A Maraviroc-Resistant HIV-1 with Narrow Cross-Resistance to Other CCR5 Antagonists Depends on both N-Terminal and Extracellular Loop Domains of Drug-Bound CCR5

Abstract

CCR5 antagonists inhibit HIV entry by binding to a coreceptor and inducing changes in the extracellular loops (ECLs) of CCR5. In this study, we analyzed viruses from 11 treatment-experienced patients who experienced virologic failure on treatment regimens containing the CCR5 antagonist maraviroc (MVC). Viruses from one patient developed high-level resistance to MVC during the course of treatment. Although resistance to one CCR5 antagonist is often associated with broad cross-resistance to other agents, these viruses remained sensitive to most other CCR5 antagonists, including vicriviroc and aplaviroc. MVC resistance was dependent upon mutations within the V3 loop of the viral envelope (Env) protein and was modulated by additional mutations in the V4 loop. Deep sequencing of pretreatment plasma viral RNA indicated that resistance appears to have occurred by evolution of drug-bound CCR5 use, despite the presence of viral sequences predictive of CXCR4 use. Envs obtained from this patient before and during MVC treatment were able to infect cells expressing very low CCR5 levels, indicating highly efficient use of a coreceptor. In contrast to previous reports in which CCR5 antagonist-resistant viruses interact predominantly with the N terminus of CCR5, these MVC-resistant Envs were also dependent upon the drug-modified ECLs of CCR5 for entry. Our results suggest a model of CCR5 cross-resistance whereby viruses that predominantly utilize the N terminus are broadly cross-resistant to multiple CCR5 antagonists, whereas viruses that require both the N terminus and antagonist-specific ECL changes demonstrate a narrow cross-resistance profile.

CCR5 Antagonist TD-0680 Uses a Novel Mechanism for Enhanced Potency against HIV-1 Entry, Cell-mediated Infection, and a Resistant Variant

“…Although rare, treatment failure has been documented due to Maraviroc-resistant R5-tropic-remaining viruses detected in Maraviroc-treated patients (45). It should be mentioned that despite rigorous efforts, we have not been able to obtain a TD-0680-resistant virus even though non-nucleoside reverse transcriptase inhibitor F18-resistant viruses were readily generated in our laboratory (18).…”

“…This mechanism may explain the superior activity of TD-0680 against the TAK-779/Maraviroc-resistant HIV-1 BaL -c5.6r strain, which is a competitive resistant virus and may use a different yet ECL2-dependent conformation for entry (44). Besides the physical barrier, it is possible that the inhibitory mechanism of TD-0680 also involves a bigger conformational change in the ECL2 of CCR5 that is no longer recognizable by HIV-1 through an allosteric binding to the transmembrane domains (22,41,45). These novel findings have important implications for drug design.…”

Chemokine Receptors as Therapeutic Targets in HIV Infection

“…Nevertheless, introducing the three FP changes together into a heterologous virus, JR-FL, did not create a VCV-resistant variant [126]. CCR5 inhibitor resistance is usually dependent upon the Env genetic context and it is not transferred when introduced into other viruses [124,126,132], but that is not always the case [129]. ND, Not determined; I322aV occurs at an amino acid not present in HXB2 located between residues 322 and 323 and is designated 322a.…”

“…Thus, a subtype D, VCV-resistant patient isolate recognizes the drug-bound form of CCR5 more efficiently but still uses both the Nt and ECL2 [123]. A recently proposed model suggests that broad cross-resistance to multiple inhibitors is associated with an increased dependence on the N-terminus, while a more specific pattern of resistance to individual compounds involves more subtle changes in how the virus interacts with both the Nt and ECL2 [129].…”

Point Mutations Associated with HIV-1 Drug Resistance, Evasion of the Immune Response and AIDS Pathogenesis

“…Further complicating the genetic basis of maraviroc or CCR5 inhibitor resistance is the observation that the same inhibitor may select for different mutations in different HIV-1 isolates (Westby et al, 2007). The mutations observed in maraviroc-resistant strains isolated from patients are variable and differed for each HIV-1 isolate (Seclen et al, 2011;Tilton et al, 2011). and T275M, these mutations confer complete resistance to maraviroc.…”