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Journal of Virology, June 2002, p. 5959-5965, Vol. 76, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.12.5959-5965.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Inefficient Enhancement of Viral Infectivity and CD4 Downregulation by Human Immunodeficiency Virus Type 1 Nef from Japanese Long-Term Nonprogressors

Department of Tumor Virology, Research Institute for Microbial Diseases, Osaka University, Osaka,¹ Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo,³ Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, Japan,⁴ Department of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee²

Received 13 December 2001/ Accepted 15 March 2002

It has been reported that patients infected with nef-defective human immunodeficiency virus type 1 (HIV-1) do not progress to AIDS; however, mutations that abrogate Nef expression are not common in long-term nonprogressors (LTNPs). We postulated that Nef function might be impaired in LTNPs, irrespective of the presence or absence of detectable amino acid sequence anomalies. To challenge this hypothesis we compared in vitro function of nef alleles that were derived from three groups of Japanese patients: LTNPs, progressors, and asymptomatic carriers (ACs). The patient-derived nef alleles were subcloned into a nef-defective infectious HIV-1 molecular clone and an expression vector. We first examined Nef-dependent enhancement of infection in a single-round infectivity assay by the use of MAGNEF cells, in which Nef is required more strictly for the infection than in the parent MAGI cells. All nef alleles from LTNPs showed reduced enhancement in the infectivity of nef-defective HIV-1 mutants compared to the nef alleles of progressors or ACs. Second, we found that nef alleles from LTNPs were less efficient in CD4 downregulation than those of progressors or ACs. Third, all nef alleles from LTNPs, progressors, and ACs reduced the cell surface expression of major histocompatibility complex class I to a similar level. Last, there was no correlation between Hck-binding activity of Nef and clinical grouping. In conclusion, we detected inefficient enhancement of HIV-1 infectivity and CD4 downregulation by HIV-1 nef alleles of LTNPs. It awaits further study to conclude that these characteristics of nef alleles are the cause or the consequence of the long-term nonprogression after HIV-1 infection.

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