title: Genetic and functional analysis of HIV type 1 nef gene derived from long-term nonprogressor children: association of attenuated variants with slow progression to pediatric AIDS.
abstract: Among persons infected by HIV-1, the rate of progression to AIDS is multifactorial being affected by host and viral factors, including the HIV-encoded negative factor (Nef). Our aim was to define whether variations in the nef gene as well as its functions may be associated with slower HIV disease course in infected children. The proviral HIV-1 nef gene was cloned, sequenced, and compared in children with contrasting disease course: 10 long-term nonprogressors (LTNP) and six rapid progressor (RP). The CD4 and MHC-I down-modulation ability of nef alleles derived from LTNP and RP children was analyzed. We observed that only one of our 10 LTNP had a protective genetic background, and out of them, 40% had defective nef genes, carrying substitutions at the (AWLEAQ(56-61)) and the (Rxx(22-24)) domains, and that those alleles were unable of down-regulate CD4 and MHC-I. The emergence or presence of Nef L58V substitution was associated with viral attenuation, indicated by a reduction in HIV viral loads, a persistent preservation of CD4(+) T cell counts, and lack of AIDS-related symptoms. Our results demonstrate that HIV-1 perinatally infected children carrying functionally defective nef HIV-1 strains have prolonged asymptomatic phases without therapy, suggesting a relevant role of CD4 and MHC-I down-modulation Nef domains on in vivo HIV-1 pathogenesis and pediatric immunodeficiency outcome.
authors.affiliation: Laboratorio de Biología Celular y Retrovirus, Hospital de Pediatría Prof. Dr. Juan P. Garran, Buenos Aires, Argentina. gcorro2@gmail.com
authors.forename: Guillermo
authors.initials: G
authors.lastname: Corró
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Rocco
authors.forename: Cristian
authors.initials: C
authors.lastname: De Candia
authors.forename: Gabriel
authors.initials: G
authors.lastname: Catano
authors.forename: Gabriela
authors.initials: G
authors.lastname: Turk
authors.forename: Andrea
authors.initials: A
authors.lastname: Mangano
authors.forename: Paula C
authors.initials: PC
authors.lastname: Aulicino
authors.forename: Rosa
authors.initials: R
authors.lastname: Bologna
authors.forename: Luisa
authors.initials: L
authors.lastname: Sen
mesh_terms: D000293:Adolescent; D018791:CD4 Lymphocyte Count; D002648:Child; D002675:Child, Preschool; D004279:DNA, Viral / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D014644:Genetic Variation; D015658:HIV Infections / Q000821:virology*; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D011533:Proviruses / Q000235:genetics; D017422:Sequence Analysis, DNA; D014774:Virulence; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D004279:DNA, Viral; D015395:Histocompatibility Antigens Class I; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1