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Vpr R77Q is associated with long-term nonprogressive HIV infection and impaired induction of apoptosis

Julian J. Lum, … , Eric A. Cohen, Andrew D. Badley

Julian J. Lum, … , Eric A. Cohen, Andrew D. Badley

Published May 15, 2003
Citation Information: J Clin Invest. 2003;111(10):1547-1554. https://doi.org/10.1172/JCI16233.

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Article Immunology

Association overstated?

Submitter: Yuqi Zhao | yzhao@northwestern.edu

Departments of Pediatrics, Microbiology-Immunology, Northwestern University

Published June 12, 2003

I read with interest the recent article entitled “Vpr R77Q is associated with long-term nonprogressive HIV infection and impaired induction of apoptosis” by Lum et al. (1), which was published in May, 2003. In this article, the authors demonstrated with convincing data that an amino acid substitution at the residue 77 of HIV-1 Vpr, which was isolated from a HIV-1 viral strain HxBRU, from arginine to glutamine (R77Q) impaired the ability of Vpr to induce apoptosis. However, the authors have overstated their findings by further proposing that R77Q mutation is associated with long-term nonprogressive HIV infection for the following reasons.

Vpr R77 is not a conserved residue. The authors stated in their abstract that “The (H[F/S]RIG)2 domain of viral protein R (Vpr) induces apoptosis and may contribute to HIV-induced T cell depletion. We demonstrate a higher frequency of R77Q Vpr mutations in patients with LTNP than in patients with progressive disease.” This statement is misleading because there is no indication to show that R77 is a conserved residue of Vpr, even though the residue 77 is localized between the two (H[F/S]RIG)₂ motifs (2). In contrary, residue 77 is quite variable. For example, only 75 out of the total 368 HIV-1 Vpr protein sequences (20%) deposited in the Los Alamos HIV-1 Vpr database are arginine at residue 77. Considering that the protein sequence of HIV-1 Vpr is one of the most conserved regions of the HIV-1 viral genome with estimated similarities of 87% from all of the viruses isolated so far (3, 4), finding arginine present only in 20% of Vpr protein sequences suggests that it is probably one of the most variable residues.

Vpr Q77 is more conserved than Vpr R77. In contrast to Vpr R77 and unlike what the authors have presented in table 1 (1), glutamine at the residue 77 of Vpr (Q77) is commonly found in the Vpr protein sequences. Out of the 368 HIV-1 Vpr protein sequences deposited in the Los Alamos HIV-1 Vpr database, 65% (239/368) of them are Q77. Even after removing those 146 Vpr sequences from LTNPs as described by Lum et al. in their article (1), there are still 59% (130/222) of Vpr carry Q77.

Vpr Q77 has been commonly found in HIV-1 Vpr with wild type activities including induction of cell death. Vpr Q77 has been found in many of the HIV-1 Vpr protein sequences with wild type activities including normal level of Vpr-induced cell death. For example, 5 out of 11 Vpr isolated from the commonly used HIV-1 strains carry Q77 and have been previously shown to have the wild type level of Vpr-induced cell death (5). Furthermore, 8 out of 11 Vpr protein sequences, isolated from two long-term nonprogressors, also carried Q77 (73%) and exhibited the wild type level of Vpr-induced cell death (5). Together, these data suggest that impairment of Vpr-induced apoptosis by the R77Q Vpr mutation may only be relevant in the backbone of its original Vpr protein sequence, i.e., the HIV-1 viral strain HxBRU. The same Vpr Q77 present on other Vpr sequences may not have the same effect on Vpr-induced apoptosis. Thus, it may not be the alteration of Vpr Q77 per se that causes the impairment of Vpr-induced apoptosis but the overall structural conformation of Vpr that determines the functions of Vpr. Similarly, the Vpr protein sequences shown in table 1 could potentially be biased as no N-terminal Vpr sequences were presented. Were these sequences identical at N-terminal? If not, will variations of those amino acids contribute to Vpr-induced apoptosis? Obviously, functional characterization of the Vpr activities should be examined individually among these LTNPs before an association of R77Q mutation with non-progressive HIV infections can be made.

In summary, even though the authors have clearly demonstrated the consequence of HIV-1 HxBRU Vpr R77Q mutation in Vpr-induced apoptosis, their data did not provide compelling evidence to suggest that Vpr Q77 is associated with long-term nonprogressive HIV infection.

References:

1. Lum, J.J, Cohen, O.J., Nie, Z., Weaver, J.G., Gomez, T. S., Yao, X-J., Lynch, D., Pilon, A.A., Hawley, N. Kim, J.E., Chen, Z., Montpetit, M., Sanchez-Dardon, J., Cohen, E.A., and Badley, A.D. 2003. Vpr R77Q is associated with long-term nonprogressive HIV infection and impaired induction of apoptosis. J. Clin Invest. 111:1547-1555.

2. Macreadie, IG., Castelli LA, Hewish DR, Kirkpatrick A, Ward AC, Azad AA. 1995. A domain of human immunodeficiency virus type 1 Vpr containing repeated H(S/F)RIG amino acid motifs causes cell growth arrest and structural defects. Proc Natl Acad Sci U S A. 92:2770-4.

3. Kuiken, C., Foley, B. Hahn, B.H., Marx, P., McCutchan, F., Mellors, J., Mullins, J., Sodroski, J., Wolinsky, S.M., Korber, B. 2000. HIV Sequence Compendium, second ed. Los Alamos Natoinal Laboratory, p592.

4. Levy, J. HIV and the Pathogenesis of AIDS. Second ed. ASM Press, p. 588.

5. Zhao, Y., Chen, M. Wang, B., Yang, J., Elder, R.T., Song, X-q, Yu, M., and Saksena, N.K. 2002. Functional conservation of HIV-1 Vpr and variability in a mother-child pair of long-term non-progressors. Virus Res. 89:103-121.