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

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Abstract
It has been reported that patients infected withnef-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 ofnefalleles that were derived from three groups of Japanese patients: LTNPs, progressors, and asymptomatic carriers (ACs). The patient-derivednefalleles were subcloned into anef-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. Allnefalleles from LTNPs showed reduced enhancement in the infectivity ofnef-defective HIV-1 mutants compared to thenefalleles of progressors or ACs. Second, we found thatnefalleles from LTNPs were less efficient in CD4 downregulation than those of progressors or ACs. Third, allnefalleles 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-1nefalleles of LTNPs. It awaits further study to conclude that these characteristics ofnefalleles are the cause or the consequence of the long-term nonprogression after HIV-1 infection.