Abstract
Viral resistance to small molecule allosteric inhibitors of CCR5 is well documented, and involves either selection of preexisting CXCR4-using HIV-1 variants or envelope sequence evolution to use inhibitor-bound CCR5 for entry. Resistance to macromolecular CCR5 inhibitors has been more difficult to demonstrate, although selection of CXCR4-using variants might be expected. We have compared the in vitro selection of HIV-1 CC1/85 variants resistant to either the small molecule inhibitor maraviroc (MVC) or the macromolecular inhibitor 5P12-RANTES. High level resistance to MVC was conferred by the same envelope mutations as previously reported after 16–18 weeks of selection by increasing levels of MVC. The MVC-resistant mutants were fully sensitive to inhibition by 5P12-RANTES. By contrast, only transient and low level resistance to 5P12-RANTES was achieved in three sequential selection experiments, and each resulted in a subsequent collapse of virus replication. A fourth round of selection by 5P12-RANTES led, after 36 weeks, to a “resistant” variant that had switched from CCR5 to CXCR4 as a coreceptor. Envelope sequences diverged by 3.8% during selection of the 5P12-RANTES resistant, CXCR4-using variants, with unique and critical substitutions in the V3 region. A subset of viruses recovered from control cultures after 44 weeks of passage in the absence of inhibitors also evolved to use CXCR4, although with fewer and different envelope mutations. Control cultures contained both viruses that evolved to use CXCR4 by deleting four amino acids in V3, and others that maintained entry via CCR5. These results suggest that coreceptor switching may be the only route to resistance for compounds like 5P12-RANTES. This pathway requires more mutations and encounters more fitness obstacles than development of resistance to MVC, confirming the clinical observations that resistance to small molecule CCR5 inhibitors very rarely involves coreceptor switching.
Highlights
Primary transmission of human immunodeficiency virus type 1 (HIV-1) infection is highly selective in two respects
Our primary finding is that resistance to the small molecule chemokine receptor 5 (CCR5) inhibitor MVC could be generated in the same time frame and by the same apparent mechanism as previously described [39], whereas resistance to the macromolecular CCR5 inhibitor 5P12-RANTES developed only after four successive rounds of selection by coreceptor switching to CXCR4
This route to resistance must be viewed in the context of control cultures where virus evolution to the use of CXCR4 as a coreceptor occurred, albeit at a slower pace, with fewer and different envelope mutations, and with better preservation of CCR5 use
Summary
Primary transmission of human immunodeficiency virus type 1 (HIV-1) infection is highly selective in two respects. Transmission of HIV-1 strains that use C-C chemokine receptor 5 (CCR5) as the entry coreceptor is highly favored [5,6,7,8,9,10], consistent with the observation that individuals with deletion mutations in the coding region of CCR5 are highly resistant to HIV-1 infection [11,12,13] These results imply that blocking HIV-1 binding to CCR5 is a viable strategy to prevent transmission, and non-human primate studies fully support this concept [14,15,16,17,18]. Maraviroc (Pfizer) was the first of these CCR5 inhibitors to be approved for clinical use, and has proven to be an effective antiviral agent in both treatment-naive and treatment-experienced individuals with predominately CCR5-using (R5) HIV-1 infection [34,35,36]
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