title: Inhibition of lysosome and proteasome function enhances human immunodeficiency virus type 1 infection.
abstract: We previously reported that inhibition of endosomal/lysosomal function can dramatically enhance human immunodeficiency virus type 1 (HIV-1) infectivity, suggesting that under these conditions productive HIV-1 infection can occur via the endocytic pathway. Here we further examined this effect with bafilomycin A1 (BFLA-1) and show that this enhancement of infectivity extends to all HIV-1 isolates tested regardless of coreceptor usage. However, isolate-specific differences were observed in the magnitude of the effect. This was particularly evident in the case of the weakly infectious HIV-1(SF2), for which we observed the greatest enhancement. Using reciprocal chimeric viruses, we were able to determine that both the disproportionate increase in the infectivity of HIV-1(SF2) in response to BFLA-1 and its weak infectivity in the absence of BFLA-1 mapped to its envelope gene. Further, we found HIV-1(SF2) to have lower fusion activity and to be 12-fold more sensitive to the fusion inhibitor T-20 than HIV-1(NL4-3). Proteasomal inhibitors also enhance HIV-1 infectivity, and we report that the combination of a lysosomal and a proteasomal inhibitor greatly enhanced infectivity of all isolates tested. Again, HIV-1(SF2) was unique in exhibiting a synergistic 400-fold increase in infectivity. We also determined that inhibition of proteasomal function increased the infectivity of HIV-1 pseudotyped with vesicular stomatitis virus G protein. The evidence presented here highlights the important role of the lysosomes/proteasomes in the destruction of infectious HIV-1(SF2) and could have implications for the development of novel antiviral agents that might take advantage of these innate defenses.
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, TX 75390, USA.
authors.forename: Bangdong L
authors.initials: BL
authors.lastname: Wei
authors.forename: Paul W
authors.initials: PW
authors.lastname: Denton
authors.forename: Eduardo
authors.initials: E
authors.lastname: O'Neill
authors.forename: Tianci
authors.initials: T
authors.lastname: Luo
authors.forename: John L
authors.initials: JL
authors.lastname: Foster
authors.forename: J Victor
authors.initials: JV
authors.lastname: Garcia
mesh_terms: D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015658:HIV Infections / Q000235:genetics / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D018942:Macrolides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011995:Recombination, Genetic; D013045:Species Specificity; D014779:Virus Replication
chemical_list: D004791:Enzyme Inhibitors; D018942:Macrolides; D061988:Proteasome Inhibitors; C040929:bafilomycin A1; D046988:Proteasome Endopeptidase Complex