HIV-1 Binding Research Articles

The Microvesicle Component of HIV-1 Inocula Modulates Dendritic Cell Infection and Maturation and Enhances Adhesion to and Activation of T Lymphocytes

HIV-1 is taken up by immature monocyte derived dendritic cells (iMDDCs) into tetraspanin rich caves from which the virus can either be transferred to T lymphocytes or enter into endosomes resulting in degradation. HIV-1 binding and fusion with the DC membrane results in low level de novo infection that can also be transferred to T lymphocytes at a later stage. We have previously reported that HIV-1 can induce partial maturation of iMDDCs at both stages of trafficking. Here we show that CD45+ microvesicles (MV) which contaminate purified HIV-1 inocula due to similar size and density, affect DC maturation, de novo HIV-1 infection and transfer to T lymphocytes. Comparing iMDDCs infected with CD45-depleted HIV-1BaL or matched non-depleted preparations, the presence of CD45+ MVs was shown to enhance DC maturation and ICAM-1 (CD54) expression, which is involved in DC∶T lymphocyte interactions, while restricting HIV-1 infection of MDDCs. Furthermore, in the DC culture HIV-1 infected (p24+) MDDCs were more mature than bystander cells. Depletion of MVs from the HIV-1 inoculum markedly inhibited DC∶T lymphocyte clustering and the induction of alloproliferation as well as limiting HIV-1 transfer from DCs to T lymphocytes. The effects of MV depletion on these functions were reversed by the re-addition of purified MVs from activated but not non-activated SUPT1.CCR5-CL.30 or primary T cells. Analysis of the protein complement of these MVs and of these HIV-1 inocula before and after MV depletion showed that Heat Shock Proteins (HSPs) and nef were the likely DC maturation candidates. Recombinant HSP90α and β and nef all induced DC maturation and ICAM-1 expression, greater when combined. These results suggest that MVs contaminating HIV-1 released from infected T lymphocytes may be biologically important, especially in enhancing T cell activation, during uptake by DCs in vitro and in vivo, particularly as MVs have been detected in the circulation of HIV-1 infected subjects.

Thwarting HIV evasion of antibody avidity with novel antibody architectures (P4489)

Abstract Despite decades of effort, no current vaccine elicits neutralizing antibodies at concentrations blocking HIV infection. In addition to structural features of HIV's envelope spike that facilitate antibody evasion, a hypothesis for the ineffective immune response lies in the low density and limited mobility of HIV envelope spikes, which impedes bivalent binding by antibodies, reducing avidity, minimizing the potential for high affinity binding and virus neutralization. We intend to engineer anti-HIV reagents that bind with high avidity to single spikes, overcoming potential problems with the low density of HIV spikes. Here, we demonstrate a strategy to use dsDNA as a rigid molecular ruler to map epitopes on the HIV envelope protein to gain insight into the relatively unknown spatial environment of the spike trimer. Upon determining the optimal separation distance between epitopes, the dsDNA linker will be replaced with a structured protein linker. This technique should allow for the development of a novel multivalent antibody reagent improving binding and increasing avidity. Optimal HIV binding proteins will be trimerized by attaching a trimerization motif, reducing the concentration required for sterilizing immunity. To date, we have several bispecific DNA reagents that have the ability to neutralize various strains of HIV with greater potency than its individual components. These results demonstrate the promise for discovery of optimal anti-HIV reagents using this technology.

