A naturally occurring splice variant of CXCL12/stromal cell-derived factor 1 is a potent human immunodeficiency virus type 1 inhibitor with weak chemotaxis and cell survival activities

Jeffrey D. Altenburg, Hal Broxmeyer, Qingwen Jin, Scott Cooper, Sunanda Basu, Ghalib Alkhatib

Research output: Contribution to journalArticle

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Abstract

CXCL12/stromal cell-derived factor 1 is a member of the CXC family of chemokines that plays an important role in hematopoiesis and signals through CXCR4 and CXCR7. Two splice variants of human CXCL12 (CXCL12α and CXCL12α) induce chemotaxis of CXCR4+ cells and inhibit X4 infection. Recent studies described four other novel splice variants of human CXCL12; however, their antiviral activities were not investigated. We constructed and expressed all of the CXCL12 splice variants in Escherichia coli. Recombinant proteins were purified through a His affinity column, and their biological properties were analyzed. All six CXCL12 variants induced chemotaxis of CXCR4+ and CXCR7+ cell lines. Enhancement of survival and replating capacity of human hematopoietic progenitor cells were observed with CXCL12α, CXCL12β, and CXCL12ε but not with the other variants. CXCL12γ showed the greatest antiviral activity in X4 inhibition assays and the weakest chemotaxis activity through CXCR4. The order of potency in X4 inhibition assays was as follows: CXCLI2γ > CXCL12β > CXCL12α > CXCL12θ > CXCL12ε > CXCL12δ. The order of anti-human immunodeficiency virus (HIV) activity was associated with the number of BBXB motifs present in each variant; the most potent inhibitor was CXCLI2γ, with five BBXB domains. The results suggest that the different C termini of CXCL12 variants may contain important molecular determinants for the observed differences in antiviral effects and other biological functions. These studies implicate CXCLI2γ as a potent HIV-1 entry inhibitor with significantly reduced chemotaxis activity and small or absent effects on progenitor cell survival or replating capacity, providing important insight into the structure-function relationships of CXCL12.

Original languageEnglish (US)
Pages (from-to)8140-8148
Number of pages9
JournalJournal of Virology
Volume81
Issue number15
DOIs
StatePublished - Aug 2007
Externally publishedYes

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Chemokine CXCL12
chemotaxis
Chemotaxis
Human immunodeficiency virus 1
cell viability
HIV-1
Cell Survival
Antiviral Agents
CXC Chemokines
Virus Internalization
hematopoiesis
Human immunodeficiency virus
Hematopoiesis
assays
chemokines
structure-activity relationships
Hematopoietic Stem Cells
Recombinant Proteins
recombinant proteins
stem cells

ASJC Scopus subject areas

  • Immunology

Cite this

A naturally occurring splice variant of CXCL12/stromal cell-derived factor 1 is a potent human immunodeficiency virus type 1 inhibitor with weak chemotaxis and cell survival activities. / Altenburg, Jeffrey D.; Broxmeyer, Hal; Jin, Qingwen; Cooper, Scott; Basu, Sunanda; Alkhatib, Ghalib.

In: Journal of Virology, Vol. 81, No. 15, 08.2007, p. 8140-8148.

Research output: Contribution to journalArticle

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abstract = "CXCL12/stromal cell-derived factor 1 is a member of the CXC family of chemokines that plays an important role in hematopoiesis and signals through CXCR4 and CXCR7. Two splice variants of human CXCL12 (CXCL12α and CXCL12α) induce chemotaxis of CXCR4+ cells and inhibit X4 infection. Recent studies described four other novel splice variants of human CXCL12; however, their antiviral activities were not investigated. We constructed and expressed all of the CXCL12 splice variants in Escherichia coli. Recombinant proteins were purified through a His affinity column, and their biological properties were analyzed. All six CXCL12 variants induced chemotaxis of CXCR4+ and CXCR7+ cell lines. Enhancement of survival and replating capacity of human hematopoietic progenitor cells were observed with CXCL12α, CXCL12β, and CXCL12ε but not with the other variants. CXCL12γ showed the greatest antiviral activity in X4 inhibition assays and the weakest chemotaxis activity through CXCR4. The order of potency in X4 inhibition assays was as follows: CXCLI2γ > CXCL12β > CXCL12α > CXCL12θ > CXCL12ε > CXCL12δ. The order of anti-human immunodeficiency virus (HIV) activity was associated with the number of BBXB motifs present in each variant; the most potent inhibitor was CXCLI2γ, with five BBXB domains. The results suggest that the different C termini of CXCL12 variants may contain important molecular determinants for the observed differences in antiviral effects and other biological functions. These studies implicate CXCLI2γ as a potent HIV-1 entry inhibitor with significantly reduced chemotaxis activity and small or absent effects on progenitor cell survival or replating capacity, providing important insight into the structure-function relationships of CXCL12.",
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