Meta-Analysis To Test the Association of HIV-1 nef Amino Acid Differences and Deletions with Disease Progression

Abstract

Previous relatively small studies have associated particular amino acid replacements and deletions in the HIV-1 nef gene with differences in the rate of HIV disease progression. We tested more rigorously whether particular nef amino acid differences and deletions are associated with HIV disease progression. Amino acid replacements and deletions in patients' consensus sequences were investigated for 153 progressor (P), 615 long-term nonprogressor (LTNP), and 2,311 unknown progressor sequences from 582 subtype B HIV-infected patients. LTNPs had more defective nefs (interrupted by frameshifts or stop codons), but on a per-patient basis there was no excess of LTNP patients with one or more defective nef sequences compared to the Ps (P = 0.47). The high frequency of amino acid replacement at residues S⁸, V¹⁰, I¹¹, A¹⁵, V⁸⁵, V¹³³, N¹⁵⁷, S¹⁶³, V¹⁶⁸, D¹⁷⁴, R¹⁷⁸, E¹⁸², and R¹⁸⁸ in LTNPs was also seen in permuted datasets, implying that these are simply rapidly evolving residues. Permutation testing revealed that residues showing the greatest excess over expectation (A¹⁵, V⁸⁵, N¹⁵⁷, S¹⁶³, V¹⁶⁸, D¹⁷⁴, R¹⁷⁸, and R¹⁸⁸) were not significant (P = 0.77). Exploratory analysis suggested a hypothetical excess of frameshifting in the regions ⁹SVIG and ¹¹⁸QGYF among LTNPs. The regions V¹⁰ and ¹⁵²KVEEA of nef were commonly deleted in LTNPs. However, permutation testing indicated that none of the regions displayed significantly excessive deletion in LTNPs. In conclusion, meta-analysis of HIV-1 nef sequences provides no clear evidence of whether defective nef sequences or particular regions of the protein play a significant role in disease progression.

Citation

Pushker R., Jacqué J.M. and Shields D.C. (2010) Meta-analysis to test the association of HIV-1 nef amino acid differences and deletions with disease progression. Journal of Virology, 84(7): 3644-3653.