Reverse transcriptase inhibitors as potential colorectal microbicides.
We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.
Herrera
Carolina
C
Division of Cellular and Molecular Medicine, St George's University of London, Cranmer Terrace, London SW17 0RE, United Kingdom.
Cranage
Martin
M
McGowan
Ian
I
Anton
Peter
P
Shattock
Robin J
RJ
D000225:Adenine / Q000031:analogs & derivatives; D000813:Anilides; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D000891:Anti-Infective Agents, Local / Q000494:pharmacology / Q000627:therapeutic use; D003106:Colon / Q000187:drug effects / Q000821:virology; D024882:Drug Resistance, Viral; D005663:Furans; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007963:Leukocytes, Mononuclear; D063065:Organophosphonates; D011743:Pyrimidines; D012007:Rectum / Q000187:drug effects / Q000821:virology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000068698:Tenofovir; D013854:Thioamides; D046509:Tissue Culture Techniques / Q000379:methods*; D014779:Virus Replication
D000813:Anilides; D019380:Anti-HIV Agents; D000891:Anti-Infective Agents, Local; D005663:Furans; D063065:Organophosphonates; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D013854:Thioamides; D000068698:Tenofovir; D000225:Adenine; C100668:UC-781; C481671:Dapivirine