scholarly journals A Novel CXCR4 Targeting Protein SDF-1/54 as an HIV-1 Entry Inhibitor

Viruses ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 874 ◽  
Author(s):  
Suiyi Tan ◽  
Wenjuan Li ◽  
Zhaofeng Li ◽  
Yujing Li ◽  
Jiangyan Luo ◽  
...  
Keyword(s):  
Seminal Fluid ◽  
Therapeutic Potential ◽  
Infectious Clone ◽  
Antiretroviral Drugs ◽  
Entry Inhibitor ◽  
Target Cells ◽  
Vaginal Fluid ◽  
Functional Region ◽  
Anti Hiv ◽  
Hiv 1

CXC chemokine receptor 4 (CXCR4) is a co-receptor for HIV-1 entry into target cells. Its natural ligand, the chemokine SDF-1, inhibits viral entry mediated by this receptor. However, the broad expression pattern of CXCR4 and its critical roles in various physiological and pathological processes indicate that the direct application of SDF-1 as an entry inhibitor might have severe consequences. Previously, we constructed an effective SDF-1 mutant, SDF-1/54, by deleting the α-helix of the C-terminal functional region of SDF-1. Of note, SDF-1/54 shows remarkable decreased chemotoxic ability, but maintains a similar binding affinity to CXCR4, suggesting SDF-1/54 might better serve as a CXCR4 inhibitor. Here, we found that SDF-1/54 exhibited potent antiviral activity against various X4 HIV-1 strains, including the infectious clone HIV-1 NL4-3, laboratory-adapted strain HIV-1 IIIB, clinical isolates and even drug-resistant strains. By using time-of-addition assay, non-infectious and infectious cell–cell fusion assay and CXCR4 internalization assay, we demonstrated SDF-1/54 is an HIV-1 entry inhibitor. A combination of SDF-1/54 with several antiretroviral drugs exhibited potent synergistic anti-HIV-1 activity. Moreover, SDF-1/54 was stable and its anti-HIV-1 activity was not significantly affected by the presence of seminal fluid, vaginal fluid simulant and human serum albumin. SDF-1/54 showed limited in vitro cytotoxicity to lymphocytes and vaginal epithelial cells. Based on these findings, SDF-1/54 could have a therapeutic potential as an HIV-1 entry inhibitor.

scholarly journals Natural Products with Inhibitory Activity against Human Immunodeficiency Virus Type 1

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Maria S. Serna-Arbeláez ◽  
Laura Florez-Sampedro ◽  
Lina P. Orozco ◽  
Katherin Ramírez ◽  
Elkin Galeano ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Natural Products ◽  
Therapeutic Potential ◽  
Low Cost ◽  
Antiviral Agent ◽  
Complementary Therapy ◽  
Antiretroviral Drugs ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

Infections caused by human immunodeficiency virus (HIV) are considered one of the main public health problems worldwide. Antiretroviral therapy (ART) is the current modality of treatment for HIV-1 infection. It comprises the combined use of several drugs and can decrease the viral load and increase the CD4+ T cell count in patients with HIV-1 infection, thereby proving to be an effective modality. This therapy significantly decreases the rate of morbidity and mortality owing to acquired immunodeficiency syndrome (AIDS) and prolongs and improves the quality of life of infected patients. However, nonadherence to ART may increase viral resistance to antiretroviral drugs and transmission of drug-resistant strains of HIV. Therefore, it is necessary to continue research for compounds with anti-HIV-1 activity, exhibiting a potential for the development of an alternative or complementary therapy to ART with low cost and fewer side effects. Natural products and their derivatives represent an excellent option owing to their therapeutic potential against HIV. Currently, the derivatives of natural products available as anti-HIV-1 agents include zidovudine, an arabinonucleoside derivative of the Caribbean marine sponge (Tectitethya crypta), which inhibits the reverse transcriptase of the virus. This was the first antiviral agent approved for treatment of HIV infection. Additionally, bevirimat (isolated from Syzygium claviflorum) and calanolide A (isolated from Calophyllum sp.) are inhibitors of viral maturation and reverse transcription process, respectively. In the present review, we aimed to describe the wide repertoire of natural compounds exhibiting anti-HIV-1 activity that can be considered for designing new therapeutic strategies to curb the HIV pandemic.

