Effect of chloroquine on reducing HIV-1 replication in vitro and the DC-SIGN mediated transfer of virus to CD4+ T-lymphocytes.
BACKGROUND
Chloroquine (CQ) has been shown to inhibit HIV-1 replication in vitro as well as in vivo and has been proposed to alter the glycosylation pattern of the gp120 envelope. These activities indicate that the compound can be used not only as an effective HIV-1 therapeutic agent but also as a modulator of the gp120 envelope protein structure enabling for the production of broader neutralizing Ab responses.


RESULTS
We confirm here that HIV-1 replication on CD4+ T-lymphocytes can be reduced in the presence of CQ and show that the reduced replication is producer cell mediated, with viruses generated in the presence of CQ not being inhibited for subsequent infectivity and replication. By analysing the gp120 envelope protein sequences from viruses cultured long-term in the absence or presence of CQ we demonstrate variant evolution patterns. One noticeable change is the reduction in the number of potential N-linked glycosylation sites in the V3 region as well as within the 2G12 Ab binding and neutralization epitope. We also demonstrate that HIV-1 produced in the presence of CQ has a reduced capacity for transfer by Raji-DC-SIGN cells to CD4+ T-lymphocytes, indicating another means whereby virus transmission or replication may be reduced in vivo.


CONCLUSIONS
These results indicate that CQ should be considered as an HIV-1 therapeutic agent with its influence exerted through a number of mechanisms in vivo, including modulation of the gp120 structure.
Naarding
Marloes A
MA
Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. m.a.naarding@amc.uva.nl
Baan
Elly
E
Pollakis
Georgios
G
Paxton
William A
WA
D000962:Antimalarials / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D015815:Cell Adhesion Molecules / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D012692:Serial Passage; D014779:Virus Replication / Q000187:drug effects*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D000962:Antimalarials; D015815:Cell Adhesion Molecules; D002738:Chloroquine; D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin