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The Impact of Macrophage Nucleotide Pools on HIV-1 Reverse Transcription, Viral Replication, and the Development of Novel Antiviral Agents

DOI: 10.1155/2012/625983

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Macrophages are ubiquitous and represent a significant viral reservoir for HIV-1. Macrophages are nondividing, terminally differentiated cells, which have a unique cellular microenvironment relative to actively dividing T lymphocytes, all of which can impact HIV-1 infection/replication, design of inhibitors targeting viral replication in these cells, emergence of mutations within the HIV-1 genome, and disease progression. Scarce dNTPs drive rNTP incorporation into the proviral DNA in macrophages but not lymphocytes. Furthermore, the efficacy of a ribose-based inhibitor that potently inhibits HIV-1 replication in macrophages, has prompted a reconsideration of the previously accepted dogma that 2′-deoxy-based inhibitors demonstrate effective inhibition of HIV-1 replication. Additionally, higher levels of dUTP and rNTP incorporation in macrophages, and lack of repair mechanisms relative to lymphocytes, provide a further mechanistic understanding required to develop targeted inhibition of viral replication in macrophages. Together, the concentrations of dNTPs and rNTPs within macrophages comprise a distinctive cellular environment that directly impacts HIV-1 replication in macrophages and provides unique insight into novel therapeutic mechanisms that could be exploited to eliminate virus from these cells. 1. Introduction Macrophages are a key reservoir for HIV-1, and their ubiquitous nature, multiple, and often independent microenvironments in which they are contained, coupled with their susceptibility to HIV-1 infection [1–3], dictate that further understanding must be garnered about the distinctive characteristics of macrophages and the subsequent impact on the dynamics of HIV-1 infection in these cells. Despite these factors, most of the attention on reservoirs for latent HIV-1 has focused on cells of lymphoid origin, most notably CD4+/CD45RO+ memory lymphocytes [4]. Consequently, the interplay between HIV-1 infection in macrophages and macrophage-like cells is markedly less defined. Additionally, the relationship between in vitro observations and in vivo dynamics is not fully elucidated. Much evidence exists to support the existence of HIV-1 replication in macrophage/macrophage-like cells in vivo [5–11], including a recent report from Deleage et al., and confirmed the presence of HIV-1 in macrophages within seminal vesicles of patients on effective highly active antiretroviral therapy (HAART) [12]. Correspondingly, a variety of studies have presented evidence that monocytes harbor productive viral replication in patients receiving HAART [13, 14], with


[1]  G. Alkhatib, C. Combadiere, C. C. Broder et al., “CC CKR5: a RANTES, MIP-1α, MIP-1β receptor as a fusion cofactor for macrophage-tropic HIV-1,” Science, vol. 272, no. 5270, pp. 1955–1958, 1996.
[2]  C. Gavegnano and R. F. Schinazi, “Antiretroviral therapy in macrophages: implication for HIV eradication,” Antiviral Chemistry and Chemotherapy, vol. 20, no. 2, pp. 63–78, 2009.
[3]  S. Aquaro, P. Bagnarelli, T. Guenci et al., “Long-term survival and virus production in human primary macrophages infected by human immunodeficiency virus,” Journal of Medical Virology, vol. 68, no. 4, pp. 479–488, 2002.
[4]  K. G. Lassen, A. M. Hebbeler, D. Bhattacharyya, et al., “A flexible model of HIV-1 latency permitting evaluation of many primary CD4 T-cell reservoirs,” PLoS ONE, vol. 7, no. 1, Article ID e30176, 2012.
[5]  A. Alexaki, Y. Liu, and B. Wigdahl, “Cellular reservoirs of HIV-1 and their role in viral persistence,” Current HIV Research, vol. 6, no. 5, pp. 388–400, 2008.
[6]  T. Fischer-Smith, C. Bell, S. Croul, M. Lewis, and J. Rappaport, “Monocyte/macrophage trafficking in acquired immunodeficiency syndrome encephalitis: lessons from human and nonhuman primate studies,” Journal of NeuroVirology, vol. 14, no. 4, pp. 318–326, 2008.
[7]  W. K. Kim, S. Corey, X. Alvarez, and K. Williams, “Monocyte/macrophage traffic in HIV and SIV encephalitis,” Journal of Leukocyte Biology, vol. 74, no. 5, pp. 650–656, 2003.
