Inefficient enhancement of viral infectivity and CD4 downregulation by human immunodeficiency virus type 1 Nef from Japanese long-term nonprogressors.
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.
Tobiume
Minoru
M
Department of Tumor Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Takahoko
Mikako
M
Yamada
Takeshi
T
Tatsumi
Masashi
M
Iwamoto
Aikichi
A
Matsuda
Michiyuki
M
D000483:Alleles; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D002353:Carrier State / Q000821:virology; D002460:Cell Line; D018450:Disease Progression; D015536:Down-Regulation; D015693:Gene Products, nef / Q000235:genetics / Q000378:metabolism*; D005805:Genes, MHC Class I / Q000235:genetics / Q000528:radiation effects; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D007564:Japan; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051572:Proto-Oncogene Proteins c-hck; D054311:nef Gene Products, Human Immunodeficiency Virus
D015693:Gene Products, nef; D011518:Proto-Oncogene Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; D011505:Protein-Tyrosine Kinases; C496631:HCK protein, human; D051572:Proto-Oncogene Proteins c-hck