CD4 and major histocompatibility complex class I downregulation by the human immunodeficiency virus type 1 nef protein in pediatric AIDS progression.
The human immunodeficiency virus type 1 (HIV-1) nef gene is a crucial determinant in AIDS disease progression. Although several in vitro activities have been attributed to the Nef protein, identifying the one critical for in vivo pathogenicity remains elusive. In this study, we examined a large number of nef alleles derived at various time points from 13 perinatally infected children showing different progression rates: six nonprogressors (NPs), three slow progressors (SPs), and four rapid progressors (RPs). The patient-derived nef alleles were analyzed for their steady-state expression of a Nef protein, for their relative ability to downregulate cell surface expression of CD4 and major histocompatibility complex class I (MHC-I) and for their capacity to bind the clathrin adaptor AP-1 complex. We found that NP-derived nef alleles, compared to nef alleles isolated from SPs and RPs, had reduced CD4 and MHC-I downregulation activities. In contrast, SP- and RP-derived nef alleles did not differ and efficiently downregulated both CD4 and MHC-I. AP-1 binding was a conserved function of primary nef alleles not correlated with clinical progression. Defective Nef proteins from NPs, rather than sharing common specific changes in their sequences, accumulated various amino acid substitutions, mainly located outside the conserved domains previously associated with Nef biological properties. Our data indicate that Nef-mediated downregulation of cell surface CD4 and MHC-I significantly contributes to the expression of the pathogenic potential of HIV-1.
Casartelli
Nicoletta
N
Division of Immunology and Infectious Disease, Children's Hospital Bambino Gesù, Rome, Italy.
Di Matteo
Gigliola
G
Potestà
Marina
M
Rossi
Paolo
P
Doria
Margherita
M
D000483:Alleles; D015704:CD4 Antigens / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation; D015693:Gene Products, nef / Q000235:genetics / Q000378:metabolism*; D015754:Genes, nef; D015658:HIV Infections / Q000503:physiopathology* / Q000821:virology; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000472:pathogenicity; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D018808:Transcription Factor AP-1 / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus
D015704:CD4 Antigens; D015693:Gene Products, nef; D015395:Histocompatibility Antigens Class I; D018808:Transcription Factor AP-1; D054311:nef Gene Products, Human Immunodeficiency Virus