Expression of a modified form of CD4 results in the release of an anti-HIV factor derived from the Env sequence.
We have studied the inhibitory effect of a CD4 chimera (CD4epsilon15) 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 CD4epsilon15 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 CD4epsilon15 gene and it opens new possibilities for antiviral treatment and vaccine development.
Zaldívar
Irene
I
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Spain.
Muñoz-Fernández
María Angeles
MA
Alarcón
Balbino
B
San José
Ester
E
D000998:Antiviral Agents; D024201:Bystander Effect; D015704:CD4 Antigens / Q000235:genetics / Q000494:pharmacology*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D019302:HIV Envelope Protein gp160 / Q000737:chemistry*; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D010446:Peptide Fragments / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D015704:CD4 Antigens; D019302:HIV Envelope Protein gp160; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins