Anti-HIV effects of chloroquine: mechanisms of inhibition and spectrum of activity.
OBJECTIVE
To investigate the mechanisms and spectrum of the anti-HIV activity of chloroquine.


METHODS
MT-4 cells or peripheral blood mononuclear cells were infected with X4, R5 or R5/X4 HIV-1 strains from clades A-E and HIV-2. The cells were then treated with clinically relevant and achievable chloroquine concentrations (i.e. 0-12.5 microM), so as to determine the EC50. The effects of chloroquine on reverse transcription and integration were tested using a replication-defective reporter HIV-1 construct (pRRL.sin.hPGK.GFP). The effects of the drug on the viral envelope were assessed by syncytium assays and immunoprecipitation, using antibodies to different epitopes of gp120.


RESULTS
In de-novo infected MT-4 cells, chloroquine selectively inhibited HIV-1 IIIB replication but not pRRL.sin.hPGK.GFP. In chronically HIV-1-infected H9 IIIB cells, chloroquine decreased the infectivity of the newly produced virus and the ability of these cells to form syncytia in co-culture with MT-2 cells. These effects were associated with structural changes in the gp120 glycoprotein, such as a reduction of reactivity with antibodies directed against the glycosylated 2G12 epitope. Although affecting a variable target such as gp120, chloroquine was capable of inhibiting X4, R5 and R5/X4 primary HIV-1 isolates from subtypes A, B, C, D, E and HIV-2.


CONCLUSIONS
At clinically achievable concentrations chloroquine inhibits HIV-1 post-integrationally by affecting newly produced viral envelope glycoproteins, and the drug has broad-spectrum anti-HIV-1 and HIV-2 activity.
Savarino
A
A
Department of Clinical Immunology, Mount Sinai School of Medicine, New York, NY, USA.
Gennero
L
L
Chen
H C
HC
Serrano
D
D
Malavasi
F
F
Boelaert
J R
JR
Sperber
K
K
D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology* / Q000633:toxicity; D016655:HIV Core Protein p24 / Q000096:biosynthesis; D015699:HIV Envelope Protein gp120 / Q000096:biosynthesis*; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D015498:HIV-2 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D013045:Species Specificity; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D016655:HIV Core Protein p24; D015699:HIV Envelope Protein gp120; D002738:Chloroquine