Clinical resistance to vicriviroc through adaptive V3 loop mutations in HIV-1 subtype D gp120 that alter interactions with the N-terminus and ECL2 of CCR5

Ogert, Robert A.; Yan, Huihuang; Ba, Lei; Wojcik, Lisa; Qiu, Ping; Murgolo, Nicholas; Duca, José S.; Dunkle, Lisa M.; Ralston, Robert; Howe, John A.

doi:10.1016/j.virol.2010.01.037

Cited by 40 publications

(56 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Resistance to CCR5 antagonists has been described for HIV-1 from subjects with subtypes B, C, and D (6,26,27,34,35,48,54). Mutations in the V3 loop have been observed in most but not all cases.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Clinical Isolates Resistant to CCR5 Antagonists Exhibit Delayed Entry Kinetics That Are Corrected in the Presence of Drug

Putcharoen

Lee

Henrich

et al. 2012

J Virol

View full text Add to dashboard Cite

HIV CCR5 antagonists select for env gene mutations that enable virus entry via drug-bound coreceptor. To investigate the mechanisms responsible for viral adaptation to drug-bound coreceptor-mediated entry, we studied viral isolates from three participants who developed CCR5 antagonist resistance during treatment with vicriviroc (VCV), an investigational small-molecule CCR5 antagonist. VCV-sensitive and -resistant viruses were isolated from one HIV subtype C-and two subtype B-infected participants; VCV-resistant isolates had mutations in the V3 loop of gp120 and were cross-resistant to TAK-779, an investigational antagonist, and maraviroc (MVC). All three resistant isolates contained a 306P mutation but had variable mutations elsewhere in the V3 stem. We used a virus-cell ␤-lactamase (BlaM) fusion assay to determine the entry kinetics of recombinant viruses that incorporated full-length VCV-sensitive and -resistant envelopes. VCV-resistant isolates exhibited delayed entry rates in the absence of drug, relative to pretherapy VCV-sensitive isolates. The addition of drug corrected these delays. These findings were generalizable across target cell types with a range of CD4 and CCR5 surface densities and were observed when either populationderived or clonal envelopes were used to construct recombinant viruses. V3 loop mutations alone were sufficient to restore virus entry in the presence of drug, and the accumulation of V3 mutations during VCV therapy led to progressively higher rates of viral entry. We propose that the restoration of pre-CCR5 antagonist therapy HIV entry kinetics drives the selection of V3 loop mutations and may represent a common mechanism that underlies the emergence of CCR5 antagonist resistance. Human immunodeficiency virus entry is a competition at the target cell membrane between viral inactivation and successful binding to CD4 and a coreceptor, either CCR5 or CXCR4 (16,30,32,33,37,38). Engagement of receptor and coreceptor by gp120 and the subsequent rearrangement of gp41, the HIV fusion glycopeptides, leads to fusion (18,21,29,57,60,63). Smallmolecule antagonists that bind CCR5 and inhibit gp120-CCR5 binding through an allosteric mechanism have been developed (9,23,51,53,56,61). Maraviroc (MVC) is an FDA-approved CCR5 antagonist, and vicriviroc (VCV) is an investigational compound whose development has been halted (10, 47).HIV can escape CCR5 antagonism through the outgrowth of preexisting CXCR4-using populations or by the selection of resistance mutations (2, 52, 58). Mutations in the third hypervariable loop (V3 loop) of HIV-1 gp120 most commonly cause CCR5 antagonist resistance, but no canonical sites or amino acid substitutions have been identified; resistance mutations from one isolate generally do not confer resistance when transferred into unrelated env backbones (12, 17, 24, 26, 27, 34-36, 49, 54). This varied nature of HIV CCR5 antagonist genotypic resistance contrasts with resistance patterns established in other antiretroviral drug classes, for which canonical mutations (M184V in r...

show abstract

Section: Discussionmentioning

confidence: 99%

HIV-1 Clinical Isolates Resistant to CCR5 Antagonists Exhibit Delayed Entry Kinetics That Are Corrected in the Presence of Drug

Putcharoen

Lee

Henrich

et al. 2012

J Virol

View full text Add to dashboard Cite

show abstract

“…Virus-CCR5 binding involves interactions between the Tyr-sulfated N terminus (NT) and the second extracellular loop (ECL2) of the coreceptor and the 4-stranded bridging sheet and V3 region of the gp120 glycoprotein, respectively (20,21). In the most common genetic route to resistance, multiple sequence changes in V3 make the virus more dependent on the CCR5 NT (4,7,27,(37)(38)(39)55). A much rarer pathway involves changes in the fusion peptide (FP) of the gp41 protein, but the resistance mechanism is unknown (3).…”

mentioning

confidence: 99%

Multiple CCR5 Conformations on the Cell Surface Are Used Differentially by Human Immunodeficiency Viruses Resistant or Sensitive to CCR5 Inhibitors

