The V1/V2 Region of Human Immunodeficiency Virus Type 1 Modulates the Sensitivity to Neutralization by Soluble CD4 and Cellular Tropism

Morikita, Tatsuma; Maeda, Yosuke; Fujii, Shin‐ichiro; Matsushita, Shuzo; Obaru, Kenshi; Takatsuki, Kiyoshi

doi:10.1089/aid.1997.13.1291

Cited by 38 publications

(43 citation statements)

References 50 publications

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“…The V1-specific Xeno-mAbs were all highly specific for rgp120 SF162 , consistent with this domain being the most highly variable in region in gp120 (52). The V2-specific Xeno-mAb, 8.22.2, reacted with all three R5 clade B rgp120s but with none of the X4 clade B rgp120s, consistent with both the existence of regions of significant sequence similarity (52) and the presence of determinants of tropism within this variable domain (53)(54)(55)(56). The V3-specific Xeno-mAbs recognized four or five rgp120s within clade B with no obvious bias with respect to coreceptor usage.…”

Section: Extent Of Conservation Of Epitopes Recognized By Xeno-mabsmentioning

confidence: 53%

Efficient Isolation of Novel Human Monoclonal Antibodies with Neutralizing Activity Against HIV-1 from Transgenic Mice Expressing Human Ig Loci

He¹,

Honnen²,

Krachmarov³

et al. 2002

The Journal of Immunology

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Despite considerable interest in the isolation of mAbs with potent neutralization activity against primary HIV-1 isolates, both for identifying useful targets for vaccine development and for the development of therapeutically useful reagents against HIV-1 infection, a relatively limited number of such reagents have been isolated to date. Human mAbs (hu-mAbs) are preferable to rodent mAbs for treatment of humans, but isolation of hu-mAbs from HIV-infected subjects by standard methods of EBV transformation of B cells or phage display of Ig libraries is inefficient and limited by the inability to control or define the original immunogen. An alternative approach for the isolation of hu-mAbs has been provided by the development of transgenic mice that produce fully hu-mAbs. In this report, we show that immunizing the XenoMouse G2 strain with native recombinant gp120 derived from HIVSF162 resulted in robust humoral Ab responses against gp120 and allowed the efficient isolation of hybridomas producing specific hu-mAbs directed against multiple regions and epitopes of gp120. hu-mAbs possessing strong neutralizing activity against the autologous HIVSF162 strain were obtained. The epitopes recognized were located in three previously described neutralization domains, the V2-, V3- and CD4-binding domains, and in a novel neutralization domain, the highly variable C-terminal region of the V1 loop. This is the first report of neutralizing mAbs directed at targets in the V1 region. Furthermore, the V2 and V3 epitopes recognized by neutralizing hu-mAbs were distinct from those of previously described human and rodent mAbs and included an epitope requiring a full length V3 loop peptide for effective presentation. These results further our understanding of neutralization targets for primary, R5 HIV-1 viruses and demonstrate the utility of the XenoMouse system for identifying new and interesting epitopes on HIV-1.

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Section: Extent Of Conservation Of Epitopes Recognized By Xeno-mabsmentioning

confidence: 53%

Efficient Isolation of Novel Human Monoclonal Antibodies with Neutralizing Activity Against HIV-1 from Transgenic Mice Expressing Human Ig Loci

He¹,

Honnen²,

Krachmarov³

et al. 2002

The Journal of Immunology

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“…The V3 region is not the sole determinant of biological phenotype or coreceptor utilization, and other envelope regions, namely the V1 and V2, have been implicated as important (32)(33)(34)(35)(36)(37)(38)(39)(40)(41). The V4 and V5 regions, in conjunction with the V1 and V3, have also been shown to influence coreceptor usage of a dual-tropic R5X4 virus (42).…”

mentioning

confidence: 99%

N-Linked Glycosylation of the HIV Type-1 gp120 Envelope Glycoprotein as a Major Determinant of CCR5 and CXCR4 Coreceptor Utilization

