Persistence of attenuated rev genes in a human immunodeficiency virus type 1-infected asymptomatic individual.
With the goal of examining the functional diversity of human immunodeficiency virus type 1 (HIV-1) env genes within the peripheral blood mononuclear cells of an asymptomatic individual, we substituted four complete env genes into the replication-competent NL4-3 provirus. Despite encoding full-length open reading frames for gp120 and gp41 and the second coding exon of tat and rev, each chimera was replication defective. Site-directed mutagenesis of codon 78 in the Rev activation domain (from a hitherto unique Ile to the subtype B consensus Leu) partially restored infectivity for two of three chimeras tested. Similarly, mutagenesis of rev codon 78 of NL4-3 from Leu to Ile partially attenuated this virus. Ile-78 was found in all 13 clones examined from samples taken from this asymptomatic subject 4.5 years after infection, including 9 from peripheral blood mononuclear cells and 4 from a virus isolate, as well as 4 additional clones each from peripheral blood mononuclear cells sampled 37 and 51 months later. We next examined conservation of the Rev activation domain within and among long-term survivors (LTS) and patients with AIDS, as well as T-cell-line-adapted strains of HIV-1. Putative attenuating mutations were found in a minority of sequences from all five LTS and two of four patients with AIDS. Of the 11 T-cell-line-adapted viruses examined, none had these changes. Among and within LTS virus population had marginally higher levels of diversity in Rev than in Env; patients with AIDS had similar levels of diversity in the two reading frames; and T-cell-line-adapted viruses had higher levels of diversity in Env. These results are consistent with the hypothesis that asymptomatic individuals harbor attenuated variants of HIV-1 which correlate with and contribute to their lack of disease progression.
Iversen
A K
AK
Department of Microbiology and Immunology, Stanford University School of Medicine, California 94305-5402, USA.
Shpaer
E G
EG
Rodrigo
A G
AG
Hirsch
M S
MS
Walker
B D
BD
Sheppard
H W
HW
Merigan
T C
TC
Mullins
J I
JI
D000163:Acquired Immunodeficiency Syndrome / Q000401:mortality / Q000821:virology*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D002678:Chimera; D002522:Chlorocebus aethiops; D017931:DNA Primers; D004279:DNA, Viral / Q000378:metabolism; D005091:Exons; D015967:Gene Expression Regulation, Viral; D015694:Gene Products, rev / Q000096:biosynthesis* / Q000235:genetics; D015757:Genes, rev; D016679:Genome, Viral; D015700:HIV Envelope Protein gp41 / Q000096:biosynthesis* / Q000235:genetics; D018023:HIV Seronegativity / Q000276:immunology; D006679:HIV Seropositivity / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000302:isolation & purification; D018451:Homosexuality, Male; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D007668:Kidney; D008214:Lymphocytes / Q000276:immunology* / Q000821:virology; D008264:Macrophages / Q000276:immunology / Q000821:virology; D008297:Male; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology / Q000821:virology; D016297:Mutagenesis, Site-Directed; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction; D011533:Proviruses / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D015183:Restriction Mapping; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D001616:beta-Galactosidase / Q000096:biosynthesis; D054321:rev Gene Products, Human Immunodeficiency Virus
D017931:DNA Primers; D004279:DNA, Viral; D015694:Gene Products, rev; D015700:HIV Envelope Protein gp41; D007376:Interleukin-2; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; D054321:rev Gene Products, Human Immunodeficiency Virus; D001616:beta-Galactosidase