Target Molecules and Delivery Vehicles for Anti-HIV Drugs In vitro and In vivo

2018 ◽  
Vol 24 (29) ◽  
pp. 3393-3401 ◽  
Author(s):  
Azam Bolhassani
Keyword(s):  
Drug Targeting ◽  
Immune Deficiency Syndrome ◽  
Antiretroviral Drugs ◽  
Host Cells ◽  
Target Cells ◽  
Hiv Drugs ◽  
Anti Hiv ◽  
Hiv 1

Acquired Immune Deficiency Syndrome (AIDS) is the most serious stage of Human Immunodeficiency Virus (HIV) infection. The combinatorial Anti-Retroviral Therapy (cART) is widely used in suppressing HIV-1 infection and enhancing life span of infected patients to a significant level. However, delivery of therapeutic molecules is still a major challenge in vivo. The studies showed that the anti-HIV drugs delivered via nanocarriers could be selectively accumulated in infected cells accompanied by low side effects. On the other hand, HIV-1 infection kinetics is different in macrophages and T-cells suggesting various effects of antiretroviral drugs against HIV-1 in these target cells. Current anti-HIV therapeutic studies have focused on developing drug delivery systems targeted specifically to HIV-infected host cells. Indeed, the drug targeting can significantly lead to reduce in drug toxicity, drug dose, and increase in treatment efficacy through localizing its pharmacological activity to the site of interest. This review describes development of novel drug targeting systems used in suppressing the transmission and treatment of HIV infections.

scholarly journals ADS-J1 Inhibits Semen-Derived Amyloid Fibril Formation and Blocks Fibril-Mediated Enhancement of HIV-1 Infection

2015 ◽  
Vol 59 (9) ◽  
pp. 5123-5134 ◽  
Author(s):  
Tianrong Xun ◽  
Wenjuan Li ◽  
Jinquan Chen ◽  
Fei Yu ◽  
Wei Xu ◽  
...  
Keyword(s):  
Viral Infection ◽  
Amyloid Fibrils ◽  
Synergistic Effects ◽  
Sexual Transmission ◽  
Prostatic Acid Phosphatase ◽  
Fibril Formation ◽  
Antiretroviral Drugs ◽  
Target Cells ◽  
Additional Function ◽  
Hiv 1

ABSTRACTSemen-derived enhancer of viral infection (SEVI) is composed of amyloid fibrils that can greatly enhance HIV-1 infectivity. By its cationic property, SEVI promotes viral sexual transmission by facilitating the attachment and internalization of HIV-1 to target cells. Therefore, semen-derived amyloid fibrils are potential targets for microbicide design. ADS-J1 is an anionic HIV-1 entry inhibitor. In this study, we explored an additional function of ADS-J1: inhibition of SEVI fibril formation and blockage of SEVI-mediated enhancement of viral infection. We found that ADS-J1 bound to an amyloidogenic peptide fragment (PAP248–286, comprising amino acids 248 to 286 of the enzyme prostatic acid phosphatase), thereby inhibiting peptide assembly into amyloid fibrils. In addition, ADS-J1 binds to mature amyloid fibrils and antagonizes fibril-mediated enhancement of viral infection. Unlike cellulose sulfate, a polyanion that failed in clinical trial to prevent HIV-1 sexual transmission, ADS-J1 shows no ability to facilitate fibril formation. More importantly, the combination of ADS-J1 with several antiretroviral drugs exhibited synergistic effects against HIV-1 infection in semen, with little cytotoxicity to vaginal epithelial cells. Our results suggest that ADS-J1 or a derivative may be incorporated into a combination microbicide for prevention of the sexual transmission of HIV-1.

