11
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Griffithsin carrageenan fast dissolving inserts prevent SHIV HSV-2 and HPV infections in vivo

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) strategies with proven in vivo efficacy rely on antiretroviral drugs, creating the potential for drug resistance and complicated treatment options in individuals who become infected. Moreover, on-demand products are currently missing from the PrEP development portfolio. Griffithsin (GRFT) is a non-antiretroviral HIV entry inhibitor derived from red algae with an excellent safety profile and potent activity in vitro. When combined with carrageenan (CG), GRFT has strong activity against herpes simplex virus-2 (HSV-2) and human papillomavirus (HPV) in vitro and in vivo. Here, we report that GRFT/CG in a freeze-dried fast dissolving insert (FDI) formulation for on-demand use protects rhesus macaques from a high dose vaginal SHIV SF162P3 challenge 4 h after FDI insertion. Furthermore, the GRFT/CG FDI also protects mice vaginally against HSV-2 and HPV pseudovirus. As a safe, potent, broad-spectrum, on-demand non-antiretroviral product, the GRFT/CG FDI warrants clinical development.

          Abstract

          Safety and efficacy remain important challenges for non-antiretroviral-based microbicides. Here, Derby et al. show that a Griffithsin-Carrageenan fast dissolving vaginal insert provides on-demand protection against SHIV infections in macaques, paving the way for the development of pre-exposure prophylaxis on-demand products.

          Related collections

          Most cited references43

          • Record: found
          • Abstract: found
          • Article: not found

          Glycerol monolaurate prevents mucosal SIV transmission

          While there has been great progress in treating HIV-1 infection1, preventing transmission has thus far proven an elusive goal. Indeed, recent trials of a candidate vaccine and microbicide have been disappointing, both for want of efficacy and concerns about increased rates of transmission2–4. Nonetheless, studies of vaginal transmission in the SIV-rhesus macaque model point to opportunities in the earliest stages of infection where a vaccine or microbicide might be protective, by limiting the expansion of infected founder populations at the portal of entry5, 6. Here we show in this SIV-macaque model, that an outside-in endocervical mucosal signalling system, involving MIP-3α, plasmacytoid dendritic cells and CCR5+cell-attracting chemokines produced by these cells, in combination with the innate immune and inflammatory responses to infection in both cervix and vagina, recruit CD4+T cells to fuel this obligate expansion. We then show that glycerol monolaurate, a widely used antimicrobial compound 7 with inhibitory activity against production of MIP-3α and other proinflammatory cytokines8, can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIV in vitro, and in vivo can protect rhesus macaques from acute infection despite repeated intra-vaginal exposure to high doses of SIV. This novel approach, plausibly linked to interfering with innate host responses that recruit the target cells necessary to establish systemic infection, opens a promising new avenue for development of effective interventions to block HIV-1 mucosal transmission.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Isolation and characterization of griffithsin, a novel HIV-inactivating protein, from the red alga Griffithsia sp.

            Griffithsin (GRFT), a novel anti-HIV protein, was isolated from an aqueous extract of the red alga Griffithsia sp. The 121-amino acid sequence of GRFT has been determined, and biologically active GRFT was subsequently produced by expression of a corresponding DNA sequence in Escherichia coli. Both native and recombinant GRFT displayed potent antiviral activity against laboratory strains and primary isolates of T- and M- tropic HIV-1 with EC50 values ranging from 0.043 to 0.63 nM. GRFT also aborted cell-to-cell fusion and transmission of HIV-1 infection at similar concentrations. High concentrations (e.g. 783 nM) of GRFT were not lethal to any tested host cell types. GRFT blocked CD4-dependent glycoprotein (gp) 120 binding to receptor-expressing cells and bound to viral coat glycoproteins (gp120, gp41, and gp160) in a glycosylation-dependent manner. GRFT preferentially inhibited gp120 binding of the monoclonal antibody (mAb) 2G12, which recognizes a carbohydrate-dependent motif, and the (mAb) 48d, which binds to CD4-induced epitope. In addition, GRFT moderately interfered with the binding of gp120 to sCD4. Further data showed that the binding of GRFT to soluble gp120 was inhibited by the monosaccharides glucose, mannose, and N-acetylglucosamine but not by galactose, xylose, fucose, N-acetylgalactosamine, or sialic acid-containing glycoproteins. Taken together these data suggest that GRFT is a new type of lectin that binds to various viral glycoproteins in a monosaccharide-dependent manner. GRFT could be a potential candidate microbicide to prevent the sexual transmission of HIV and AIDS.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Effect of HSV-2 infection on subsequent HIV acquisition: an updated systematic review and meta-analysis

