HIV-1 nef mutations and clinical long-term nonprogression. A molecular epidemiology study.

Objectives: To analyze HIV-1 nef gene mutations in a cohort of Italian and Swedish long-term nonprogressors (LTNP) and to investigate whether particular amino acid substitutions are associated with LTNP.

Study design/methods: nef alleles from 21 LTNP and 8 progressor controls were amplified by polymerase chain reaction (PCR) and sequenced. The amino acid sequences were compared with the previously reported sequences of 16 North American LTNP and of 28 patients with progressive infection.

Results: An untruncated intact open reading frame was observed as major sequence in all LTNP and controls. None of the amino acid substitutions in known biologically functional sites was linked to LTNP. A valine/isoleucine at the variable position 11 was associated with both European (P = .0001) and American (P = .001) LTNP. The interpatient nef variation was lower among European LTNP (P = .002) than in European progressor controls.

Conclusions: Nef amino acid heterogeneity is lower among LTNP, probably reflecting the lower HIV-1 replication rate. Nef gene defects appear uncommon in both Swedish and Italian LTNP, although the presence of a valine/isoleucine at position 11 is statistically associated with a lower probability to progress to disease.