scholarly journals Slaying the Trojan Horse: Natural Killer Cells Exhibit Robust Anti-HIV-1 Antibody-Dependent Activation and Cytolysis against Allogeneic T Cells

2014 ◽  
Vol 89 (1) ◽  
pp. 97-109 ◽  
Author(s):  
Shayarana L. Gooneratne ◽  
Jonathan Richard ◽  
Wen Shi Lee ◽  
Andrés Finzi ◽  
Stephen J. Kent ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Target Cells ◽  
Dependent Manner ◽  
Inhibitory Receptors ◽  
Cell Responses ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTMany attempts to design prophylactic human immunodeficiency virus type 1 (HIV-1) vaccines have focused on the induction of neutralizing antibodies (Abs) that block infection by free virions. Despite the focus on viral particles, virus-infected cells, which can be found within mucosal secretions, are more infectious than free virus bothin vitroandin vivo. Furthermore, assessment of human transmission couples suggests infected seminal lymphocytes might be responsible for a proportion of HIV-1 transmissions. Although vaccines that induce neutralizing Abs are sought, only some broadly neutralizing Abs efficiently block cell-to-cell transmission of HIV-1. As HIV-1 vaccines need to elicit immune responses capable of controlling both free and cell-associated virus, we evaluated the potential of natural killer (NK) cells to respond in an Ab-dependent manner to allogeneic T cells bearing HIV-1 antigens. This study presents data measuring Ab-dependent anti-HIV-1 NK cell responses to primary and transformed allogeneic T-cell targets. We found that NK cells are robustly activated in an anti-HIV-1 Ab-dependent manner against allogeneic targets and that tested target cells are subject to Ab-dependent cytolysis. Furthermore, the educated KIR3DL1+NK cell subset from HLA-Bw4+individuals exhibits an activation advantage over the KIR3DL1−subset that contains both NK cells educated through other receptor/ligand combinations and uneducated NK cells. These results are intriguing and important for understanding the regulation of Ab-dependent NK cell responses and are potentially valuable for designing Ab-dependent therapies and/or vaccines.IMPORTANCENK cell-mediated anti-HIV-1 antibody-dependent functions have been associated with protection from infection and disease progression; however, their role in protecting from infection with allogeneic cells infected with HIV-1 is unknown. We found that HIV-1-specific ADCC antibodies bound to allogeneic cells infected with HIV-1 or coated with HIV-1 gp120 were capable of activating NK cells and/or trigging cytolysis of the allogeneic target cells. This suggests ADCC may be able to assist in preventing infection with cell-associated HIV-1. In order to fully utilize NK cell-mediated Ab-dependent effector functions, it might also be important that educated NK cells, which hold the highest activation potential, can become activated against targets bearing HIV-1 antigens and expressing the ligands for self-inhibitory receptors. Here, we show that with Ab-dependent stimulation, NK cells expressing inhibitory receptors can mediate robust activation against targets expressing the ligands for those receptors.

scholarly journals PSGL-1 restricts HIV-1 infectivity by blocking virus particle attachment to target cells

2020 ◽  
Vol 117 (17) ◽  
pp. 9537-9545 ◽  
Author(s):  
Yajing Fu ◽  
Sijia He ◽  
Abdul A. Waheed ◽  
Deemah Dabbagh ◽  
Zheng Zhou ◽  
...  
Keyword(s):  
Virus Particle ◽  
Influenza A ◽  
Leukemia Virus ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Target Cells ◽  
Viral Glycoprotein ◽  
Selectin Binding ◽  
Anti Hiv ◽  
Hiv 1

