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Is the Vpr R77Q mutation associated with long-term non-progression of HIV infection?

Fischer, Aureliea; Lejczak, Cyrillea; Lambert, Christinea; Roman, Françoisa; Servais, Jeanb; Karita, Etienneb; Allen, Susanc; Schmit, Jean-Claudea,d; Arendt, Victora,d

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aRetrovirology Laboratory, CRP-Santé, Luxembourg; bTreatment and Research AIDS Center, Kigali, Rwanda; cSchool of Public Health, University of Alabama, Birmingham, AL, USA; and dNational Service of Infectious Diseases, Centre Hospitalier de Luxembourg, Luxembourg.

Sponsorship: This study was supported by the Centre de Recherche Public Santé, Luxembourg, and the Fondation Recherche sur le SIDA, Luxembourg.

Received: 2 December 2003; accepted: 23 December 2003.

Vpr is a highly conserved accessory protein of HIV-1. Its N-terminal domain is mainly involved in the migration of the preintegration viral complex into the nucleus of non-dividing cells. Its C-terminal domain participates in the second function of the protein, which is to arrest dividing cells in the G2 phase and to induce apoptosis.

Earlier studies have shown that point mutations and deletions in the C-terminus alter the protein function, affect viral pathogenesis and are involved in the mechanism of the long-term non-progression of HIV infection. In particular, in a recent study, Lum and colleagues [1] demonstrated that an amino acid substitution at position 77 from arginine (R) to glutamine (Q) was more frequent in long-term non-progressors and impaired the ability of Vpr to induce apoptosis. The authors also compared the sequence of the protein in long-term non-progressors versus progressor patients and found that R77Q was present in eight out of 10 long-term non-progressors, whereas it was only present in five out of 15 patients with progressive disease. They concluded that R77Q is associated with long-term non-progressive HIV infection.

We performed a similar sequence analysis in 29 patients from Rwanda (mostly subtypes A) and in 26 patients from the Luxembourg HIV cohort (predominantly subtypes B). Fourteen patients from Rwanda were characterized as long-term non-progressors (CD4 cell counts > 500 cells/μl for more than 12 years) and 15 had progressive disease and AIDS-defining conditions. The 26 patients from the Luxembourg cohort consisted of 20 slow progressors (CD4 cell counts > 400 cells/μl and viral loads < 25 000 copies/ml without treatment) and of six progressors.

Viral RNA was extracted, reverse transcribed and amplified using the Qiagen One Step reverse transcriptase–polymerase chain reaction (PCR) kit (Westburg, Leusden, the Netherlands) with primers Vpr1F and Vpr1R [1]. PCR products were then amplified again in a nested PCR using the Qiagen Hot Start kit with primers Vpr2F and Vpr2R [1] and purified using the Qiagen QIAquick PCR purification kit. Direct sequencing was performed with primers Vpr2F and Vpr2R using the Big Dye Terminator Cycle Sequencing kit v3.0 (Applied Biosystems, Lennik, Belgium). Sequences were aligned with ClustalX and screened for mutations using GeneDoc software, in comparison with HXB2.

R77Q was present in 19 out of 34 long-term non-progressors (55.9%) or slow progressors and in 12 out of 21 progressors (57.1%). There was thus no significant difference in R77Q frequency between both groups. However, we observed that Vpr R77Q was clearly more frequent in subtype A than in subtype B viruses (21 out of 25, 84%; and eight out of 25, 32%, respectively, P < 0.05).

No other Vpr mutation was statistically associated with non-progression or slow progression. However, one slow progressor presented an unusual deletion of the four amino acids ‘EPYN’ in the N-terminal region of Vpr at positions 13–16. Residues 14–16 consist of a gamma turn that is part of a well-defined gamma turn (14–16)-alpha helix (17–33)-turn (34–36), structure that may be important for Vpr function [2]. In particular, residue 14 is a proline that has been shown to play an important role in the secondary structure of the protein [3]. Another slow progressor patient showed a deletion in the C-terminal region, at positions 84 and 85. A deletion between residues 83 and 90, a region involvelved in G2 cell cycle arrest, has already been described in a long-term non-progressor [4].

In conclusion, our results are in contradiction with the study of Lum et al. [1], and we can not confirm an association between R77Q and long-term non- progression. Indeed, we observed that R77Q was associated with the viral subtype more than with disease progression. We also described a unusual deletion in the Vpr N-terminal domain in a slow progressor. Further investigation of the relationship between this deletion and Vpr activity would be of interest.

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References

1. Lum JJ, Cohen OJ, Nie Z, Weaver JG, Gomez TS, Yao KJ, et al. Vpr R77Q is associated with long-term non-progressive HIV infection and impaired induction of apoptosis. J Clin Invest 2003, 111:1547–1554.

2. Wecker K, Morellet N, Bouaziz S, Roques BP. NMR structure of the HIV-1 regulatory protein Vpr in H2O/trifluoroethanol. Comparison with the Vpr N-terminal (1–51) and C-terminal (52–96) domains. AIDS Res Hum Retroviruses 2001, 17:911–923.

3. Bruns K, Fossen T, Wray V, Henklein P, Tessmer U, Schubert U. Structural characterization of the HIV-1 Vpr N-terminus: evidence of cis/trans proline isomerism. J Biol Chem 2003, 278:43188–43201.

4. Saksena NK, Ge YC, Wang B, Xiang SH, Dwyer DE, Randle C, et al. An HIV-1 infected long-term non-progressor (LTNP): molecular analysis of HIV-1 strains in the vpr and nef genes. Ann Acad Med Singapore 1996; 25:848–854.

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