Surfactant Protein D Modulates HIV Infection of Both T-Cells and Dendritic Cells

Surfactant Protein D (SP-D) is an oligomerized C-type lectin molecule with immunomodulatory properties and involvement in lung surfactant homeostasis in the respiratory tract. SP-D binds to the enveloped viruses, influenza A virus and respiratory syncytial virus and inhibits their replication in vitro and in vivo. SP-D has been shown to bind to HIV via the HIV envelope protein gp120 and inhibit infectivity in vitro. Here we show that SP-D binds to different strains of HIV (BaL and IIIB) and the binding occurs at both pH 7.4 and 5.0 resembling physiological relevant pH values found in the body and the female urogenital tract, respectively. The binding of SP-D to HIV particles and gp120 was inhibited by the presence of several hexoses with mannose found to be the strongest inhibitor. Competition studies showed that soluble CD4 and CVN did not interfere with the interaction between SP-D and gp120. However, soluble recombinant DC-SIGN was shown to inhibit the binding between SP-D and gp120. SP-D agglutinated HIV and gp120 in a calcium dependent manner. SP-D inhibited the infectivity of HIV strains at both pH values of 7.4 and 5.0 in a concentration dependent manner. The inhibition of the infectivity was abolished by the presence of mannose. SP-D enhanced the binding of HIV to immature monocyte derived dendritic cells (iMDDCs) and was also found to enhance HIV capture and transfer to the T-cell like line PM1. These results suggest that SP-D can bind to and inhibit direct infection of T-cells by HIV but also enhance the transfer of infectious HIV particles from DCs to T-cells in vivo.

Dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin mediates HIV-1 infection of and transmission by M2a-polarized macrophages in vitro

To assess in-vitro effects of monocyte-derived macrophage (MDM) polarization into M1 and M2a cells on HIV-1 replication and transmission and obtain new insights into the potential importance of macrophage polarization in vivo. Human peripheral blood monocytes were differentiated into MDM for 7 days. Control and MDM polarized into M1 or M2a cells were exposed to different strains of HIV-1 and assessed for their ability to bind and transmit virus to CD4 T lymphocytes. MDM were incubated with either tumour necrosis factor-alpha (TNF-α) along with interferon-gamma (IFN-γ) or with interleukin-4 (IL-4) for 18 h to obtain M1 or M2a cells, respectively. Expression of cell surface antigens, including CD4 and dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN), was evaluated by flow cytometry. C-C chemokine receptor type 5 (CCR5)-dependent (R5) HIV-1 binding, DNA synthesis and viral replication were assessed in the presence or absence of anti-DC-SIGN blocking mAbs. Transmission of C-X-C chemokine receptor type 4 (CXCR4)-dependent (X4) and R5 HIV-1 from MDM to IL-2 activated CD4 T cells was also investigated. DC-SIGN was strongly upregulated on M2a-MDM and downregulated on M1-MDM compared with control MDM. DC-SIGN facilitated HIV-1 entry and DNA synthesis in M2a-MDM, compensating for their low levels of CD4 cell expression. M2a-MDM efficiently transmitted both R5 and X4 HIV-1 to CD4 T cells in a DC-SIGN-dependent manner. DC-SIGN facilitates HIV-1 infection of M2a-MDM, and HIV-1 transfer from M2a-MDM to CD4 T cells. M2a-polarized tissue macrophages may play an important role in the capture and spread of HIV-1 in mucosal tissues and placenta.

Pannexin1 hemichannels are critical for HIV infection of human primary CD4+ T lymphocytes

HIV is a major public health issue, and infection of CD4(+) T lymphocytes is one of its key features. Whereas several cellular proteins have been identified that facilitate viral infection and replication, the role of hemichannels in these processes has not been fully characterized. We now show that the HIV isolates, R5 and X4, induced a transient-early (5-30 min) and a later, persistent (48-120 h) opening of Panx1 hemichannels, which was dependent on the binding of HIV to CD4 and CCR5/CXCR4 receptors. Blocking Panx1 hemichannels by reducing their opening or protein expression inhibited HIV replication in CD4(+) T lymphocytes. Thus, our findings demonstrate that Panx1 hemichannels play an essential role in HIV infection.

