Inhibition of lysosome and proteasome function enhances human immunodeficiency virus type 1 infection

Bangdong L. Wei, Paul W. Denton, Eduardo O'Neill, Tianci Luo, John L. Foster, J. Victor Garcia

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

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-1SF2, 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-1SF2 in response to BFIA-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-1NL4-3. Proteasomal inhibitors also enhance HIV-1 infectivity, and we report that the combination of a lysosomal and a proteasomal inhibitor greatly enhanced infectrvity of all isolates tested. Again, HIV-1SF2 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-1SF2 and could have implications for the development of novel antiviral agents that might take advantage of these innate defenses.

Original languageEnglish (US)
Pages (from-to)5705-5712
Number of pages8
JournalJournal of virology
Volume79
Issue number9
DOIs
StatePublished - May 2005
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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