<i>In Vitro</i>Antiviral Characteristics of HIV-1 Attachment Inhibitor BMS-626529, the Active Component of the Prodrug BMS-663068

Nowicka-Sans, Beata; Gong, Yi-Fei; McAuliffe, Brian; Dicker, Ira B.; Ho, Hsu‐Tso; Zhou, Nannan; Eggers, Betsy J.; Lin, Pin‐Fang; Ray, Neelanjana; Wind‐Rotolo, Megan; Zhu, Li; Majumdar, Antara; Stock, David A.; Lataillade, Max; Hanna, George J.; Matiskella, John D.; Ueda, Yasutsugu; Wang, Tao; Kadow, John F.; Meanwell, Nicholas A.; Krystal, Mark

doi:10.1128/aac.00426-12

Cited by 125 publications

(132 citation statements)

References 31 publications

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“…M-tropic Env proteins effected a 62-fold increase in average entry at the lowest density of CD4 over subject-matched T-tropic Env proteins (t paired ϭ 4.2, df ϭ 6, P value ϭ 0.006). M-tropic Env proteins also had enhanced CD4 usage over the entire range of CD4 densities as described by a 2.7-fold-lower EC 50 (t paired ϭ 3.1, df ϭ 6, P value ϭ 0.02) and a 1.8-fold-lower Hill slope (t paired ϭ 10, df ϭ 6, P value Ͻ 0.0001) compared to subject-matched T-tropic Env proteins. (b) Five pairs of T-tropic and M-tropic env genes were pseudotyped in triplicate with either a subtype B (top, transfections 1 to 3) or subtype C (bottom, transfections 4 to 6) env-deficient HIV-1 genome containing a firefly (subtype B) or Renilla (subtype C) luciferase reporter gene.…”

Section: Identification Of Macrophage-tropic and Paired T Cell-tropicmentioning

confidence: 99%

“…In general, the IC 50 s were indistinguishable between paired M-tropic and T-tropic viruses and ranged from 0.34 nM to 4.2 nM, which is typical for primary isolates. Two exceptions were the 5002T Env protein, which was highly resistant (IC 50 ϭ 310 nM) and contained the known resistance mutation S375M (50), and the 4013T Env protein, which was moderately resistant (IC 50 ϭ 42.0 nM) and had no known resistance mutations. A tight range of IC 50 s across Env proteins suggests that the BMS-626529 inhibitor is able to access and interact similarly with its target in the CD4bs on both M-tropic and T-tropic Env proteins.…”

Section: Identification Of Macrophage-tropic and Paired T Cell-tropicmentioning

confidence: 99%

“…We also probed the CD4bs of these viruses using the inhibitor BMS-626529 (Table 2), which is thought to interact with a target overlapping the CD4bs, though there are conflicting reports about whether BMS-626529 competes with CD4 for binding to the CD4bs or whether it binds outside the CD4bs and prevents assumption of the CD4i Env protein conformation (49,50). In general, the IC 50 s were indistinguishable between paired M-tropic and T-tropic viruses and ranged from 0.34 nM to 4.2 nM, which is typical for primary isolates.…”

Section: Identification Of Macrophage-tropic and Paired T Cell-tropicmentioning

confidence: 99%

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Phenotypic Correlates of HIV-1 Macrophage Tropism