[8]  A. J. Quayle, C. Xu, K. H. Mayer, and D. J. Anderson, “T lymphocytes and macrophages, but not motile spermatozoa, are a significant source of human immunodeficiency virus in semen,” Journal of Infectious Diseases, vol. 176, no. 4, pp. 960–968, 1997.
[9]  C. N. B. Shikuma, B. Shiramizu, C. Y. Liang, et al., “Antiretroviral Monocyte Efficacy Score Linked to Cognitive Impairment in HIV,” Antiviral Therapy. In press.
[10]  B. Shiramizu, J. Ananworanich, T. Chalermchai, et al., “Failure to clear intra-monocyte HIV infection linked to persistent neuropsychological testing impairment after first-line combined antiretroviral therapy,” Journal For Neurovirology. In press.
[11]  E. Balestra, C. F. Perno, S. Aquaro et al., “Macrophages: a crucial reservoir for human immunodeficiency virus in the body,” Journal of Biological Regulators and Homeostatic Agents, vol. 15, no. 3, pp. 272–276, 2001.
[12]  C. Deleage, M. Moreau, N. Rioux-Leclercq, et al., “Human immunodeficiency virus infects human seminal vesicles in vitro and in vivo,” The American Journal of Pathology, vol. 179, pp. 2397–2408, 2011.
[13]  T. Zhu, D. Muthui, S. Holte et al., “Evidence for human immunodeficiency virus type 1 replication in vivo in CD14+ monocytes and its potential role as a source of virus in patients on highly active antiretroviral therapy,” Journal of Virology, vol. 76, no. 2, pp. 707–716, 2002.
[14]  S. Sonza, H. P. Mutimer, R. Oelrichs et al., “Monocytes harbour replication-competent, non-latent HIV-1 in patients on highly active antiretroviral therapy,” AIDS, vol. 15, no. 1, pp. 17–22, 2001.
[15]  P. J. Ellery, E. Tippett, Y. L. Chiu et al., “The CD16+ monocyte subset is more permissive to infection and preferentially harbors HIV-1 in vivo,” Journal of Immunology, vol. 178, no. 10, pp. 6581–6589, 2007.
[16]  A. M. Spivak, M. Salgado, S. A. Rabi, et al., “Circulating monocytes are not a major reservoir of HIV-1 in elite suppressors,” Journal of Virology, vol. 85, pp. 10399–10403, 2011.
[17]  A. M. Ortiz, N. R. Klatt, B. Li, et al., “Depletion of CD4 T cells abrogates post-peak decline of viremia in SIV-infected rhesus macaques,” The Journal of Clinical Investigation, vol. 121, pp. 4433–4445, 2011.
[18]  E. Fromentin, C. Gavegnano, A. Obikhod, and R. F. Schinazi, “Simultaneous quantification of intracellular natural and antiretroviral nucleosides and nucleotides by liquid chromatography-tandem mass spectrometry,” Analytical Chemistry, vol. 82, no. 5, pp. 1982–1989, 2010.
[19]  E. M. Kennedy, C. Gavegnano, L. Nguyen et al., “Ribonucleoside triphosphates as substrate of human immunodeficiency virus type 1 reverse transcriptase in human macrophages,” Journal of Biological Chemistry, vol. 285, no. 50, pp. 39380–39391, 2010.
[20]  H. Lahouassa, W. Daddacha, H. Hofmann, et al., “SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates,” Nature Immunology, vol. 13, pp. 223–228, 2012.
[21]  V. K. Jamburuthugoda, P. Chugh, and B. Kim, “Modification of human immunodeficiency virus type 1 reverse transcriptase to target cells with elevated cellular dNTP concentrations,” Journal of Biological Chemistry, vol. 281, no. 19, pp. 13388–13395, 2006.
[22]  H. Lahouassa, W. Daddacha, H. Hofmann, et al., “SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates,” Nature Immunology, vol. 13, pp. 223–228, 2012.
[23]  P. F. Lewis and M. Emerman, “Passage through mitosis is required for oncoretroviruses but not for the human immunodeficiency virus,” Journal of Virology, vol. 68, no. 1, pp. 510–516, 1994.
[24]  T. L. Diamond, M. Roshal, V. K. Jamburuthugoda et al., “Macrophage tropism of HIV-1 depends on efficient cellular dNTP utilization by reverse transcriptase,” Journal of Biological Chemistry, vol. 279, no. 49, pp. 51545–51553, 2004.
