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Expression of a Modified Form of CD4 Results in the Release of an Anti-HIV Factor Derived from the Env Sequence¹

Irene Zaldívar^*, María Ángeles Muñoz-Fernández, Balbino Alarcón^2,* and Ester San José^*

^* Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, and Laboratorio de Inmuno-Biología, Hospital Universitario Gregorio Marañón, Madrid, Spain

We have studied the inhibitory effect of a CD4 chimera (CD415) on HIV replication. This chimera is retained in the endoplasmic reticulum and traps the HIV envelope precursor gp160, preventing its maturation. Retroviral expression of the chimera strongly inhibited HIV replication even when it is expressed by only a minority of the T cell population. This protective effect on bystander nontransduced cells is mediated by a soluble factor that we identified as a fragment of HIV gp120 envelope protein and accordingly, we named this factor Env-derived antiviral factor (EDAF). Biochemical and immunoreactivity data show that EDAF is comprised of the gp120 C3-C5 regions and indeed, a recombinant protein bearing this sequence reproduces the anti-HIV properties of EDAF. Surprisingly, three tryptic peptides derived from EDAF are homologous but not identical with the corresponding sequences of the HIV isolate used to generate EDAF. We propose that EDAF results from an alternative intracellular processing of the Env protein provoked by its association to CD415 and the selection of the best fitted Env protein sequences contained within the HIV isolate. The presence of EDAF improves the therapeutic potential of the CD415 gene and it opens new possibilities for antiviral treatment and vaccine development.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants SAF2003-04137 and SAF2006-01391 from the "Comisión Interministerial de Ciencia y Tecnología," Grants 08.2/0027.1/2003 and S-SAL-0159-2006 from the "Comunidad de Madrid," and Grants QLK2 2000-01040 and LIFE/STREP/03/0594 from the "Fundación Rodríguez Pascual" and from the European Union. The institutional support of "Fundación Ramón Areces" to the Centro de Biología Molecular is also acknowledged.

² Address correspondence and reprint requests to Dr. Balbino Alarcón, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28049, Spain. E-mail address: balarcon{at}cbm.uam.es

³ Abbreviations used in this paper: HAART, highly active antiretroviral therapy; EDAF, Env-derived antiviral factor; ER, endoplasmic reticulum; MOI, multiplicity of infection; HA, hemagglutinin; MS, mass spectrometry; HIV-1, HIV type 1.