title: Fullerene Derivatives Strongly Inhibit HIV-1 Replication by Affecting Virus Maturation without Impairing Protease Activity.
abstract: Three compounds (1, 2, and 3) previously reported to inhibit HIV-1 replication and/or in vitro activity of reverse transcriptase were studied, but only fullerene derivatives 1 and 2 showed strong antiviral activity on the replication of HIV-1 in human CD4(+) T cells. However, these compounds did not inhibit infection by single-round infection vesicular stomatitis virus glycoprotein G (VSV-G)-pseudotyped viruses, indicating no effect on the early steps of the viral life cycle. In contrast, analysis of single-round infection VSV-G-pseudotyped HIV-1 produced in the presence of compound 1 or 2 showed a complete lack of infectivity in human CD4(+) T cells, suggesting that the late stages of the HIV-1 life cycle were affected. Quantification of virion-associated viral RNA and p24 indicates that RNA packaging and viral production were unremarkable in these viruses. However, Gag and Gag-Pol processing was affected, as evidenced by immunoblot analysis with an anti-p24 antibody and the measurement of virion-associated reverse transcriptase activity, ratifying the effect of the fullerene derivatives on virion maturation of the HIV-1 life cycle. Surprisingly, fullerenes 1 and 2 did not inhibit HIV-1 protease in an in vitro assay at the doses that potently blocked viral infectivity, suggesting a protease-independent mechanism of action. Highlighting the potential therapeutic relevance of fullerene derivatives, these compounds block infection by HIV-1 resistant to protease and maturation inhibitors.
authors.affiliation: Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, USA.
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Martinez
authors.affiliation: Department of Chemistry, University of Texas at El Paso, El Paso, Texas, USA.
authors.forename: Edison
authors.initials: E
authors.lastname: Castro
authors.affiliation: Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, USA.
authors.forename: Chang-Soo
authors.initials: CS
authors.lastname: Seong
authors.affiliation: Department of Chemistry, University of Texas at El Paso, El Paso, Texas, USA.
authors.forename: Maira R
authors.initials: MR
authors.lastname: Cerón
authors.affiliation: Department of Chemistry, University of Texas at El Paso, El Paso, Texas, USA echegoyen@utep.edu mllano@utep.edu.
authors.forename: Luis
authors.initials: L
authors.lastname: Echegoyen
authors.affiliation: Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, USA echegoyen@utep.edu mllano@utep.edu.
authors.forename: Manuel
authors.initials: M
authors.lastname: Llano
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D024882:Drug Resistance, Viral / Q000187:drug effects; D037741:Fullerenes / Q000737:chemistry / Q000494:pharmacology*; D016655:HIV Core Protein p24 / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D014771:Virion / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D037741:Fullerenes; D016655:HIV Core Protein p24; D017320:HIV Protease Inhibitors; D054301:gag Gene Products, Human Immunodeficiency Virus; C514799:p24 protein, Human Immunodeficiency Virus Type 1