Isolation of TAK-779-resistant HIV-1 from an R5 HIV-1 GP120 V3 Loop Library

Yusa, Kosuke; Maeda, Yosuke; Fujioka, Aki; Monde, Kazuaki; Harada, Shinji

doi:10.1074/jbc.m414360200

Cited by 32 publications

(40 citation statements)

References 44 publications

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“…There are other differences in the pattern of amino acid variability in these two subtypes beyond the differences in the consensus VOL. 82,2008 DIFFERENCES IN SUBTYPE B AND C V3 CONFORMATIONS 905 sequences, in which patterns of substitution differ dramatically even at those positions with the same consensus amino acid (adding detail to the entropy differences). In this analysis, we found that 13 individual positions in subtype B and C sequences differed significantly in patterns of substitution (positions 5, 11 to 16, 18 to 20, 22, 24, and 25), with only positions 5 and 25 occurring outside of the stem and turn regions from positions 9 to 24 ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

Subtype-Specific Conformational Differences within the V3 Region of Subtype B and Subtype C Human Immunodeficiency Virus Type 1 Env Proteins

Patel

Hoffman

Swanstrom

2008

J Virol

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The V3 region of the human immunodeficiency virus type 1 gp120 Env protein is a key domain in Env due to its role in interacting with the coreceptors CCR5 and CXCR4. We examined potential subtype-specific V3 region differences by comparing patterns of amino acid variability and probing for subtype-specific structures using 11 anti-V3 monoclonal antibodies (V3 MAbs). Differences between the subtypes in patterns of variability were most evident in the stem and turn regions of V3 (positions 9 to 24), with the two subtypes being very similar in the base region. The characteristics of the binding of V3 MAbs to Env proteins of the subtype B virus JR-FL and the subtype C virus BR025 suggested three patterns, as each group of MAbs recognized a specific conformation-or sequence-based epitope. Viruses pseudotyped with Env from JR-FL and BR025 were resistant to neutralization by the V3 MAbs, although the replacement of the Env V3 region of the SF162 virus with the JR-FL V3 created a pseudotyped virus that was hypersensitive to neutralization. A single mutation in V3 (H13R) made this chimeric Env selectively resistant to one group of V3 MAbs, consistent with the mAb binding properties. We hypothesize that there are intrinsic differences in V3 conformation between subtype B and subtype C that are localized to the stem and turn regions and that these differences have two important biological consequences: first, subtype B and subtype C V3 regions can have subtype-specific epitopes that will inherently limit antibody cross-reactivity, and second, V3 conformational differences may potentiate the frequent evolution of R5-into X4-tropic variants of subtype B but limit subtype C virus from using the same mechanism to evolve X4-tropic variants as efficiently.The binding of the human immunodeficiency virus type 1 (HIV-1) to its target cell is mediated by the viral envelope glycoprotein Env. The glycoprotein is expressed as a gp160 precursor that is proteolytically cleaved into two mature subunits, the gp120 surface protein and the gp41 transmembrane protein. On the surface of the virus, Env is present as a trimer of the gp120 and gp41 heterodimers (2, 62). When the virus binds to its primary receptor, CD4, Env undergoes conformational changes, exposing previously hidden regions and creating new structural elements. Env then binds to a coreceptor, usually the chemokine receptor CCR5 or CXCR4 (23, 26, 80), which triggers further structural changes that promote fusion to the target cell (27, 35).The Env sequence can be viewed as being composed of regions that are relatively constant (C1 to C5) and regions that on a population basis are much more variable (V1 to V5) (70). As the only viral protein expressed on the surface of the virus, Env is the sole target of neutralizing antibodies that supply selective pressure to favor mutated variants capable of evading the immune response (47, 79). The V3 region is associated with coreceptor preference and physically contacts the chemokine receptor as part of the fusion process (23,26,80). Sequen...

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Section: Resultsmentioning

confidence: 99%

Subtype-Specific Conformational Differences within the V3 Region of Subtype B and Subtype C Human Immunodeficiency Virus Type 1 Env Proteins

Patel

Hoffman

Swanstrom

2008

J Virol

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“…Loop Library in PM1/CCR5 Cells-An R5 HIV-1 V3 loop library was constructed carrying a set of random combinations of 0 -10 amino acid substitutions in the V3 loop (34) (Fig. 1).…”

Section: Replication Suppression Of Viruses From the R5 Hiv-1 V3mentioning

confidence: 99%

“…R5 viruses, carrying a set of random amino acid substitutions in the gp120 V3 loop, were derived from the HIV-1 V3 loop library (34). For construction of V3 loop mutant viruses, amino acid substitutions were introduced into the gp120 V3 loop of pJR-FL an , as described previously (34). For virus preparation, 293T cells (1 ϫ 10 6 ) were transfected with 10 g of molecular clone DNA using the calcium phosphate ProFection Mammalian Transfection System (Promega).…”

Section: Cells and Viruses-the Human Cd4mentioning

confidence: 99%

“…This paper addresses whether the level of CCR5 in CD4 ϩ T-cell lines influences R5 HIV-1 replication, including late stages of the viral lifecycle. To evaluate the effect of V3 loop on viral replication with respect to CCR5 expression, 45 replication-competent mutant viruses carrying multiple amino acid substitutions in the gp120 V3 loop were used which were derived from an R5 HIV-1 V3 loop library using HIV-1 JR-FLan as background (34). The library contained a set of random combinations of 0 -10 polymorphic amino acid substitutions observed in 31 R5 clinical isolates.…”

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confidence: 99%

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Gp120 V3-dependent Impairment of R5 HIV-1 Infectivity Due to Virion-incorporated CCR5