[25]  E. Kennedy, W. Daddacha, R. Slater, et al., “Frequent incorporation of rNTPs and non-canonical dUTP by HIV-1 reverse transcriptase in primary human macrophages,” in Proceedings of the 6th International AIDS Society Conference on HIV-1 Pathogenesis, Treatment, and Prevention, Rome, Italy, July 2011.
[26]  A. M. Woodside and F. P. Guengerich, “Effect of the substituent on misincorporation kinetics catalyzed by DNA polymerases at -methylguanine and -benzylguanine,” Biochemistry, vol. 41, no. 3, pp. 1027–1038, 2002.
[27]  L. L. Furge and F. P. Guengerich, “Analysis of nucleotide insertion and extension at 8-oxo-7,8- dihydroguanine by replicative T7 polymerase exo- and human immunodeficiency virus-1 reverse transcriptase using steady-state and pre-steady-state kinetics,” Biochemistry, vol. 36, no. 21, pp. 6475–6487, 1997.
[28]  G. I. Rice, J. Bond, A. Asipu et al., “Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response,” Nature Genetics, vol. 41, no. 7, pp. 829–832, 2009.
[29]  E. M. Kennedy, W. Daddacha, R. Slater et al., “Abundant non-canonical dUTP found in primary human macrophages drives its frequent incorporation by HIV-1 reverse transcriptase,” Journal of Biological Chemistry, vol. 286, no. 28, pp. 25047–25055, 2011.
[30]  K. Hrecka, C. Hao, M. Gierszewska et al., “Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein,” Nature, vol. 474, no. 7353, pp. 658–661, 2011.
[31]  N. Laguette, B. Sobhian, N. Casartelli et al., “SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx,” Nature, vol. 474, no. 7353, pp. 654–657, 2011.
[32]  T. W. Traut, “Physiological concentrations of purines and pyrimidines,” Molecular and Cellular Biochemistry, vol. 140, no. 1, pp. 1–22, 1994.
[33]  S. Aquaro and C. F. Perno, “Assessing the relative efficacy of antiretroviral activity of different drugs on macrophages,” Methods in Molecular Biology, vol. 304, pp. 445–453, 2005.
[34]  C. F. Perno, R. Yarchoan, J. Balzarini et al., “Different pattern of activity of inhibitors of the human immunodeficiency virus in lymphocytes and monocyte/macrophages,” Antiviral Research, vol. 17, no. 4, pp. 289–304, 1992.
[35]  J. Ji, J. S. Hoffmann, and L. Loeb, “Mutagenicity and pausing of HIV reverse transcriptase during HIV plus-strand DNA synthesis,” Nucleic Acids Research, vol. 22, no. 1, pp. 47–52, 1994.
[36]  C. Liang, L. Rong, M. G?tte et al., “Mechanistic studies of early pausing events during initiation of HIV-1 reverse transcription,” Journal of Biological Chemistry, vol. 273, no. 33, pp. 21309–21315, 1998.
[37]  C. Gavegnano, E. Fromentin, and R. F. Schinazi, “Nucleoside analogue triphosphate levels are significantly lower in primary human macrophages than lymphocytes,” Global Antiviral Journal. In press, IHL Press, vol 6, supplement 2, page 18, abstract 32, 2009.
[38]  L. Jones, D. Mcdonald, and D. H. Canaday, “Rapid MHC-II antigen presentation of HIV type 1 by human dendritic cells,” AIDS Research and Human Retroviruses, vol. 23, no. 6, pp. 812–816, 2007.
[39]  S. D. Kraft-Terry, I. L. Engebretsen, D. K. Bastola, H. S. Fox, P. Ciborowski, and H. E. Gendelman, “Pulsed stable isotope labeling of amino acids in cell culture uncovers the dynamic interactions between HIV-1 and the monocyte-derived macrophage,” Journal of Proteome Research, vol. 10, no. 6, pp. 2852–2862, 2011.
[40]  Y. Becker, “The changes in the T helper 1 (Th1) and T helper 2 (Th2) cytokine balance during HIV-1 infection are indicative of an allergic response to viral proteins that may be reversed by Th2 cytokine inhibitors and immune response modifiers—a review and hypothesis,” Virus Genes, vol. 28, no. 1, pp. 5–18, 2004.
[41]  K. Kedzierska, S. M. Crowe, S. Turville, and A. L. Cunningham, “The influence of cytokines, chemokines and their receptors on HIV-1 replication in monocytes and macrophages,” Reviews in Medical Virology, vol. 13, no. 1, pp. 39–56, 2003.


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