Distinct efficacy of HIV-1 entry inhibitors to prevent cell-to-cell transfer of R5 and X4 viruses across a human placental trophoblast barrier in a reconstitution model in vitro.
METHODS
HIV-1 cell-to-cell transmission is more efficient than infection of permissive cells with cell-free particles. The potency of HIV-1 entry inhibitors to inhibit such transmission is not well known. Herein, we evaluated the efficacy of this new class of antiretrovirals to block cell-to-cell transmission of HIV-1 in a model of reconstitution of the human placental trophoblast barrier in vitro.


RESULTS
Our data show that CCR5 antagonists and T20 inhibit the passage of the virus across the BeWo cell monolayer in contact with PBMCs infected with an R5 (Ba-L) and a dualtropic (A204) HIV-1 with IC50s in the range of 100 - 5,000 nM for TAK779; 90 to 15,000 nM for SCH-350581 and 3,000 to 20,000 nM for T20. The CXCR4 antagonist AMD3100 is also effective against X4 HIV-1 infected PBMCs in our model with IC50 comprised between 4 nM and 640 nM. HIV-1 entry inhibitors are less efficient to block cell-to-cell virus transmission than cell-free HIV-1 infection of PBMCs and CCR5 antagonists do not prevent PBMC infection by dual tropic HIV-1 in contrast to cell-to-cell infection in our model.Surprisingly, T20 (and C34) do not block cell-to-cell transmission of X4 HIV-1 but, rather, increase 80 to 140 fold, compared to control without drug, the passage of the virus across the trophoblast barrier. Additional experiments suggest that the effect of T20 on BeWo/PBMC-X4 HIV-1 is due to an increase of effector-target cells fusion.


CONCLUSIONS
Our results support further evaluation of HIV-1 coreceptor antagonists, alone or combined to other antiretrovirals, in a perspective of prevention but warn on the use of T20 in patients bearing X4 HIV-1 at risk of transmission.
Ayouba
Ahidjo
A
Institut Pasteur, Département de Virologie, Unité Régulation des Infections Rétrovirales, 25 rue du Dr Roux, 75724 Paris cedex 15, France. ahidjo.ayouba@mpl.ird.fr
Cannou
Claude
C
Nugeyre
Marie-Thérèse
MT
Barré-Sinoussi
Françoise
F
Menu
Elisabeth
E
D001596:Benzylamines; D065100:CCR5 Receptor Antagonists; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D002450:Cell Communication / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D000080027:Cyclams; D000077560:Enfuvirtide; D005260:Female; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008954:Models, Biological; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010920:Placenta / Q000821:virology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000821:virology*; D014779:Virus Replication
C523280:AD 101; D001596:Benzylamines; D065100:CCR5 Receptor Antagonists; D000080027:Cyclams; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D006571:Heterocyclic Compounds; D010446:Peptide Fragments; D010879:Piperazines; D019718:Receptors, CXCR4; C407149:peptide C34; D000077560:Enfuvirtide; D009536:Niacinamide; C088327:plerixafor