title: Functional analysis of HIV type 1 Nef gene variants from adolescent and adult survivors of perinatal infection.
abstract: Throughout the world, infants and children with HIV-1 infection are increasingly surviving into adolescence and adulthood. As HIV Nef is an important determinant of the pathogenic potential of the virus, we examined nef alleles in a cohort of extreme long-term survivors of HIV infection (average age of 16.6 years) to determine if Nef defects might have contributed to patient survival. HIV nef gene sequences were amplified for phylogenetic analysis from 15 adolescents and adults infected by mother-to-child transmission (n=10) or by blood transfusion (n=5). Functional analysis was performed by inserting patient-derived nef sequences into an HIV-derived vector that permits simultaneous evaluation of the impact of the Nef protein on MHC-I and CD4 cell surface expression. We found evidence of extensive nef gene diversity, including changes in known functional domains involved in the downregulation of cell surface MHC-I and CD4. Only 3 of 15 individuals (20%) had nef alleles with a loss of the ability to downregulate either CD4 or MHC-I. Survival into adulthood with HIV infection acquired in infancy is not uniformly linked to loss of function in nef. The Nef protein remains a potential target for immunization or pharmacologic intervention.
authors.affiliation: UCLA AIDS Institute and the David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095-1752, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zuo
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Suen
authors.forename: Alanna
authors.initials: A
authors.lastname: Wong
authors.forename: Martha
authors.initials: M
authors.lastname: Lewis
authors.forename: Ali
authors.initials: A
authors.lastname: Ayub
authors.forename: Marvin
authors.initials: M
authors.lastname: Belzer
authors.forename: Joseph
authors.initials: J
authors.lastname: Church
authors.forename: Otto O
authors.initials: OO
authors.lastname: Yang
authors.forename: Paul
authors.initials: P
authors.lastname: Krogstad
mesh_terms: D000293:Adolescent; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D015536:Down-Regulation; D005260:Female; D014644:Genetic Variation; D020276:HIV Long-Term Survivors / Q000706:statistics & numerical data*; D006679:HIV Seropositivity / Q000235:genetics / Q000276:immunology* / Q000635:transmission; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018445:Infectious Disease Transmission, Vertical / Q000706:statistics & numerical data*; D015141:Los Angeles; D008297:Male; D010802:Phylogeny; D055815:Young Adult; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D054311:nef Gene Products, Human Immunodeficiency Virus