              Summary Background HIV and herpes simplex virus type 2 (HSV-2) infections cause a substantial global disease burden and are epidemiologically correlated. Two previous systematic reviews of the association between HSV-2 and HIV found evidence that HSV-2 infection increases the risk of HIV acquisition, but these reviews are now more than a decade old. Methods For this systematic review and meta-analysis, we searched PubMed, MEDLINE, and Embase (from Jan 1, 2003, to May 25, 2017) to identify studies investigating the risk of HIV acquisition after exposure to HSV-2 infection, either at baseline (prevalent HSV-2 infection) or during follow-up (incident HSV-2 infection). Studies were included if they were a cohort study, controlled trial, or case-control study (including case-control studies nested within a cohort study or clinical trial); if they assessed the effect of pre-existing HSV-2 infection on HIV acquisition; and if they determined the HSV-2 infection status of study participants with a type-specific assay. We calculated pooled random-effect estimates of the association between prevalent or incident HSV-2 infection and HIV seroconversion. We also extended previous investigations through detailed meta-regression and subgroup analyses. In particular, we investigated the effect of sex and risk group (general population vs higher-risk populations) on the relative risk (RR) of HIV acquisition after prevalent or incident HSV-2 infection. Higher-risk populations included female sex workers and their clients, men who have sex with men, serodiscordant couples, and attendees of sexually transmitted infection clinics. Findings We identified 57 longitudinal studies exploring the association between HSV-2 and HIV. HIV acquisition was almost tripled in the presence of prevalent HSV-2 infection among general populations (adjusted RR 2·7, 95% CI 2·2–3·4; number of estimates [Ne]=22) and was roughly doubled among higher-risk populations (1·7, 1·4–2·1; Ne=25). Incident HSV-2 infection in general populations was associated with the highest risk of acquisition of HIV (4·7, 2·2–10·1; Ne=6). Adjustment for confounders at the study level was often incomplete but did not significantly affect the results. We found moderate heterogeneity across study estimates, which was explained by risk group, world region, and HSV-2 exposure type (prevalent vs incident). Interpretation We found evidence that HSV-2 infection increases the risk of HIV acquisition. This finding has important implications for management of individuals diagnosed with HSV-2 infection, particularly for those who are newly infected. Interventions targeting HSV-2, such as new HSV vaccines, have the potential for additional benefit against HIV, which could be particularly powerful in regions with a high incidence of co-infection. Funding World Health Organization.
                Bookmark

                Author and article information

                Contributors
                nderby@popcouncil.org
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                24 September 2018
                24 September 2018
                2018
                : 9
                Affiliations
                [1 ]ISNI 0000 0004 0441 8543, GRID grid.250540.6, Center for Biomedical Research, Population Council, ; 1230 York Ave, New York, NY 10065 USA
                [2 ]ISNI 0000 0000 8940 7771, GRID grid.415269.d, PATH, ; 2201 Westlake Ave, Suite 200, Seattle, WA 98121 USA
                [3 ]ISNI 0000 0004 0535 8394, GRID grid.418021.e, AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., , Frederick National Laboratory for Cancer Research, ; 8560 Progress Dr, Frederick, MD 21701 USA
                [4 ]ISNI 0000 0004 0445 7016, GRID grid.421937.a, MPI Research, ; 54943 N. Main St, Mattawan, MI 49071 USA
                [5 ]ISNI 0000 0001 2163 0069, GRID grid.416738.f, Centers for Disease Control, ; 1600 Clifton Rd, Atlanta, GA 30333 USA
                [6 ]ISNI 0000 0004 1936 8075, GRID grid.48336.3a, Molecular Targets Program, Center for Cancer Research, and Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, , National Cancer Institute, ; Building 560, Room 21-105, Frederick, MD 21702-1201 USA
                [7 ]MJR4CONSULTING, New York, 10065 NY USA
                [8 ]ISNI 0000 0001 2217 8588, GRID grid.265219.b, Tulane National Primate Research Center, ; 18703 Three Rivers Rd, Covington, LA 70433-8915 USA
                [9 ]ISNI 0000 0004 0421 0304, GRID grid.280587.0, Aaron Diamond AIDS Research Center, ; 455 1st Ave. #7, New York, NY 10016 USA
                [10 ]ISNI 0000 0004 0387 4272, GRID grid.253205.3, Science Department, , Borough of Manhattan Community College, ; 199 Chambers St, New York, NY 10007 USA
                Article
                6349
                10.1038/s41467-018-06349-0
                6155161
                30250170
                6f68b101-2990-4957-b629-bde38ab3beed
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/100000200, United States Agency for International Development (USAID);
                Award ID: GPO-A-00-04-00019-00
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000054, U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI);
                Award ID: HHSN261200800001E
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health & Human Services | National Institutes of Health (NIH);
                Award ID: P51OD011104-56
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2018

                Uncategorized
                Uncategorized

                Comments

                Comment on this article