Frequency of amino acid changes associated with resistance to attachment inhibitor BMS-626529 in R5- and X4-tropic HIV-1 subtype B

Resistance to attachment inhibitor BMS-626529, which inhibits the binding of HIV to CD4, involves mutations in the HIV-1 gp120 gene. There is a lack of information on the primary resistance of HIV-1 subtype B to attachment inhibitors, so we decided to investigate. Sequences from 109 attachment-inhibitor-naive patients infected with HIV-1 subtype B were analysed for the presence of previously described in vivo resistance mutations associated with attachment inhibitor BMS-626529 and tropism determination. The M426L substitution associated with a reduced efficacy of the attachment inhibitor BMS-626529 was present at 7.3%. There was no difference in mutation distribution according to virus tropism (R5 or X4). The attachment inhibitor BMS-626529 is suitable for most patients infected with HIV-1 subtype B.

Structural and Thermodynamic Basis of Amprenavir/Darunavir and Atazanavir Resistance in HIV-1 Protease with Mutations at Residue 50

Drug resistance occurs through a series of subtle changes that maintain substrate recognition but no longer permit inhibitor binding. In HIV-1 protease, mutations at I50 are associated with such subtle changes that confer differential resistance to specific inhibitors. Residue I50 is located at the protease flap tips, closing the active site upon ligand binding. Under selective drug pressure, I50V/L substitutions emerge in patients, compromising drug susceptibility and leading to treatment failure. The I50V substitution is often associated with amprenavir (APV) and darunavir (DRV) resistance, while the I50L substitution is observed in patients failing atazanavir (ATV) therapy. To explain how APV, DRV, and ATV susceptibility are influenced by mutations at residue 50 in HIV-1 protease, structural and binding thermodynamics studies were carried out on I50V/L-substituted protease variants in the compensatory mutation A71V background. Reduced affinity to both I50V/A71V and I50L/A71V double mutants is largely due to decreased binding entropy, which is compensated for by enhanced enthalpy for ATV binding to I50V variants and APV binding to I50L variants, leading to hypersusceptibility in these two cases. Analysis of the crystal structures showed that the substitutions at residue 50 affect how APV, DRV, and ATV bind the protease with altered van der Waals interactions and that the selection of I50V versus I50L is greatly influenced by the chemical moieties at the P1 position for APV/DRV and the P2 position for ATV. Thus, the varied inhibitor susceptibilities of I50V/L protease variants are largely a direct consequence of the interdependent changes in protease inhibitor interactions.

Generation of an HIV Resistant T-cell Line by Targeted “Stacking” of Restriction Factors

Restriction factors constitute a newly appreciated line of innate immune defense, blocking viral replication inside of infected cells. In contrast to these antiviral proteins, some cellular proteins, such as the CD4, CCR5, and CXCR4 cell surface receptors, facilitate HIV replication. We have used zinc finger nucleases (ZFNs) to insert a cocktail of anti-HIV restriction factors into the CCR5 locus in a T-cell reporter line, knocking out the CCR5 gene in the process. Mirroring the logic of highly active antiretroviral therapy, this strategy provides multiple parallel blocks to infection, dramatically limiting pathways for viral escape, without relying on random integration of transgenes into the genome. Because of the combination of blocks that this strategy creates, our modified T-cell lines are robustly resistant to both CCR5-tropic (R5-tropic) and CXCR4-tropic (X4-tropic) HIV-1. While zinc finger nuclease-mediated CCR5 disruption alone, which mimics the strategy being used in clinical trials, confers 16-fold protection against R5-tropic HIV, it has no effect against X4-tropic virus. Rhesus TRIM5α, chimeric human-rhesus TRIM5α, APOBEC3G D128K, or Rev M10 alone targeted to CCR5 confers significantly improved resistance to infection by both variants compared with CCR5 disruption alone. The combination of three factors targeted to CCR5 blocks infection at multiple stages, providing virtually complete protection against infection by R5-tropic and X4-tropic HIV.