Arrildt

LaBranche

Joseph

et al. 2015

J Virol

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HIV-1 is typically CCR5 using (R5) and T cell tropic (T-tropic), targeting memory CD4؉ T cells throughout acute and chronic infections. However, viruses can expand into alternative cells types. Macrophage-tropic (M-tropic) HIV-1 variants have evolved to infect macrophages, which have only low levels of surface CD4. Most M-tropic variants have been isolated from the central nervous system during late-stage chronic infection. We used the HIV-1 env genes of well-defined, subject-matched M-tropic and T-tropic viruses to characterize the phenotypic features of the M-tropic Env protein. We found that, compared to T-tropic viruses, M-tropic viruses infect monocyte-derived macrophages (MDMs) on average 28-fold more efficiently, use low-density CD4 more efficiently, have increased sensitivity to soluble CD4 (sCD4), and show trends toward sensitivity to some CD4 binding site antibodies but no difference in sensitivity to antibodies targeting the CD4-bound conformation. M-tropic viruses also displayed a trend toward resistance to neutralization by monoclonal antibodies targeting the V1/V2 region of Env, suggesting subtle changes in Env protein conformation. The paired M-and T-tropic viruses did not differ in autologous serum neutralization, temperature sensitivity, entry kinetics, intrinsic infectivity, or Env protein incorporation. We also examined viruses with modestly increased CD4 usage. These variants have significant sensitivity to sCD4 and may represent evolutionary intermediates. CD4 usage is strongly correlated with infectivity of MDMs over a wide range of CD4 entry phenotypes. These data suggest that emergence of M-tropic HIV-1 includes multiple steps in which a phenotype of increased sensitivity to sCD4 and enhanced CD4 usage accompany subtle changes in Env conformation. IMPORTANCE HIV-1 typically replicates in CD4؉ T cells. However, HIV-1 can evolve to infect macrophages, especially within the brain. Understanding how CCR5-using macrophage-tropic viruses evolve and differ from CCR5-using T cell-tropic viruses may provide insights into viral evolution and pathogenesis within the central nervous system. We characterized the HIV-1 env viral entry gene from subject-matched macrophage-tropic and T cell-tropic viruses to identify entry features of macrophage-tropic viruses. We observed several differences between T cell-tropic and macrophage-tropic Env proteins, including functional differences with host CD4 receptor engagement and possible changes in the CD4 binding site and V1/V2 region. We also identified viruses with phenotypes between that of "true" macrophage-tropic and T cell-tropic viruses, which may represent evolutionary intermediates in a multistep process to macrophage tropism. HIV-1 host cell entry is determined solely by the virion surface protein Env. The Env protein precursor gp160 is cleaved into two proteins: the external gp120 protein and the membrane-spanning gp41 protein, which remain associated as a heterodimer and form trimers of these heterodimers. Attachment of gp120 to the host CD4 ...

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Section: Identification Of Macrophage-tropic and Paired T Cell-tropicmentioning

confidence: 99%

Section: Identification Of Macrophage-tropic and Paired T Cell-tropicmentioning

confidence: 99%

Section: Identification Of Macrophage-tropic and Paired T Cell-tropicmentioning

confidence: 99%

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Phenotypic Correlates of HIV-1 Macrophage Tropism

Arrildt

LaBranche

Joseph

et al. 2015

J Virol

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“…2A and B) also raises the possibility that in addition to binding the closed conformation, broadly neutralizing antibodies may inhibit transition out of the ground state, thereby preventing activation of Env. A potent small-molecule HIV-1 entry inhibitor, BMS-626529 (15), similarly stabilized the closed ground state. This suggests that ground state stabilization may be a general means of inhibiting HIV-1 entry.…”

