Anti-HIV effects of chloroquine: inhibition of viral particle glycosylation and synergism with protease inhibitors.
OBJECTIVE
We tested the effects of chloroquine (CQ) on glycosylation of HIV particles and in combination with protease inhibitors (PIs) on HIV replication and on P-glycoprotein (P-gp)/multidrug resistance protein-1 (MRP1).


METHODS
CD4 cell lines were infected with laboratory strains and peripheral blood mononuclear cells were infected with primary isolates for evaluation of the anti-HIV effects. Peripheral blood lymphocytes were evaluated for of P-gp and MRP1 functions.


METHODS
HIV replication was assessed by enzyme-linked immunosorbent assay. HIV glycosylation was measured by metabolic labeling of viral particles with [H] glucosamine. Synergism was tested using isobolograms. P-gp and MRP1 functions were assayed using rhodamine 123 (Rh123) and carboxyfluorescein (CF) efflux assays, respectively.


RESULTS
CQ alone inhibited HIV replication and glycosylation in a dose-dependent manner. In combination with indinavir (IDV), ritonavir, or saquinavir (SQV), CQ had a synergistic effect at concentrations found in plasma of subjects receiving malaria prophylaxis. CQ decreased the 50% effective concentration of IDV in primary isolates from Africa and restored the response to IDV or SQV in 3 PI-resistant isolates. CQ increased the block of Rh123 and CF efflux activity exerted by PIs.


CONCLUSIONS
The inhibitory effects of CQ on HIV glycosylation are associated with synergistic effects in combination with PIs. The CQ/PI combination exerts combined inhibitory effects on P-gp and MRP1 function.
Savarino
Andrea
A
Department of Infectious Diseases, Università Cattolica del Sacro Cuore, Rome, Italy. asavarino@medscape.com
Lucia
Mothanje B
MB
Rastrelli
Elena
E
Rutella
Sergio
S
Golotta
Caterina
C
Morra
Emanuella
E
Tamburrini
Enrica
E
Perno
Carlo Federico
CF
Boelaert
Johan R
JR
Sperber
Kirk
K
Cauda
Roberto
R
D019380:Anti-HIV Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D003545:Cysteine / Q000378:metabolism; D004357:Drug Synergism; D006031:Glycosylation; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D019469:Indinavir / Q000494:pharmacology; D008715:Methionine / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D015215:Zidovudine; D019469:Indinavir; D002738:Chloroquine; D008715:Methionine; D003545:Cysteine