Saquinavir inhibits early events associated with establishment of HIV-1 infection: potential role for protease inhibitors in prevention.
The maturation of newly formed human immunodeficiency virus type 1 (HIV-1) virions is a critical step for the establishment of productive infection. We investigated the potential of saquinavir (SQV), a protease inhibitor (PI) used in highly active antiretroviral therapy (HAART), as a candidate microbicide. SQV inhibited replication of clade B and clade C isolates in a dose-dependent manner in all cellular models tested: PM-1 CD4 T cells, peripheral blood mononuclear cells (PBMCs), monocyte-derived macrophages (MDMs), and immature monocyte-derived dendritic cells (iMDDCs). SQV also inhibited production of infectious virus in cervical, penile, and colorectal explants cocultured with T cells. Moreover, SQV demonstrated inhibitory potency against trans infection of T cells by in vitro-derived dendritic cells and by primary dendritic cells that emigrate from penile and cervical tissue explants. No cellular or tissue toxicity was detected in the presence of SQV, suggesting that this drug could be considered for development as a component of an effective microbicide, capable of blocking viral maturation and transmission of HIV-1 at mucosal surfaces.
Centre for Infection, Department of Cellular and Molecular Medicine, St. George's University of London, London, United Kingdom.
Martha
M
Stefanidou
Carolina
C
Herrera
Naomi
N
Armanasco
Robin J
RJ
Shattock
D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002460:Cell Line; D002584:Cervix Uteri / Q000821:virology; D018920:Coculture Techniques; D003106:Colon / Q000821:virology; D003713:Dendritic Cells / Q000821:virology; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000517:prevention & control*; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008264:Macrophages / Q000821:virology; D008297:Male; D010413:Penis / Q000821:virology; D012007:Rectum / Q000821:virology; D019258:Saquinavir / Q000494:pharmacology* / Q000633:toxicity; D013601:T-Lymphocytes / Q000821:virology
D017320:HIV Protease Inhibitors; D019258:Saquinavir