The role of conventional antibodies targeting the CD4 binding site and CD4-induced epitopes in the control of HIV-1 CRF01_AE viruses

Thida, Win; Kuwata, Takeo; Maeda, Yosuke; Yamashiro, Tetsu; Tran, Giang Van; Nguyen, Kinh Van; Takiguchi, Masafumi; Gatanaga, Hiroyuki; Tanaka, Kazuki; Matsushita, Shuzo

doi:10.1016/j.bbrc.2018.11.063

Cited by 6 publications

(6 citation statements)

References 29 publications

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“…As we cloned only the V3 regions to determine coreceptor usage from plasma vRNAs, we next confirmed whether the cloned full-length Envs were functional and had the same coreceptor usages as those of the cloned V3 regions. Env expression vectors were constructed as previously described (45), and luciferase reporter HIV-1 viruses with these Envs were produced. NP-2/CD4 cells that expressed CCR5 or CXCR4 were used to determine the coreceptor usage of these pseudotyped viruses (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Existence of Replication-Competent Minor Variants with Different Coreceptor Usage in Plasma from HIV-1-Infected Individuals

Maeda

Takemura

Chikata

et al. 2020

J Virol

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Cell entry by HIV-1 is mediated by its principal receptor, CD4, and a coreceptor, either CCR5 or CXCR4, with viral envelope glycoprotein gp120. Generally, CCR5-using HIV-1 variants, called R5, predominate over most of the course of infection, while CXCR4-using HIV-1 variants (variants that utilize both CCR5 and CXCR4 [R5X4, or dual] or CXCR4 alone [X4]) emerge at late-stage infection in half of HIV-1-infected individuals and are associated with disease progression. Although X4 variants also appear during acute-phase infection in some cases, these variants apparently fall to undetectable levels thereafter. In this study, replication-competent X4 variants were isolated from plasma of drug treatment-naive individuals infected with HIV-1 strain CRF01_AE, which dominantly carries viral RNA (vRNA) of R5 variants. Next-generation sequencing (NGS) confirmed that sequences of X4 variants were indeed present in plasma vRNA from these individuals as a minor population. On the other hand, in one individual with a mixed infection in which X4 variants were dominant, only R5 replication-competent variants were isolated from plasma. These results indicate the existence of replication-competent variants with different coreceptor usage as minor populations. IMPORTANCE The coreceptor switch of HIV-1 from R5 to CXCR4-using variants (R5X4 or X4) has been observed in about half of HIV-1-infected individuals at late-stage infection with loss of CD4 cell count and disease progression. However, the mechanisms that underlie the emergence of CXCR4-using variants at this stage are unclear. In the present study, CXCR4-using X4 variants were isolated from plasma samples of HIV-1-infected individuals that dominantly carried vRNA of R5 variants. The sequences of the X4 variants were detected as a minor population using next-generation sequencing. Taken together, CXCR4-using variants at late-stage infection are likely to emerge when replication-competent CXCR4-using variants are maintained as a minor population during the course of infection. The present study may support the hypothesis that R5-to-X4 switching is mediated by the expansion of preexisting X4 variants in some cases.

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Section: Resultsmentioning

confidence: 99%

“…The phylogenetic tree was constructed by the neighbor-joining method. The full-length Env expression vector was constructed as previously described (45).…”

Section: Methodsmentioning

confidence: 99%

Existence of Replication-Competent Minor Variants with Different Coreceptor Usage in Plasma from HIV-1-Infected Individuals

Maeda

Takemura

Chikata

et al. 2020

J Virol

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“…reported that bnmAbs recognizing CD4bs and MPER also showed good neutralizing activity against CRF01_AE pseudoviruses from Thailand [13], Japan and Vietnam [14]. Ju et al rst isolated HIV-1 nAbs named F6 from a CRF01_AE-infected donor, it may be more suitable for neutralizing CRF01_AE pseudovirus [15].…”

Section: Discussionmentioning

confidence: 99%

Neutralization Characteristics of HIV-1 CRF01_AE Env Clones From Infections in China

