1. At the early stages of my career I studied the problems of cell adhesion. These problems are directly linked to tissue morphogenesis and designing of non-adhesive materials that can be used in human bodies. Together with my colleagues we found that phospholipid liquid-crystalline surface is un-adhesive for various cells including platelets. In a surface formed by phospholipids but in a gel state becomes adhesive. contrast phase. By forming domains in different states cells my control it adhesiveness, in particular unadhesiveness of endothelial cells for platelets.
    1. 1. O. Yu. Ivanova, L.B. Margolis (1973) Use of phospholipid film for shaping cell cultures. Nature 242:200-1.
    2. 2. L.B Margolis, Yu. M. Vasiliev, I.M Gelfand (1979) Upper surface of epithelial sheets and of fluid lipid films are unadhesive for platelets. Proc. Natl. Acad. Sci. USA 76:2303-05.
    3. 3. L.B Margolis, A.N Tikhonov, E. Yu. Vasilieva (1980) Platelet adhesion to fluid and solid phospholipid membranes. Cell 19:1996-9.
  2. In my laboratory at the NIH we developed a system of human lymphoid tissue in which HIV pathogenesis is now widely studied. This system preserves it cytoarchitecture and many of important aspects of tissues in vivo. Since the critical events of HIV infection in vivo occurs in tissues, this system allows one to address important problems of HIV transmission and pathogenesis in in vivo-like system under controlled laboratory conditions. Various antivirals can be tested in this pre-clinical system.
    1. S. Glushakova, B.Baibakov, L.B.Margolis (, and J.Zimmerberg (1996). Infection of tonsil histocultures: a model for HIV pathogenesis. Nature Med. 1:1320-1322.
    2. J-C. Grivel, and L Margolis (2009) Culture of human tissue explants to study human infectious agents. Nature Protocols 4:256-69
    3. E. Saba, Grivel JC, C. Vanpouille, B. Brichacek, W. Fitzgerald, L. Margolis (corresponding author), A. Lisco (2010) HIV-1 sexual transmission: early events of HIV-1 infection of human cervico-vaginal tissue in an optimized ex vivo model. Mucosal Immunol. 3: 280-90.
    4. A. Introini, C.Vanpouille, A. Lisco, J-C. Grivel, L.Margolis (2013) Interleukin-7 facilitates HIV-1 transmission to cervico-vaginal tissue ex vivo. PLoS Pathogen 9(2): 1-10. e1003148. doi:10.1371
  3. In the system of human tissues ex vivo we investigated the difference in pathogenesis between CCR5-tropic and CXCR-4 tropic HIV-1 variants. It was thought that the former variant typical for the early stages of HIV infection is less pathogenic for cells than the latter which is often found at the late stages of the HIV disease. We found that both variants are equally pathogenic but the CCR-5 tropic variant has fewer cell targets in human lymphoid tissue.
    1. J-C. Grivel, L.B.Margolis (1999) CCR5-tropic HIV-1 isolates are highly cytopathic but only for CCR5+/CD4+ T cells in human lymphopid tissue ex vivo. Nature Med. 5:344-346. (See comment Nature Med. 5: 592-593
    2. S. Glushakova, Y. Yi, J-Ch Grivel, A. Singh, D.Schols, E. De Clercq, R. G. Collman, L. Margolis (1999) Preferential usage of CCR5 or CXCR4 co-receptors by dual-tropic HIV-1 in human lymphoid tissue ex vivo: Consequences for cytopathicity. J.Clin Inv. 104: R7-R11. (See comments J.Clin Inv. 104: 531-532).
    3. M. Penn, J-C. Grivel, B. Schramm, M. Goldsmith, L.B. Margolis (1999). CXCR4 utilization is sufficient to trigger CD4+ T cell depletion in HIV-1 infected human lymphoid tissue. Proc.Natl. Acad. Sci. USA 96: 663-668.
    4. N. Malkevich, N. C. Womack, A. Fauci, L. Margolis (2001) Human Immunodeficiency Virus Type 1 (HIV-1) Non-B Subtypes Are Similar to HIV-1 Subtype B in that coreceptor specificity is a determinant of cytopathicity in human lymphoid tissue infected ex vivo. J. Virol. 75:10520-10522.