CD4 detected from Lactobacillus helps understand the interaction between Lactobacillus and HIV

Human immunodeficiency virus (HIV) preferentially infects and destroys CD4+ cells and leads to a gradual decline in the number of CD4 cells. Despite evidence that probiotics increase CD4+ T lymphocytes in patients with HIV/acquired immunodeficiency syndrome (AIDS) and lower the risk of HIV transmission, little is known about the detailed mechanism underlying these effects. In this study, we investigated the cell surface protein of Lactobacillus and its role in blocking HIV-1 transmission by lactobacilli. Using reverse transcription–polymerase chain reaction (RT–PCR), immunofluorescence, and flow cytometry (fluorescence-activated cell sorting, FACS), we detected the CD4 receptor on the surface of Lactobacillus. Monoclonal antibody (mAb) for the CD4 receptor could partially inhibit HIV-1 binding to Lactobacillus. In addition, Lactobacillus could decrease HIV-1 pseudovirus infection of TZM-bl cells in vitro by 60–70%. Our data suggest that Lactobacillus can use this receptor to bind HIV and block HIV infection. This may in turn increase the CD4 T lymphocyte count in patients with HIV. These data provide direct evidence that Lactobacillus expresses the CD4 receptor and utilizes it to block HIV transmission.

Association of Human Mannose Receptor in Sexual Transmission of Human Immunodeficiency Virus in Serodiscordant Couples

HIV binds specifically to the human mannose receptor (hMR) on vaginal epithelial cells that are devoid of a conventional CD4 receptor. HIV binding to hMR on vaginal epithelial cells induces the production of matrix metalloproteinase 9 (MMP9) leading to degradation of the extracellular matrix, which may increase the risk of HIV entry into vaginal epithelial cells and further transmission into distal cells. Immunofluorescent localization of hMR on vaginal epithelial cells of seronegative females from the general population included the control group (n=52) and seronegative females from serodiscordant couples. There was PCR amplification of DNA from peripheral blood mononuclear cells (PBMCs) of the serodiscordant females for the CCR5 gene flanking the CCR5-Δ32 region; PCR amplification and sequencing of the C2-V3 region of HIV variants in PBMCs and sperm of the infected male partners of the serodiscordant couples; and the presence of hMR on 0-11% of the vaginal epithelial cells of seronegative females (n=39) from serodiscordant couples and 90-95% that of a control group of females (n=52). Nine of these serodiscordant females did not show a CCR5-Δ32 deletion. The translated amino acid sequence of the C2-V3 region of the env gene of HIV-1C in PBMCs (n=9) and sperm (n=5) of the male partners showed the presence of distinct variants and the variation in PBMCs and sperm of serodiscordant males was almost similar to that of infected males from concordant couples. The presence of hMR in a smaller number of vaginal epithelial cells of serodiscordant females prevented binding and HIV entry into these cells and therefore prevented sexual transmission of HIV.

Siglec-1 Is a Novel Dendritic Cell Receptor That Mediates HIV-1 Trans-Infection Through Recognition of Viral Membrane Gangliosides

Author SummaryMature dendritic cells (mDCs) capture and store infectious HIV-1 and subsequently infect neighboring CD4+ T cells in lymphoid organs. This process, known as trans-infection, is a key contributor to HIV pathogenesis, but the precise mechanism and the identity of the receptor on the mDC surface that recognizes viral particles remain controversial. Although the interaction of HIV-1 envelope glycoproteins with the C-type lectin DC-SIGN has been suggested to mediate HIV-1 capture and trans-infection, later studies revealed an envelope glycoprotein-independent virus capture mechanism in mDCs. Here, we identify Siglec-1 as the surface receptor on mDCs that boosts their uptake of HIV-1 and their capacity to trans-infect CD4+ cells, leading in turn to HIV-1 disease progression. Siglec-1 captures the virus by interacting with sialyllactose-containing gangliosides exposed on viral membranes. This indicates that Siglec-1 functions as a general binding molecule for any vesicle carrying sialyllactose in its membrane, including exosomes and other viruses. We suggest that this natural pathway through mDC, which would normally lead to antigen processing and presentation, has been subverted by HIV-1 for its own storage and transmission.

Sexual violence and HIV transmission: summary proceedings of a scientific research planning meeting.

