidic fusion inhibitors against other enveloped viruses with class I fusion proteins. IMPORTANCE The hydrophobic groove of the human immunodeficiency virus type 1 (HIV-1) gp41 NHR trimer has been known as the classic drug target to develop fusion inhibitors derived from the gp41 CHR. Here, we developed a novel and simple strategy to improve the existing peptide-based HIV fusion inhibitors. We identified a shallow pocket adjacent to the groove in the NHR trimer and added a short artificial peptide consisting of three amino acids (IDL) to the C terminus of a fusion inhibitor to fit this new target. The inhibition activity of this new conjugated peptide was significantly enhanced, by 77-fold, making it much more potent than T20 (enfuvirtide) and suggesting that the IDL tail can be adopted for optimizing existing HIV-1 CHR peptide fusion inhibitors. This new approach of identifying a potential binding pocket outside the traditional target and creating an artificial tail anchor can be widely applied to design novel fusion inhibitors against other class I enveloped viruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV).

scholarly journals Kinetics of Antiviral Activity by Human Immunodeficiency Virus Type 1-Specific Cytotoxic T Lymphocytes (CTL) and Rapid Selection of CTL Escape Virus In Vitro

1998 ◽  
Vol 72 (8) ◽  
pp. 6851-6857 ◽  
Author(s):  
C. A. Van Baalen ◽  
M. Schutten ◽  
R. C. Huisman ◽  
P. H. M. Boers ◽  
R. A. Gruters ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Virus Production ◽  
Virus Release ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Kinetics Of ◽  
Hiv 1 ◽  
Selection Of

ABSTRACT The antiviral activity of a CD8+ cytotoxic T-lymphocyte (CTL) clone (TCC108) directed against a newly identified HLA-B14-restricted epitope, human immunodeficiency virus type 1 (HIV-1) Rev(67-75) SAEPVPLQL, was analyzed with respect to its kinetics of target cell lysis and inhibition of HIV-1 production. Addition of TCC108 cells or CD8+ reverse transcriptase-specific CTLs to HLA-matched CD4+ T cells at different times after infection with HIV-1 IIIB showed that infected cells became susceptible to CTL-mediated lysis before peak virus production but after the onset of progeny virus release. When either of these CTLs were added to part of the infected cells immediately after infection, p55 expression and virus production were significantly suppressed. These data support a model in which CTLs, apart from exerting cytolytic activity which may prevent continued virus release, can interfere with viral protein expression during the eclipse phase via noncytolytic mechanisms. TCC108-mediated inhibition of virus replication in peripheral blood mononuclear cells caused rapid selection of a virus with a mutation (69E→K) in the Rev(67-75) CTL epitope which abolished recognition by TCC108 cells. Taken together, these data suggest that both cytolytic and noncytolytic antiviral mechanisms of CTLs can be specifically targeted to HIV-1-infected cells.

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