  4. My laboratory was one of the first to focus n the mechanisms of interations of HIV co-pathogens with HIV itself. In particular, we found that common HIV co-pathogens herpesviruses may significantly affect HIV infection. Molecular mechanisms of these interactions involve chemokines and other soluble factors as well as interactions between pathogens’ cell targets. Deciphering of these mechanisms led to the use of common antiherpetics to suppress HIV replication. This effect first discovered in our ex vivo tissue system was confirmed in a clinical study.
    1. J-C. Grivel, S.Santoro, G. Faga, M. Malnati, Y. Ito, W. Fitzgerald, P. Lusso, L. Margolis (2001) Suppression of CCR5- but not CXCR4-tropic HIV-1 replication in lymphoid tissue by human herpesvirus 6. Nature Medicine 7 :1223-1235.
    2. A. Lisco, C.Vanpouille, E.P. Tchesnokov, J-C. Grivel, A.Biancotto B.Brichacek, J.Elliott, E.Fromentin, R. Shattock, P.Anton, R. Gorelick, J. Balzarini, C. McGuigan, M.Derudas, M. Gotte, R. F Schinazi, L. Margolis, (2008) Acyclovir is activated into a HIV-1 reverse transcriptase inhibitor in herpesvirus-infected human tissues. Cell Host &Microbe 4:260-270.
    3. G. Andrei, A. Lisco, C. Vanpouille, A.Introini, E. Balestra, J van den Oord, T. Cihlar C. Perno R. Snoeck LB Margolis (corresponding author), J. Balzarini (2011) Topical tenofovir as dual-targeted anti-human immunodeficiency virus and anti-herpesvirus microbicide. Cell Host&Microbe 10:1-11.
    4. C. Vanpouille, A. Lisco, J-C. Grivel, L. Bassit, RC.Kauffman, J. Sanchez, M.Lederman, RF. Schinazi, B.Rodriguez, and L.Margolis (2015) Valacyclovir Decreases Plasma HIV-1 RNA in HSV-2 Seronegative Individuals: A Randomized Placebo- -Controlled Crossover Trial. Clin Infect Dis. first published online doi:10.1093/cid/civ172.
  5. We developed a new a nano-technique, flow virometry, that permits analysis of single virions stained with fluorescent antibodies. Although it was long appreciated that virions in a viral preparation are highly heterogeneous, because they are too small for routine flow analysis similar to flow cytometry, they were analyzed predominantly in bulk. Using magnetic nano-particles we can now characterize antigenic composition of individual virions and relate it to viral biological features. We found that macrophage-derived HIV-1 carry various cellular proteins that affect immunity of the target cells. The technique has been adapted to analyze extra-cellular vesicles that carry biologically-active molecules thus mediating host cell-cell communications as well as microbiota interactions with host cells.
    1. A. Arakelyan, W. Fitzgerald, L. Margolis (corresponding author), J.-C. Grivel (2013) Nanoparticle based flow virometry for the analysis of individual virions. J Clin Invest, 123(9):3716–3727.
    2. E. Nolte-'t Hoen, T. Cremer, R.C. Gallo, L.B. Margolis (2016) Extracellular vesicles and viruses: Are they close relatives? Proc Natl Acad Sci U S A 113:9155-61.
    3. W. Fitzgerald, M.L. Freeman, M.M. Lederman, E.Vasilieva, R. Romero, L. Margolis (2018). A system of cytokines encapsulated in extracellular vesicles. Scientific Rep, 12.8, # 8973.
    4. L. Margolis, Y. Sadovsky (2019). The biology of extracellular vesicles: The known unknowns. PLoS Biol, 17(7):e3000363.
    5. R. Ñahui Palomino, C.Vanpouille, L. Laghi, C. Parolin, K. Melikov, P. Backlund, B. Vitali, L. Margolis (2019). Extracellular vesicles from symbiotic vaginal lactobacilli inhibit HIV-1 infection of human tissues. Nat Commun, 10,5656
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