Berro

Klasse

Lascano

et al. 2011

J Virol

View full text Add to dashboard Cite

Resistance to small-molecule CCR5 inhibitors arises when HIV-1 variants acquire the ability to use inhibitor-bound CCR5 while still recognizing free CCR5. Two isolates, CC101.19 and D1/85.16, became resistant via four substitutions in the gp120 V3 region and three in the gp41 fusion peptide (FP), respectively. The binding characteristics of a panel of monoclonal antibodies (MAbs) imply that several antigenic forms of CCR5 are expressed at different levels on the surfaces of U87-CD4-CCR5 cells and primary CD4؉ T cells, in a cell-typedependent manner. CCR5 binding and HIV-1 infection inhibition experiments suggest that the two CCR5 inhibitor-resistant viruses altered their interactions with CCR5 in different ways. As a result, both mutants became generally more sensitive to inhibition by CCR5 MAbs, and the FP mutant is specifically sensitive to a MAb that stains discrete cell surface clusters of CCR5 that may correspond to lipid rafts. We conclude that some MAbs detect different antigenic forms of CCR5 and that inhibitor-sensitive and -resistant viruses can use these CCR5 forms differently for entry in the presence or absence of CCR5 inhibitors.The small-molecule CCR5 inhibitors maraviroc (MVC) and vicriviroc (VVC) are, or have been, used to treat human immunodeficiency virus type 1 (HIV-1) infection. They bind in the transmembrane helices and stabilize CCR5 in a conformation the viral Env complex cannot use efficiently (14,26,47). Resistant viruses usually gain the ability to enter cells via inhibitor-bound CCR5 while retaining the use of free CCR5 (46, 57). Virus-CCR5 binding involves interactions between the Tyr-sulfated N terminus (NT) and the second extracellular loop (ECL2) of the coreceptor and the 4-stranded bridging sheet and V3 region of the gp120 glycoprotein, respectively (20,21). In the most common genetic route to resistance, multiple sequence changes in V3 make the virus more dependent on the CCR5 NT (4,7,27,(37)(38)(39)55). A much rarer pathway involves changes in the fusion peptide (FP) of the gp41 protein, but the resistance mechanism is unknown (3). These pathways were followed when resistant isolates CC101.19 and D1/85.16 were derived from CC1/85 under selection by two similar inhibitors, AD101 and VVC, in peripheral blood mononuclear cells (PBMCs); the most critical resistance-associated substitutions in the escape mutant viruses were four in V3 and three in the FP (27,33). In this study, we used infectious Env chimeric clones, Res-4V3 derived from CC101.19 and Res-3FP from D1/85.16, together with the parental clones Par-4V3 and Par-3FP, derived from CC1/85, which were chosen based on sequence similarities with Res-4V3 and Res-3FP (7).The HIV-1 coreceptors CCR5 and CXCR4 exist in heterogeneous forms (6, 29), influenced by factors such as posttranslational modifications, coupling to G proteins, and the lipid environment (5,8,15,34,35). CCR5 monoclonal antibodies (MAbs) can vary considerably in how they stain different cell types in a way that is not always explained by CCR5 expression levels (1...

show abstract

“…The altered virus-CCR5 interactions are nonetheless characterized by considerable complexity. 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].…”

Section: Mechanisms Of Resistance To Small Molecule Ccr5 Inhibitorsmentioning

confidence: 99%

Chemokine Receptors as Therapeutic Targets in HIV Infection

Anastassopoulou¹

2012

Immunodeficiency

View full text Add to dashboard Cite

Clinical resistance to vicriviroc through adaptive V3 loop mutations in HIV-1 subtype D gp120 that alter interactions with the N-terminus and ECL2 of CCR5

Cited by 40 publications

References 39 publications

HIV-1 Clinical Isolates Resistant to CCR5 Antagonists Exhibit Delayed Entry Kinetics That Are Corrected in the Presence of Drug

HIV-1 Clinical Isolates Resistant to CCR5 Antagonists Exhibit Delayed Entry Kinetics That Are Corrected in the Presence of Drug

Multiple CCR5 Conformations on the Cell Surface Are Used Differentially by Human Immunodeficiency Viruses Resistant or Sensitive to CCR5 Inhibitors

Chemokine Receptors as Therapeutic Targets in HIV Infection

Contact Info

Product

Resources

About