Monde

Maeda

Tanaka

et al. 2007

Journal of Biological Chemistry

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Entry of R5 human immunodeficiency virus type 1 (HIV-1) into target cells requires sequential interactions of the envelope glycoprotein gp120 with the receptor CD4 and the coreceptor CCR5. We investigated replication of 45 R5 viral clones derived from the HIV-1 JR-FLan library carrying 0 -10 random amino acid substitutions in the gp120 V3 loop. It was found that 6.7% (3/45) of the viruses revealed >10-fold replication suppression in PM1/CCR5 cells expressing high levels of CCR5 compared with PM1 cells expressing low levels of CCR5. In HIV-1 V3L#08 , suppression of replication was not associated with entry events and viral production but with a marked decrease in infectivity of nascent progeny virus. HIV-1 V3L#08 , generated from infected PM1/CCR5 cells, was 98% immunoprecipitated by anti-CCR5 monoclonal antibody T21/8, whereas the other infectious viruses were only partially precipitated, suggesting that incorporation of larger amounts of CCR5 into the virions caused impairment of viral infectivity in HIV-1 V3L#08 . The results demonstrate the implications of an alternative influence of CCR5 on HIV-1 replication.Entry of R5 human immunodeficiency virus type 1 (HIV-1) 2 into a target cell requires cooperative interactions of the viral envelope protein gp120 with the receptor CD4 and the coreceptor CCR5 (or CXCR4 for X4 HIV-1) (1-3). These interactions depend on the concentration and distribution of receptor and coreceptor molecules on the cell surface (4 -7). Cells with a large amount of CD4 only require trace amounts of CCR5 for maximal susceptibility to infection by R5 HIV-1, whereas cells low in CD4 require larger amounts of CCR5 for maximal infection (6,8). Sequential binding of the viral surface glycoprotein gp120 to CD4 and CCR5 initiates R5 HIV-1 infection; CD4 attachment induces a conformational change in gp120 that exposes a CCR5 binding domain (9 -11). The coreceptor-binding site located in the bridging sheet and the V3 loop of gp120 also play a crucial role in interacting with the N-terminal domains of the CCR5 (12-16). Finally, direct interaction between CCR5 and the V3 loop (35-37 amino acid residues) in gp120 induces structural rearrangements of a fusion peptide of gp41, allowing fusion of viral and cellular membranes (14,15,(17)(18)(19).Envelope viruses are known to down-modulate the receptor expression on infected cells to prevent reinfection (20, 21). Post-entry, HIV infection leads to a rapid and potent downmodulation of CD4 molecules expressed at the cell surface. Three viral gene products, Nef, Env, and Vpu, are involved in trafficking and catabolism of down-modulating CD4. Nef enhances CD4 internalization and directs the receptor to lysosomes for degradation (22-27), whereas Env and Vpu interfere with the transport of newly synthesized CD4 to the cell surface (28,29). Without strict CD4 down-modulation, CD4 induces trapping and aggregation of nascent progeny virions at the cell surface by the high affinity of gp120 for CD4 (30) and a dramatic reduction in the infectivity of released virions b...

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“…Although maraviroc (MVC), which is the first and currently only approved CCR5 antagonist for the treatment of CCR5-tropic (R5) HIV-1 infected patients, and another CCR5 inhibitor, vicriviroc (VCV), can efficiently suppress HIV-1 replication, drug-resistant variants can arise both in vitro and in vivo using drug-bound CCR5 for cellular entry (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). The presence of MVC-resistant HIV-1 variants may be due to the outgrowth of pre-existing CXCR4-tropic (X4) HIV-1 viruses (19,20) or the selection of MVC-resistant R5 mutants (12,17).…”

Section: Introductionmentioning

confidence: 99%

Impact of the Maraviroc-Resistant Mutation M434I in the C4 Region of HIV-1 gp120 on Sensitivity to Antibody-Mediated Neutralization

et al. 2016

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SUMMARY:We previously reported that a maraviroc (MVC)-resistant human immunodeficiency virus type 1variant, generated using in vitro selection, exhibited high sensitivity to several neutralizing monoclonal antibodies (NMAbs) and autologous plasma IgGs. The MVC-resistant variant acquired 4 sequential mutations in gp120: T297I, M434I, V200I, and K305R. In this study, we examined the mutation most responsible for conferring enhanced neutralization sensitivity of the MVC-resistant variant to several NMAbs and autologous plasma IgGs. The virus with the first resistant mutation, T297I, was sensitive to all NMAbs, whereas the passage control virus was not. The neutralization sensitivity of the variant greatly increased following its acquisition of the second mutation, M434I, in the C4 region. The M434I mutation conferred the greatest neutralizing sensitivity among the 4 MVC-resistant mutations. Additionally, the single M434I mutation was sufficient for the enhanced neutralization of the virus by NMAbs, autologous plasma IgGs, and heterologous sera relative to that of the parental virus.

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Isolation of TAK-779-resistant HIV-1 from an R5 HIV-1 GP120 V3 Loop Library

Cited by 32 publications

References 44 publications

Subtype-Specific Conformational Differences within the V3 Region of Subtype B and Subtype C Human Immunodeficiency Virus Type 1 Env Proteins

Subtype-Specific Conformational Differences within the V3 Region of Subtype B and Subtype C Human Immunodeficiency Virus Type 1 Env Proteins

Gp120 V3-dependent Impairment of R5 HIV-1 Infectivity Due to Virion-incorporated CCR5

Impact of the Maraviroc-Resistant Mutation M434I in the C4 Region of HIV-1 gp120 on Sensitivity to Antibody-Mediated Neutralization

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