This summarizes proceedings of a Scientific Research Planning Meeting on Sexual Violence and HIV transmission, convened by the Social Science Research Council on 19–20 March 2012 at the Greentree Foundation in New York. The Meeting brought together an interdisciplinary group of basic, clinical, epidemiological and social science researchers and policy makers with the aim of: (1) examining what is known about the physiology of sexual violence and its role in HIV transmission, acquisition and pathogenesis; (2) specifying factors that distinguish risks throughout the maturation of the female genital tract, the reproductive cycle and among post-menopausal women; and (3) developing a research agenda to explore unanswered questions. The Meeting resulted in a consensus Research Agenda and White Paper that identify priorities for HIV research, policy and practice as it pertains to the role of sexual violence and genital injury in HIV transmission, acquisition and pathogenesis, particularly among women and girls.

Presence of IgG Anti-gp160/120 Antibodies Confers Higher HIV Capture Capacity to Erythrocytes from HIV-Positive Individuals

BackgroundHIV binding has been demonstrated in erythrocytes from HIV-positive and HIV-negative individuals. However, the presence of immunoglobulins G anti-HIV (IgG anti-HIV) in erythrocytes from HIV-positive individuals is still to be elucidated. Moreover, the capacity of erythrocytes from HIV-positive individuals to capture an additional amount of HIV has not been studied. Indeed, it is unknown if HIV binding to erythrocytes in HIV-positive persons could have consequences on the cell-free infectious virus available.Methodology/Principal FindingsIgGs anti-HIV associated to erythrocytes were found in 77.3% (58/75) of the HIV-positive individuals studied and the IgGs anti-gp160 and anti-p24 were the most frequently found. We found a positive association between detectable plasma viral load (pVL) and presence of IgGs anti-HIV associated to erythrocyte (p<0.005), though the anti-p24/160 were present with or without detectable pVL. The HIV capture capacity was higher in erythrocytes from HIV-positive than HIV-negative individuals (p<0.0001). Furthermore, among the HIV-positive individuals the higher viral capture capacity was associated with the presence of anti-gp160/gp120 on erythrocytes. Moreover, the viral capture by erythrocytes was independent of pVL (rho = 0.022, p = 0.8817). Additionally, reduction of cell-free infectious virus and available viral load was observed in the presence of erythrocytes from HIV-positive individuals.Conclusions/SignificanceResults suggest that in HIV-positive individuals, erythrocytes are capable of capturing high amounts of HIV by the presence of IgGs anti-gp160/120 on their membranes and this may produce a reduction in the available free virus. Finally, the current measurement of pVL would underestimate the real viral quantity due to the HIV binding through specific antibodies to erythrocytes.

Neutralization and enhancement of trans infection by erythrocyte-bound HIV with antibodies and complement

Background Antibodies to HIV envelope glycoproteins, with or without neutralization when assayed in standard neutralization assays, are reported to have potential to exert either inhibitory or enhancing effects through interactions with complement and/or Fc receptors. Although most of the standard neutralization assays use free virus rather than carrier-bound HIV as the infectious agent; a cell line as the target for infection; and no complement (C), these conditions may not reflect in vivo events that would include antibody-dependent innate effector mechanisms. Methods We investigated the Fc-receptor-mediated and the complement-mediated antibody-dependent enhancement in trans infection neutralization assays using two broadly neutralizing monoclonal antibodies, 4E10 and b12; primary HIV; PBMC target cells naturally expressing Fc receptors and complement receptors; and with or without complement. Results In the absence of complement, the 4E10 mAb did not neutralize erythrocyte-bound HIV, and the b12 mAb neutralized erythrocyte-bound HIV less effective than the free virus. At low concentrations, 4E10 caused enhancement of infection. In contrast, in the presence of complement, 4E10 neutralized erythrocyte-bound HIV, or caused enhancement of trans infection of erythrocytebound HIV, depending on the mechanism of binding of HIV to erythrocytes. Conclusion Our results are consistent with the concept that the binding of HIV to erythrocytes represents a mechanism of establishing a “safe harbor” for HIV from the adverse effects of antibodies and complement that might otherwise be detrimental to free circulating HIV. Our data shows that broadly neutralizing antibody 4E10 can cause both C-mediated neutralization and enhancement of trans infection. This suggests that erythrocyte-bound HIV-1 serves as a sort of battleground between neutralization and enhancement by antibodies in the presence of C. Because of this, we propose that induction of neutralizing vs. enhancing antibodies can only be differentiated by utilization of a trans infection neutralization assay that might yield more relevant results for in vivo conditions.