P-selectin glycoprotein ligand-1 (PSGL-1) is a dimeric, mucin-like, 120-kDa glycoprotein that binds to P-, E-, and L-selectins. PSGL-1 is expressed primarily on the surface of lymphoid and myeloid cells and is up-regulated during inflammation to mediate leukocyte tethering and rolling on the surface of endothelium for migration into inflamed tissues. Although it has been reported that PSGL-1 expression inhibits HIV-1 replication, the mechanism of PSGL-1–mediated anti-HIV activity remains to be elucidated. Here we report that PSGL-1 in virions blocks the infectivity of HIV-1 particles by preventing the binding of particles to target cells. This inhibitory activity is independent of the viral glycoprotein present on the virus particle; the binding of particles bearing the HIV-1 envelope glycoprotein or vesicular stomatitis virus G glycoprotein or even lacking a viral glycoprotein is impaired by PSGL-1. Mapping studies show that the extracellular N-terminal domain of PSGL-1 is necessary for its anti–HIV-1 activity, and that the PSGL-1 cytoplasmic tail contributes to inhibition. In addition, we demonstrate that the PSGL-1–related monomeric E-selectin–binding glycoprotein CD43 also effectively blocks HIV-1 infectivity. HIV-1 infection, or expression of either Vpu or Nef, down-regulates PSGL-1 from the cell surface; expression of Vpu appears to be primarily responsible for enabling the virus to partially escape PSGL-1–mediated restriction. Finally, we show that PSGL-1 inhibits the infectivity of other viruses, such as murine leukemia virus and influenza A virus. These findings demonstrate that PSGL-1 is a broad-spectrum antiviral host factor with a unique mechanism of action.

scholarly journals Neutrophil extracellular traps from healthy donors and HIV-1-infected individuals restrict HIV-1 production in macrophages

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Andrés Mojoli ◽  
Barbara Simonson Gonçalves ◽  
Jairo R. Temerozo ◽  
Bruno Cister-Alves ◽  
Victor Geddes ◽  
...  
Keyword(s):  
Virus Production ◽  
Significant Inhibition ◽  
Target Cells ◽  
Extracellular Traps ◽  
Healthy Donors ◽  
Activated Neutrophils ◽  
Immunity Mechanism ◽  
Anti Hiv ◽  
Hiv 1

Abstract Neutrophils release extracellular traps (NETs) after interaction with microorganisms and physiological or synthetic products. NETs consist of decondensed chromatin complexed with proteins, some of them with microbicidal properties. Because NETs can modulate the functioning of HIV-1 target cells, we aimed to verify whether they modify HIV-1 replication in macrophages. We found that exposure of HIV-1-infected macrophages to NETs resulted in significant inhibition of viral replication. The NET anti-HIV-1 action was independent of other soluble factors released by the activated neutrophils, but otherwise dependent on the molecular integrity of NETs, since NET-treatment with protease or DNase abolished this effect. NETs induced macrophage production of the anti-HIV-1 β-chemokines Rantes and MIP-1β, and reduced the levels of integrated HIV-1 DNA in the macrophage genome, which may explain the decreased virus production by infected macrophages. Moreover, the residual virions released by NET-treated HIV-1-infected macrophages lost infectivity. In addition, elevated levels of DNA-elastase complexes were detected in the plasma from HIV-1-infected individuals, and neutrophils from these patients released NETs, which also inhibited HIV-1 replication in in vitro infected macrophages. Our results reveal that NETs may function as an innate immunity mechanism able to restrain HIV-1 production in macrophages.

scholarly journals Design of a Potent d-Peptide HIV-1 Entry Inhibitor with a Strong Barrier to Resistance

2010 ◽  
Vol 84 (21) ◽  
pp. 11235-11244 ◽  
Author(s):  
Brett D. Welch ◽  
J. Nicholas Francis ◽  
Joseph S. Redman ◽  
Suparna Paul ◽  
Matthew T. Weinstock ◽  
...  
Keyword(s):  
Viral Entry ◽  
Mirror Image ◽  
Entry Inhibitor ◽  
Fusion Inhibitors ◽  
Hiv Entry ◽  
Viral Target ◽  
Protease Degradation ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Strong Barrier

