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Comment on "Transcription Factor FOXO3a Mediates Apoptosis in HIV-1-Infected Macrophages"

Mahdad Noursadeghi^*, Jhen Tsang^*, Robert F. Miller and David R. Katz^*

^* Department of Immunology and Molecular Pathology, University College London, London, United Kingdom Centre for Sexual Health and HIV Research, Department of Primary Care and Population Sciences, University College London, London, United Kingdom

We read with interest the recent article by Cui et al. (1) in which they show that HIV-1 infection of monocyte-derived macrophages (MDM) induces dephosphorylation and nuclear translocation of the proapoptotic transcription factor FOXO3a. This extends their previous work showing that TRAIL-mediated apoptosis of HIV-infected MDM is dependent on phosphorylation of Akt-1 upstream of FOXO3a (2). However, their interpretation in the present report suggests that HIV-1 infection directly induces apoptosis of macrophages. This misrepresents an extensive body of literature that finds no direct cytopathic effect of HIV infection in MDM (3) and indeed their own earlier results in which apoptosis is induced only after stimulation with recombinant human TRAIL (2). We are also engaged in study of HIV-1 infection in MDM and find no evidence on the basis of cell viability or genomic transcriptional profiling for direct induction of apoptosis or necrosis (see Fig. 1). The significance of this is that HIV-1 can establish a reservoir of infection in long-lived cells that may contribute to viral persistence. The possibility that HIV-1 infection can prime MDM for apoptosis is of significant interest but should be placed in context with evidence that HIV-1 may protect macrophages from apoptosis (4, 5) and that HIV-infected macrophages can induce apoptosis of bystander cells contributing to T cell or neuronal death (6, 7).

View larger version (42K): [in this window] [in a new window]   FIGURE 1. A, HIV-1 BaL can establish uniform infection of monocyte-derived macrophages demonstrated by intracellular p24 staining 7 days after infection. B and C, Electrophoretic analysis (Agilent 2100 Bioanalyzer) of RNA collected from these cultures for whole genome transcriptional profiling shows comparable traces (B) and RNA integrity (C). The electrophoretic profile and RNA integrity calculations (8 ) represent data from six separate donor cell cultures (mean ± SD).

References

1. Cui, M., Y. Huang, Y. Zhao, J. Zheng. 2008. Transcription factor FOXO3a mediates apoptosis in HIV-1-infected macrophages. J. Immunol. 180: 898-906. [Abstract/Free Full Text]
2. Huang, Y., N. Erdmann, H. Peng, S. Herek, J. S. Davis, X. Luo, T. Ikezu, J. Zheng. 2006. TRAIL-mediated apoptosis in HIV-1-infected macrophages is dependent on the inhibition of Akt-1 phosphorylation. J. Immunol. 177: 2304-2313. [Abstract/Free Full Text]
3. Cassol, E., M. Alfano, P. Biswas, G. Poli. 2006. Monocyte-derived macrophages and myeloid cell lines as targets of HIV-1 replication and persistence. J. Leukocyte Biol. 80: 1018-1030. [Abstract/Free Full Text]
4. Patel, N. R., J. Zhu, S. D. Tachado, J. Zhang, Z. Wan, J. Saukkonen, H. Koziel. 2007. HIV impairs TNF- mediated macrophage apoptotic response to Mycobacterium tuberculosis. J. Immunol. 179: 6973-6980. [Abstract/Free Full Text]
5. Swingler, S., A. M. Mann, J. Zhou, C. Swingler, M. Stevenson. 2007. Apoptotic killing of HIV-1-infected macrophages is subverted by the viral envelope glycoprotein. PLoS Pathog. 3: 1281-1290. [Medline]
6. Badley, A. D., A. A. Pilon, A. Landay, D. H. Lynch. 2000. Mechanisms of HIV-associated lymphocyte apoptosis. Blood 96: 2951-2964. [Abstract/Free Full Text]
7. Kaul, M., G. A. Garden, S. A. Lipton. 2001. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410: 988-994. [Medline]
8. Schroeder, A., O. Mueller, S. Stocker, R. Salowsky, M. Leiber, M. Gassmann, S. Lightfoot, W. Menzel, M. Granzow, T. Ragg. 2006. The RIN: an RNA integrity number for assigning integrity values to RNA measurements. BMC Mol. Biol. 7: 3[Medline]

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