Defective nef alleles in a cohort of hemophiliacs with progressing and nonprogressing HIV-1 infection.
Deletion of the nef gene results in viral attenuation and confers protection against challenge with wild-type simian immunodeficiency virus in macaques. Regarding HIV-1 infection, a few long-term nonprogressors (LTNP) with nef deletions have been described. In this study, the nef genes of a group of seven LTNP and eight progressors, all belonging to the same cohort of infected hemophiliacs, were analyzed by cloning and sequencing from both virion RNA and peripheral blood mononuclear cell-associated proviral DNA. Defective nef sequences coexisted with full-length nef open reading frames in five of seven LTNP and two of eight progressors. The proportion of disrupted nef sequences within each individual was significantly higher in LTNP (ranging from 10 to 63%) than in progressors (ranging from 9 to 21%) (P = 0.013). Moreover, in-frame small deletions predicting to encode Nef were found in all RNA- and DNA-derived clones from one LTNP and four progressors. A chimeric virus in which the nef gene of NL4.3 was substituted with the nef allele containing the deletion of two alanines at position 49-50 found in two progressors showed a defective replicative capacity compared to NL4.3 virus. In summary, hemophiliacs with either progressing or nonprogressing HIV-1 infection are characterized by the presence of defective nef variants.
Brambilla
A
A
AIDS Immunopathogenesis Unit, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy.
Turchetto
L
L
Gatti
A
A
Bovolenta
C
C
Veglia
F
F
Santagostino
E
E
Gringeri
A
A
Clementi
M
M
Poli
G
G
Bagnarelli
P
P
Vicenzi
E
E
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D003001:Cloning, Molecular; D015331:Cohort Studies; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D018450:Disease Progression; D015693:Gene Products, nef / Q000737:chemistry / Q000235:genetics; D015754:Genes, nef; D014644:Genetic Variation; D015658:HIV Infections / Q000150:complications / Q000821:virology*; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D006467:Hemophilia A / Q000150:complications*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008875:Middle Aged; D008969:Molecular Sequence Data; D010802:Phylogeny; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D054311:nef Gene Products, Human Immunodeficiency Virus
D004279:DNA, Viral; D015693:Gene Products, nef; D012367:RNA, Viral; D054311:nef Gene Products, Human Immunodeficiency Virus