ABSTRACT The HIV gp41 N-trimer pocket region is an ideal viral target because it is extracellular, highly conserved, and essential for viral entry. Here, we report on the design of a pocket-specific d-peptide, PIE12-trimer, that is extraordinarily elusive to resistance and characterize its inhibitory and structural properties. d-Peptides (peptides composed of d-amino acids) are promising therapeutic agents due to their insensitivity to protease degradation. PIE12-trimer was designed using structure-guided mirror-image phage display and linker optimization and is the first d-peptide HIV entry inhibitor with the breadth and potency required for clinical use. PIE12-trimer has an ultrahigh affinity for the gp41 pocket, providing it with a reserve of binding energy (resistance capacitor) that yields a dramatically improved resistance profile compared to those of other fusion inhibitors. These results demonstrate that the gp41 pocket is an ideal drug target and establish PIE12-trimer as a leading anti-HIV antiviral candidate.

scholarly journals Role of MxB in Alpha Interferon-Mediated Inhibition of HIV-1 Infection

2018 ◽  
Vol 92 (17) ◽  
Author(s):  
Bin Xu ◽  
Qinghua Pan ◽  
Chen Liang
Keyword(s):  
G Protein ◽  
Transmembrane Protein ◽  
Alpha Interferon ◽  
Wild Type Virus ◽  
Target Cells ◽  
Type I ◽  
Wide Range ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTType I interferon inhibits viruses through inducing the expression of antiviral proteins, including the myxovirus resistance (Mx) proteins. Compared to the human MxA protein, which inhibits a wide range of viruses, the MxB protein has been reported to specifically inhibit primate lentiviruses, including HIV-1, and herpesviruses. Further, the role of endogenous MxB in alpha interferon-mediated inhibition of HIV-1 infection was questioned by a recent study showing that MxB knockout did not increase the level of infection by HIV-1 which carried the G protein of vesicular stomatitis virus (VSV), allowing infection of CD4-negative HT1080 cells. In order to further examine the anti-HIV-1 activity of endogenous MxB, we have used CRISPR/Cas9 to deplete MxB in different cell lines and observed a substantial restoration of HIV-1 infection in the presence of alpha interferon treatment. However, this rescue effect of MxB knockout became much less pronounced when infection was performed with HIV-1 carrying the VSV G protein. Interestingly, a CRISPR/Cas9 knockout screen of alpha interferon-stimulated genes in U87-MG cells revealed that the genes for interferon-induced transmembrane protein 2 (IFITM2) and IFITM3 inhibited VSV G-pseudotyped HIV-1 much more strongly than the rest of the genes tested, including the gene for MxB. Therefore, our results demonstrate the importance of MxB in alpha interferon-mediated inhibition of HIV-1 infection, which, however, can be underestimated if infection is performed with VSV G protein-pseudotyped HIV-1, due to the high sensitivity of VSV G-mediated infection to inhibition by IFITM proteins.IMPORTANCEThe results of this study reconcile the controversial reports regarding the anti-HIV-1 function of alpha interferon-induced MxB protein. In addition to the different cell types that may have contributed to the different observations, our data also suggest that VSV G protein-pseudotyped HIV-1 is much less inhibited by alpha interferon-induced MxB than HIV-1 itself is. Our results clearly demonstrate an important contribution of MxB to alpha interferon-mediated inhibition of HIV-1 in CD4+T cells, which calls for using HIV-1 target cells and wild-type virus to test the relevance of the anti-HIV-1 activity of endogenous MxB and other restriction factors.

scholarly journals PSGL-1 Restricts HIV-1 Infectivity by Blocking Virus Particle Attachment to Target Cells

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 77
Author(s):  
Yajing Fu ◽  
Sijia He ◽  
Abdul Waheed ◽  
Deemah Dabbagh ◽  
Zheng Zhou ◽  
...  
Keyword(s):  
Virus Particle ◽  
Influenza A ◽  
Leukemia Virus ◽  
Target Cells ◽  
Viral Glycoprotein ◽  
Immunodeficiency Virus ◽  
Vesicular Stomatitis ◽  
Selectin Binding ◽  
Anti Hiv ◽  
Hiv 1

P-selectin glycoprotein ligand-1 (PSGL-1) is a dimeric, mucin-like, 120-kDa glycoprotein that binds to P-, E-, and L-selectins. PSGL-1 is primarily expressed on the surface of lymphoid and myeloid cells and is up-regulated during inflammation to mediate leukocyte tethering and rolling on the surface of endothelium for migration into inflamed tissues. Although it has been reported that PSGL-1 expression inhibits human immunodeficiency virus type 1 (HIV-1) replication, the mechanism of PSGL-1-mediated anti-HIV activity remains to be elucidated. Here, we report that PSGL-1 in virions blocks the infectivity of HIV-1 particles by preventing the binding of particles to target cells. This inhibitory activity is independent of the viral glycoprotein present on the virus particle; the binding of particles bearing the HIV-1 envelope glycoprotein, vesicular stomatitis virus G glycoprotein, or lacking a viral glycoprotein, is impaired by PSGL-1. Mapping studies show that the extracellular, N-terminal domain of PSGL-1 is necessary for its anti-HIV-1 activity, and the PSGL-1 cytoplasmic tail contributes to its inhibition. In addition, we demonstrate that the PSGL-1-related monomeric E-selectin-binding glycoprotein CD43 also effectively blocks HIV-1 infectivity. HIV-1 infection, or the expression of either Vpu or Nef, downregulates PSGL-1 from the cell surface; the expression of Vpu appears to be primarily responsible for enabling the virus to partially escape PSGL-1-mediated restriction. Finally, we show that PSGL-1 inhibits the infectivity of other viruses such as murine leukemia virus and influenza A virus. These findings demonstrate that PSGL-1 is a broad-spectrum antiviral host factor with a novel mechanism of action.

scholarly journals Plausibility of HIV-1 Infection of Oral Mucosal Epithelial Cells

2011 ◽  
Vol 23 (1) ◽  
pp. 38-44 ◽  
Author(s):  
M.C. Herzberg ◽  
A. Vacharaksa ◽  
K.H. Gebhard ◽  
R.A. Giacaman ◽  
K.F. Ross
Keyword(s):  
Target Cells ◽  
Cell Passage ◽  
Oral Keratinocytes ◽  
Protease Activated Receptors ◽  
Mucosal Surfaces ◽  
Aids Pandemic ◽  
Mucosal Vaccines ◽  
The Common ◽  
Anti Hiv ◽  
Hiv 1

The AIDS pandemic continues. Little is understood about how HIV gains access to permissive cells across mucosal surfaces, yet such knowledge is crucial to the development of successful topical anti-HIV-1 agents and mucosal vaccines. HIV-1 rapidly internalizes and integrates into the mucosal keratinocyte genome, and integrated copies of HIV-1 persist upon cell passage. The virus does not appear to replicate, and the infection may become latent. Interactions between HIV-1 and oral keratinocytes have been modeled in the context of key environmental factors, including putative copathogens and saliva. In keratinocytes, HIV-1 internalizes within minutes; in saliva, an infectious fraction escapes inactivation and is harbored and transferable to permissive target cells for up to 48 hours. When incubated with the common oral pathogen Porphyromonas gingivalis, CCR5− oral keratinocytes signal through protease-activated receptors and Toll-like receptors to induce expression of CCR5, which increases selective uptake of infectious R5-tropic HIV-1 into oral keratinocytes and transfer to permissive cells. Hence, oral keratinocytes—like squamous keratinocytes of other tissues—may be targets for low-level HIV-1 internalization and subsequent dissemination by transfer to permissive cells.

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