Involvement of LIM kinase 1 in actin polarization in human CD4 T cells

Chemokine binding to cognate receptors induces actin dynamics that are a major driving force for T cell migration and chemotactic motility. HIV-1 binding to the chemokine coreceptor CXCR4 initiates chemotactic signaling, mimicking chemokine-induced actin dynamics to facilitate infection processes such as entry, early DNA synthesis, and nuclear migration. Recently, we identified that HIV-triggered early actin polymerization is mediated through the Rac1-PAK1/2-LIMK1-cofilin pathway. Inhibition of LIMK1 (LIM domain kinase 1), a kinase phosphorylating cofilin, through shRNA knockdown decreases actin polymerization and T cell chemotaxis toward SDF-1. The LIMK1 knockdown T cells also supported lower viral entry, DNA synthesis and nuclear migration, suggesting a critical role of LIMK1-mediated actin dynamics in the initiation of HIV-1 infection. Surprisingly, LIMK1 knockdown in CEM-SS T cells did not lead to an overall change in the ratio of phospho-cofilin to total cofilin although there was a measurable decrease in the amount of actin filaments in cells. The decrease in filamentous actin in LIMK1 knockdown cells was found to mainly occur in polarized cap region rich in F-actin. These results suggest that LIMK1 may be involved in spontaneous actin polarization in transformed T cells. The inhibition of T cell chemotaxis by LIMK1 knockdown likely result from inhibition of localized LIMK1 activation and cofilin phosphorylation that are required for polarized actin polymerization for directional cell migration. The inhibition of HIV-1 infection by LIMK1 knockdown may also result from the decrease of actin-rich membrane protrusions that may be preferred viral entry sites in T cells.

Design and Characterization of a Peptide Mimotope of the HIV-1 gp120 Bridging Sheet

The Bridging Sheet domain of HIV-1 gp120 is highly conserved among the HIV-1 strains and allows HIV-1 binding to host cells via the HIV-1 coreceptors. Further, the bridging sheet domain is a major target to neutralize HIV-1 infection. We rationally designed four linear peptide epitopes that mimic the three-dimensional structure of bridging sheet by using molecular modeling. Chemically synthesized peptides BS3 and BS4 showed a fair degree of antigenicity when tested in ELISA with IgG purified from HIV+ broadly neutralizing sera while the production of synthetic peptides BS1 and BS2 failed due to their high degree of hydrophobicity. To overcome this limitation, we linked all four BS peptides to the COOH-terminus of GST protein to test both their antigenicity and immunogenicity. Only the BS1 peptide showed good antigenicity; however, no envelope specific antibodies were elicited upon mice immunization. Therefore we performed further analyses by linking BS1 peptide to the NH2-terminus of the E2 scaffold from the Geobacillus Stearothermophylus PDH complex. The E2-BS1 fusion peptide showed good antigenic results, however only one immunized rabbit elicited good antibody titers towards both the monomeric and oligomeric viral envelope glycoprotein (Env). In addition, moderate neutralizing antibodies response was elicited against two HIV-1 clade B and one clade C primary isolates. These preliminary data validate the peptide mimotope approach as a promising tool to obtain an effective HIV-1 vaccine.

Research brief

In the RV144 clinical trial, a prime-boost vaccine regimen reduced HIV-1 infection by 31·2% compared with placebo. Examination of immune variables in postimmunisation samples taken from 41 vaccinated people who became infected and from 205 vaccinated people who remained uninfected reveals that, in this trial, IgG antibody binding to variable regions 1 and 2 of HIV-1 envelope proteins (env) correlated inversely with the rate of HIV-1 infection and binding of IgA antibodies to env directly correlated with the rate of infection. These data identify the types of immune responses a vaccine might need to induce to protect against HIV-1.

