The CCR5 and CXCR4 Coreceptors—Central to Understanding the Transmission and Pathogenesis of Human Immunodeficiency Virus Type 1 Infection

Moore, John P.; Kitchen, Scott G.; Pugach, Pavel; Zack, Jerome A.

doi:10.1089/088922204322749567

Cited by 437 publications

(355 citation statements)

References 222 publications

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“…Another finding from our study shows that sifuvirtide is 6-to 20-fold more effective against X4R5 viruses than T20. It is known that R5 occurred in most patients newly infected by HIV-1, along with the progression of HIV, tropism presents by emerging of dual-mixed (X4R5) or pure X4-tropic virus, which account for 50% of the infected population (8,41). Therefore, sifuvirtide should keep active for a long time in clinical use.…”

Section: Discussionmentioning

confidence: 99%

Design and Evaluation of Sifuvirtide, a Novel HIV-1 Fusion Inhibitor

Xiao

Song

et al. 2008

Journal of Biological Chemistry

200

213

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Enfuvirtide (T20) is the first and only HIV-1 fusion inhibitor approved for clinical use, but it can easily induce drug resistance limiting its practical application. A novel anti-HIV peptide, termed sifuvirtide, was designed based on the three-dimensional structure of the HIV-1 gp41 fusogenic core conformation. Here we report its in vitro anti-HIV potency, its mechanism of action, as well as the results from Phase Ia clinical studies. We demonstrated that sifuvirtide inhibited HIV-1-mediated cellcell fusion in a dose-dependent manner and exhibited high potency against infections by a wide range of primary and laboratory-adapted HIV-1 isolates from multiple genotypes with R5 or X4 phenotypes. Notably, sifuvirtide was also highly effective against T20-resistant strains. Unlike T20, sifuvirtide could efficiently block six-helix bundle formation in a dominant negative fashion. These results suggest that sifuvirtide has a different mechanism of action from that of T20. Phase Ia clinical studies of sifuvirtide (FS0101) in 60 healthy individuals demonstrated good safety, tolerability, and pharmacokinetic profiles. A single dose regimen (5, 10, 20, 30, and 40 mg) by subcutaneous injection once daily at abdominal sites was well tolerated without serious adverse events. Pharmacokinetic studies of single and multiple administration of sifuvirtide showed that its decay half-lives were 20.0 ؎ 8.6 h and 26.0 ؎ 7.9 h, respectively. In summary, sifuvirtide has potential to become an ideal fusion inhibitor for treatment of HIV/AIDS patients, including those with HIV-1 strains resistant to T20.

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Section: Discussionmentioning

confidence: 99%

Design and Evaluation of Sifuvirtide, a Novel HIV-1 Fusion Inhibitor

Xiao

Song

et al. 2008

Journal of Biological Chemistry

200

213

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“…teraction of the surface envelope glycoprotein gp120 with the primary receptor CD4 and with the coreceptors CXCR4 or CCR5 (1)(2)(3). HIV-1 receptor and coreceptors play key roles in leukocyte signaling, which is relevant to the understanding of AIDS pathogenesis.…”

Section: E Ntry Of Hiv-1 Into Target Cells Requires the Sequential In-mentioning

confidence: 99%

CXCR4-Tropic HIV-1 Envelope Glycoprotein Functions as a Viral Chemokine in Unstimulated Primary CD4+ T Lymphocytes

Balabanian

Harriague

Décrion

et al. 2004

The Journal of Immunology

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Interaction of HIV-1 envelope glycoprotein gp120 with the chemokine receptor CXCR4 triggers not only viral entry but also an array of signal transduction cascades. Whether gp120 induces an incomplete or aberrant set of signals, or whether it can function as a full CXCR4 agonist, remains unclear. We report that, in unstimulated human primary CD4+ T cells, the spectrum of signaling responses induced by gp120 through CXCR4 paralleled that induced by the natural ligand stromal cell-derived factor 1/CXCL12. gp120 activated heterotrimeric G proteins and the major G protein-dependent pathways, including calcium mobilization, phosphoinositide-3 kinase, and Erk-1/2 MAPK activation. Interestingly, gp120 caused rapid actin cytoskeleton rearrangements and profuse membrane ruffling, as evidenced by dynamic confocal imaging. This coordinated set of events resulted in a bona fide chemotactic response. Inactivated HIV-1 virions that harbored conformationally intact envelope glycoproteins also caused actin polymerization and chemotaxis, while similar virions devoid of envelope glycoproteins did not. Thus gp120, in monomeric as well as oligomeric, virion-associated form, elicited a complex cellular response that mimicked the effects of a chemokine. HIV-1 has therefore the capacity to dysregulate the vast CD4+ T cell population that expresses CXCR4. In addition, HIV-1 may exploit its chemotactic properties to retain potential target cells and locally perturb their cytoskeleton, thereby facilitating viral transmission.

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“…Thus, although SHIV-162P3 enters cells only via CCR5, SHIV-89.6P can use both CCR5 and CXCR4, and SHIV-KU1 employs only CXCR4 (12)(13)(14). Although most naturally transmitted HIV-1 strains use only CCR5, a small but significant fraction of new infections does involve viruses that also or instead enter cells via CXCR4 (15,16). Hence, using three challenge viruses with different coreceptor usage profiles allowed us to gauge whether a single microbicide candidate could be protective in a tropism-independent manner.…”

mentioning

confidence: 99%