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Resistance to human immunodeficiency virus type 1 (HIV-1) generated by lentivirus vector-mediated delivery of the CCR532 gene despite detectable expression of the HIV-1 co-receptors

Qingwen Jin^1,

¹ Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
² Indiana University Vector Production Facility, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA

Correspondence
Ghalib Alkhatib
galkhati{at}iupui.edu

It has previously been demonstrated that there are two distinct mechanisms for genetic resistance to human immunodeficiency virus type 1 (HIV-1) conferred by the CCR532 gene: the loss of wild-type CCR5 surface expression and the generation of CCR532 protein, which interacts with CXCR4. To analyse the protective effects of long-term expression of the CCR532 protein, recombinant lentiviral vectors were used to deliver the CCR532 gene into human cell lines and primary peripheral blood mononuclear cells that had been immortalized by human T-cell leukemia virus type 1. Blasticidin S-resistant cell lines expressing the lentivirus-encoded CCR532 showed a significant reduction in HIV-1 Env-mediated fusion assays. It was shown that CD4⁺ T lymphocytes expressing the lentivirus-encoded CCR532 gene were highly resistant to infection by a primary but not by a laboratory-adapted X4 strain, suggesting different infectivity requirements. In contrast to previous studies that analysed the CCR532 protective effects in a transient expression system, this study showed that long-term expression of CCR532 conferred resistance to HIV-1 despite cell-surface expression of the HIV co-receptors. The results suggest an additional unknown mechanism for generating the CCR532 resistance phenotype and support the hypothesis that the CCR532 protein acts as an HIV-suppressive factor by altering the stoichiometry of the molecules involved in HIV-1 entry. The lentiviral–CCR532 vectors offer a method of generating HIV-resistant cells by delivery of the CCR532 gene that may be useful for stem cell- or T-cell-based gene therapy for HIV-1 infection.

Present address: Department of Neurology, Nanjing Medical University, Nanjing 21002, Jiangsu Province, PR China.