A glycomimetic compound inhibits DC-SIGN-mediated HIV infection in cellular and cervical explant models

Dendritic cell-specific intercellular adhesion molecule (ICAM)-3 grabbing nonintegrin (DC-SIGN) participates in the initial stages of sexually transmitted HIV-1 infection by recognizing highly mannosylated structures presented in multiple copies on HIV-1 gp120 and promoting virus dissemination. Inhibition of HIV interaction with DC-SIGN thus represents a potential therapeutic approach for viral entry inhibition at the mucosal level. Herein we evaluate the efficacy in inhibiting HIV-1 infection and the potential toxicity of a multimeric glycomimetic DC-SIGN ligand (Dendron 12). The ability of Dendron 12 to block HIV-1 infection was assessed in cellular and human cervical explant models. Selectivity of Dendron 12 towards DC-SIGN and langerin was evaluated by surface plasmon resonance studies. β chemokine production following stimulation with Dendron 12 was also analyzed. Toxicity of the compound was evaluated in cellular and tissue models. Dendron 12 averted HIV-1 trans infection of CD4(+) T lymphocytes in presence of elevated viral loads and prevented HIV-1 infection of human cervical tissues, under conditions mimicking compromised epithelial integrity, by multiple clades of R5 and X4 tropic viruses. Treatment with Dendron 12 did not interfere with the activity of langerin and also significantly elicited the production of the β chemokines MIP-1α, MIP-1β and RANTES. Dendron 12 thus inhibits HIV-1 infection by competition with binding of HIV to DC-SIGN and stimulation of β-chemokine production. Dendron 12 represents a promising lead compound for the development of anti-HIV topical microbicides.

Study on Synthesis Chitosan Oligomer Stabilized Silver Nanoparticles Using Green Chemistry and Their Burn Wound Healing Effects

ABSTRACTThe preparation of metal nanoparticles is a major research area in technical engineering due to their unusual properties, such as catalytic activity, novel electronic, optic and magnetic properties and biotechnology. Specially, silver has been used for years in the medical field for antimicrobial applications because it known for its antimicrobial properties and even has shown to prevent HIV binding to host cells. Common synthesis, chemical and physical methods using chemical reducing agent and organic solvent are not too suitable to have application to bioengineering because they should have associated environmental toxicity or biological hazards. Development of sustainable processes through green chemistry is attractive about the elimination or minimization of chemical waste. Here, we introduce the green method for preparation of silver nanoparticles using chitosan oligomer as both reducing and stabilizing agent in water. We expect that the use of environmentally benign solvent and chitosan oligomer to prepare silver nanoparticles offers numerous benefits and compatibility for pharmaceutical and biomedical applications.

The lectins griffithsin, cyanovirin-N and scytovirin inhibit HIV-1 binding to the DC-SIGN receptor and transfer to CD4 + cells

It is generally believed that during the sexual transmission of HIV-1, the glycan-specific DC-SIGN receptor binds the virus and mediates its transfer to CD4 + cells. The lectins griffithsin (GRFT), cyanovirin-N (CV-N) and scytovirin (SVN) inhibit HIV-1 infection by binding to mannose-rich glycans on gp120. We measured the ability of these lectins to inhibit both the HIV-1 binding to DC-SIGN and the DC-SIGN-mediated HIV-1 infection of CD4 + cells. While GRFT, CV-N and SVN were moderately inhibitory to DC-SIGN binding, they potently inhibited DC-SIGN-transfer of HIV-1. The introduction of the 234 glycosylation site abolished HIV-1 sensitivity to lectin inhibition of binding to DC-SIGN and virus transfer to susceptible cells. However, the addition of the 295 glycosylation site increased the inhibition of transfer. Our data suggest that GRFT, CV-N and SVN can block two important stages of the sexual transmission of HIV-1, DC-SIGN binding and transfer, supporting their further development as microbicides.