Pollakis

Kang

Kliphuis

et al. 2001

Journal of Biological Chemistry

206

221

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The variable V1V2 and V3 regions of the human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein (gp120) can influence viral coreceptor usage. To substantiate this we generated isogenic HIV-1 molecularly cloned viruses that were composed of the HxB2 envelope backbone containing the V1V2 and V3 regions from viruses isolated from a patient progressing to disease. We show that the V3 amino acid charge per se had little influence on altering the virus coreceptor phenotype. The V1V2 region and its N-linked glycosylation degree were shown to confer CXCR4 usage and provide the virus with rapid replication kinetics. Loss of an Nlinked glycosylation site within the V3 region had a major influence on the virus switching from the R5 to X4 phenotype in a V3 charge-dependent manner. The loss of this V3 N-linked glycosylation site was also linked with the broadening of the coreceptor repertoire to incorporate CCR3. By comparing the amino acid sequences of primary HIV-1 isolates, we identified a strong association between high V3 charge and the loss of this V3 N-linked glycosylation site. These results demonstrate that the N-linked glycosylation pattern of the HIV-1 envelope can strongly influence viral coreceptor utilization and the R5 to X4 switch.

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“…The PCR fragment from the primary isolate HIV-1KMT and the infectious chimeric molecular clones are as described previously (30). HIV-hL4-3 and HIV-1 JR _ FL envelope expression vectors (pCXNINLenv and pCXNlFLenv) were prepared as previously described (28).…”

Section: Methodsmentioning

confidence: 99%

“…In a previous study, the primary dualtropic HIV-l KMT isolate from an HIV-l infected individual was grown in a T lymphoid cell line (30). To determine which coreceptors are utilized by HIV-I KMT , individual GHOST cell lines expressing CD4 and one of the various chemokine receptors (CXCR4, CCR5, CCR2b, CCR3, CCR8, BOB, Bonzo, or V28) (8,15) were infected with the HIV-l KMT isolate.…”

Section: Coreceptor Utilization By Hiv-i Kmt Isolatementioning

confidence: 99%

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Role of V3 Independent Domains on a Dualtropic Human Immunodeficiency Virus Type 1 (HIV‐1) Envelope gp120 in CCR5 Coreceptor Utilization and Viral Infectivity

Foda

Harada

Maeda

2001

Microbiology and Immunology

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The molecular mechanism of human immunodeficiency virus type I (HIV-I) entry into cells involves specific interactions between the viral envelope glycoprotein gp120 and two target cell proteins, CD4 and either CCR5 or CXCR4 chemokine receptors. In order to delineate the functional role of HIV-I gpI20 subdomains of dualtropic strains in CCR5 coreceptor usage, we used a panel of chimeric viruses in which the V1N2 and V3 domains of gpI20 from the dualtropic HIV-hMT isolate were introduced either alone or in combination into the T-tropic HIV-IN1A-3 background. These chimeric constructs were employed in ceUcell fusion and cell-free virus infectivity assays using cell lines expressing CD4 and the CCR5 chemokine receptor. In both assays, the V3 domain of HIV-hMT but not the VIN2 domain proved to be the principal determinant of CCR5 coreceptor usage. However, in the cell-free viral infectivity assay although a chimeric virus with a combined V1N2 and V3 domains of HIV-IKMT efficiently fused with coreceptor expressing cells, yet its infectivity was markedly diminished in CCR5 as well as CXCR4 expressing cells. Restoring a comparable level of infection of such chimeric virus required the C3-V5 domain from HIV-hMT to be introduced. Our present findings confirmed that the V3 domain is the major determinant of fusion activity and cellular tropism, and demonstrated a dispensable role for the VIN2 domain. In addition the C3-V5 domain appeared to play an important role in viral infectivity when the corresponding VIN2 and V3 domains are present.

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The V1/V2 Region of Human Immunodeficiency Virus Type 1 Modulates the Sensitivity to Neutralization by Soluble CD4 and Cellular Tropism

Cited by 38 publications

References 50 publications

Efficient Isolation of Novel Human Monoclonal Antibodies with Neutralizing Activity Against HIV-1 from Transgenic Mice Expressing Human Ig Loci

Efficient Isolation of Novel Human Monoclonal Antibodies with Neutralizing Activity Against HIV-1 from Transgenic Mice Expressing Human Ig Loci

N-Linked Glycosylation of the HIV Type-1 gp120 Envelope Glycoprotein as a Major Determinant of CCR5 and CXCR4 Coreceptor Utilization

Role of V3 Independent Domains on a Dualtropic Human Immunodeficiency Virus Type 1 (HIV‐1) Envelope gp120 in CCR5 Coreceptor Utilization and Viral Infectivity

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