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confidence: 99%

Structure and Dynamics of the Native HIV-1 Env Trimer

Munro

Mothes

2015

J Virol

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bHIV-1/AIDS remains one of the worst pandemics in human history. Despite tremendous efforts, no effective vaccine has been found. Recent reports give new insights into the structure and dynamics of the HIV-1 Env trimer and renew hopes that a better understanding of Env will translate into new vaccine candidates and more-effective antiretroviral therapies. HIV type 1 (HIV-1) is the etiological agent of the AIDS pandemic. Over 70 million people have been infected by the virus, and ϳ39 million have died from AIDS-related illness. Antiretroviral therapy has reached ϳ11 million people and allows many HIV-1-infected people a long life span. However, the lifelong chemotherapy is not without side effects, and the cancer burden among HIV-1-infected people remains elevated. Despite recent hopes that a cure might be possible (1-3), the more that we learn about the viral reservoir, the more that we realize how difficult it will be to eradicate HIV-1 in an infected patient (4-6). Given this situation, a low-cost preventative, such as a vaccine or an adeno-associated virus-delivered prophylactic, might be the preferred response to protect the human population (7). However, despite tremendous efforts, no effective vaccine has been found. This is due largely to specific features of the envelope glycoprotein (Env), which is uniquely exposed on the surface of the virion and as such is the primary target of antibodies.HIV-1 Env is synthesized as a gp160 precursor and processed into a trimer of a heterodimer containing gp120 and gp41 subunits. HIV-1 Env promotes entry into target cells by recognizing cellular receptors and fusing viral and cellular membranes. The gp120 receptor-binding domain of Env first engages cellular CD4. This interaction leads to a conformational rearrangement in Env that results in presentation of the coreceptor-binding site. Interaction with the coreceptor triggers the gp41 membrane fusion domain to mediate virus entry.Why is it so hard to generate a vaccine against HIV-1? In addition to recognizing cellular receptors, Env has evolved effective means of concealing functional centers from attack by antibodies. The Env trimer has three distinct features that make it an evasive machine that escapes neutralizing antibodies. First, Env is covered by a dense glycan layer that makes up half of its total molecular weight. This glycan shield restricts access of immunoglobulins to 97% of the Env surface (8). Second, the protein surface undergoes unusually rapid sequence variation. Approximately 50% of the Env surface has genetic variability greater than 10%. Taken together, these two factors result in only 2% of the Env surface being accessible to immunoglobulins with genetic variability of less than 10% (8). Third, the Env trimer has significant structural flexibility. Env can adopt a closed conformation, in which functional centers are masked while still responding to interactions with the receptor and coreceptor. The high glycosylation and the conformationally dynamic nature of Env has for many years impeded its s...

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“…By targeting the initial step in viral attachment and entry, BMS-626529 is not affected by coreceptor tropism and is therefore active against CCR5-tropic, CXCR4-tropic, and dual CCR5-and CXCR4-tropic (R5X4) strains of HIV-1 (6)(7)(8)(9)(10). Preliminary in vitro data show that HIV-1 isolates are generally susceptible to BMS-626529 irrespective of subtype, with the exception of subtype AE and, possibly, group O (8,9). BMS-626529 also has a unique resistance profile with no in vitro cross-resistance to other classes of antiretrovirals (7,8).…”

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confidence: 99%

Pharmacokinetic Interactions between BMS-626529, the Active Moiety of the HIV-1 Attachment Inhibitor Prodrug BMS-663068, and Ritonavir or Ritonavir-Boosted Atazanavir in Healthy Subjects

Zhu

Hruska

Hwang

et al. 2015

Antimicrob Agents Chemother

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BMS-663068 is a prodrug of BMS-626529, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4 ؉ T cells. This open-label, multiple-dose, four-sequence, crossover study addressed potential two-way drug-drug interactions following coadministration of BMS-663068 (BMS-626529 is a CYP3A4 substrate), atazanavir (ATV), and ritonavir (RTV) (ATV and RTV are CYP3A4 inhibitors). Thirty-six healthy subjects were randomized 1:1:1:1 to receive one of four treatment sequences with three consecutive treatments: BMS-663068 at 600 mg twice daily (BID), BMS-663068 at 600 mg BID plus RTV at 100 mg once daily (QD), ATV at 300 mg QD plus RTV at 100 mg QD (

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In VitroAntiviral Characteristics of HIV-1 Attachment Inhibitor BMS-626529, the Active Component of the Prodrug BMS-663068

Cited by 125 publications

References 31 publications

Phenotypic Correlates of HIV-1 Macrophage Tropism

Phenotypic Correlates of HIV-1 Macrophage Tropism

Structure and Dynamics of the Native HIV-1 Env Trimer

Pharmacokinetic Interactions between BMS-626529, the Active Moiety of the HIV-1 Attachment Inhibitor Prodrug BMS-663068, and Ritonavir or Ritonavir-Boosted Atazanavir in Healthy Subjects

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