Zhang

Zhou

et al. 2021

Preprint

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Owing to the increasing prevalence of HIV-1 CRF01_AE, it is necessary to understand the neutralization properties of CRF01_AE and to develop broadly neutralizing monoclonal antibodies (bnmAbs) that can neutralize this virus. The full-length Env gene was cloned from HIV-1 CRF01_AE-infected plasma specimens collected in China and used to establish pseudoviruses. Neutralization phenotypes of the pseudoviruses were characterized with bnmAbs. The neutralizing activities of 11 bnmAbs VRC01, VRC03, IgG1b12 and 3BNC117 (targeting the CD4 binding site); PG9 (targeting the V1V2 region); 2G12 (targeting the high mannose patch), PGT135 and 10-1074 (targeting the V3 glycans); 2F5, 4E10 and 10E8 (targeting the membrane proximal external region), against 36 pseudoviruses were analyzed, demonstrating varying efficacies. In general, VRC01, 10E8 and 3BNC117 showed strong neutralizing activity, neutralizing more than 75% of the pseudoviruses; followed by PG9 and 4E10, showing moderate neutralizing activity with neutralization of 50%–60% of the pseudoviruses; whereas the efficacies of the remaining bnmAbs were poor, neutralizing less than 15% of pseudoviruses tested. Env variants of CRF01_AE from one infection also showed significant differences in resistance to neutralization. These characterized HIV-1 CRF01_AE pseudoviruses could be used for neutralization studies and evaluation of vaccines or anti-HIV-1 products in China.

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“…The detection of FcγRIIIa-mediated signaling was performed using a Jurkat NFAT-luc FCγRIIIa cell line (BPS Bioscience, CA, USA), as described previously [ 59 ]. The target cells were 293T cells expressing Env, which were transfected with Env-expressing plasmid 48 h before the ADCC assay.…”

Section: Methodsmentioning

confidence: 99%

Functional analysis of a monoclonal antibody reactive against the C1C2 of Env obtained from a patient infected with HIV-1 CRF02_AG

et al. 2021

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Background Recent data suggest the importance of non-neutralizing antibodies (nnAbs) in the development of vaccines against HIV-1 because two types of nnAbs that recognize the coreceptor binding site (CoRBS) and the C1C2 region mediate antibody-dependent cellular-cytotoxicity (ADCC) against HIV-1-infected cells. However, many studies have been conducted with nnAbs obtained from subtype B-infected individuals, with few studies in patients with non-subtype B infections. Results We isolated a monoclonal antibody 1E5 from a CRF02_AG-infected individual and constructed two forms of antibody with constant regions of IgG1 or IgG3. The epitope of 1E5 belongs to the C1C2 of gp120, and 1E5 binds to 27 out of 35 strains (77 %) across the subtypes. The 1E5 showed strong ADCC activity, especially in the form of IgG3 in the presence of small CD4-mimetic compounds (CD4mc) and 4E9C (anti-CoRBS antibody), but did not show any neutralizing activity even against the isolates with strong binding activities. The enhancement in the binding of A32, anti-C1C2 antibody isolated from a patient with subtype B infection, was observed in the presence of 1E5 and the combination of 1E5, A32 and 4E9C mediated a strong ADCC activity. Conclusions These results suggest that anti-C1C2 antibodies that are induced in patients with different HIV-1 subtype infections have common functional modality and may have unexpected interactions. These data may have implications for vaccine development against HIV-1. Graphical abstract

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The role of conventional antibodies targeting the CD4 binding site and CD4-induced epitopes in the control of HIV-1 CRF01_AE viruses

Cited by 6 publications

References 29 publications

Existence of Replication-Competent Minor Variants with Different Coreceptor Usage in Plasma from HIV-1-Infected Individuals

Existence of Replication-Competent Minor Variants with Different Coreceptor Usage in Plasma from HIV-1-Infected Individuals

Neutralization Characteristics of HIV-1 CRF01_AE Env Clones From Infections in China

Functional analysis of a monoclonal antibody reactive against the C1C2 of Env obtained from a patient infected with HIV-1 CRF02_AG

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