Specific HIV Integration Sites Are Linked to Clonal Expansion and Persistence of Infected Cells
Maldarelli, F., Wu, X., Su, L., Simonetti, F.R., Shao, W., Hill, S., Spindler, J., Ferris, A.L., Mellors, J.W., Kearney,
Coffin, J.M., and Hughes,
S.H. (2014) Science 345: 179-183.
[The following excerpt is from a press release by the National Cancer Institute announcing a research milestone reported by researchers in the HIV Drug Resistance Program and their colleagues in the 26 June 2014 issue of Science: NCI News Note — Where HIV genetic information is inserted into host DNA is linked to clonal growth and persistence of infected cells.]
Persistence of HIV-infected cells in people on combination antiretroviral therapy (cART) is a major barrier for curing HIV infections. HIV inserts a DNA copy of its genetic information into the DNA of cells it infects and insertion sites vary in different infected cells. The site of insertion specifically marks each infected cell and if an infected cell divides, all of the descendants of that cell (called a clone) will also have the viral genetic information inserted at the same place as the parent. Based on an analysis of blood cells from five HIV-infected individuals, NCI researchers have identified more than 2,400 HIV DNA insertion sites. Analysis of these sites showed that there is extensive clonal expansion (growth) of HIV-infected cells. In one patient, approximately half of the HIV-infected cells in the blood came from a single clone, and some the infected clones persisted in patients for more than 10 years. The research, by Stephen Hughes, Ph.D., director, HIV Drug Resistance Program, Center for Cancer Research, NCI, and collaborators appeared online in Science June 26, 2014.
The researchers also showed that, in some cases, the clonal expansion of HIV-infected cells was associated with the sites at which HIV DNA is inserted into the host genome. The study results show that insertion of HIV DNA in specific regions of two genes, MKL2 and BACH2, was directly involved in clonal expansion of the infected cells. These genes, and several others in which there were multiple independent HIV insertions in clonally expanded cells in patients, are known to play a role in cell growth and human cancers. These findings have important implications for designing and implementing strategies to eliminate persistent HIV infection, for the use of HIV-based vectors as tools to transfer genes into patients, and possibly for the origin of some HIV-related malignancies.
Figure 1. Some HIV-infected cells clonally expand. When HIV infects a cell, a DNA copy of the viral genetic information is inserted into host DNA. This means, as long as an HIV-infected cell lives, it will carry a copy of viral genetic information, and if the infected parent cell divides, all its descendants will also be infected and will carry a copy of the inserted viral DNA (provirus) at the same location in the host DNA as the parent cell. In an untreated patient, most HIV-infected cells die within one or two days. A small fraction of the infected cells are long-lived. Successfully treating a patient with combination antiretroviral therapy (cART) prevents any additional cells from becoming infected, and all of the short-lived infected cells die. Some of the long-lived infected cells also die; however, some long-lived cells persist in patients, which prevents patients from being cured. We show that some of the infected cells can grow and divide, and that some of these expanded clones of infected cells, which can be identified by the location of the provirus in the host DNA, can persist for more than 10 years in patients. Thus, any strategy that is developed to cure an HIV-infected patient needs to be able not only to block viral replication, but must also block the replication of infected cells.
Cohen, J. (2014) Cancer genes help HIV persist, complicating cure efforts. Science 343: 1188.
Margolis, D., and Bushman, F. (2014) Persistence by proliferation? Science 345: 143-144.
Saey, T.H. (2014) HIV hides in growth-promoting genes. ScienceNews, 26 June 2014.
Damania, B. (2014) F1000Prime recommendation of [Maldarelli F et al., Science 2014, 345(6193):179-83]. F1000Prime, 21 Jul 2014.
Cell "Leading Edge Select" feature: Opening the HIV mystery box — The right spot to integrate and persist. Cell 158: 469, 471; 31 July 2014.
National Cancer Institute. (2014) HIV integration at certain sites in host DNA is linked to the expansion and persistence of infected cells. "In the Journals," July 2014.
NCI at Frederick Poster feature: HIV integration at certain sites in host DNA is linked to the expansion and persistence of infected cells. August 2014.
Baum, C. (2014) Data vs. dogma: HIV-1 integrations driving clonal selection. Mol. Ther. 22: 1557-1558.
HIV-1–Induced AIDS in Monkeys
Hatziioannou, T., Del Prete, G.Q., Keele, B.F., Estes, J.D., McNatt, M.W., Bitzegeio, J., Raymond, A., Rodriguez, A., Schmidt, F., Trubey, C.M., Smedley, J., Piatak, M., Jr., KewalRamani, V.N., Lifson, J.D., and Bieniasz, P.D. (2014) Science 344: 1401-1405.
[The following excerpt is from the article "New animal model could boost research on AIDS drugs and vaccines" by F. Blanchard and J. Lifson, published 19 June 2014 in the online newsletter Insite.]
In a research milestone reported in the June 20 issue of the journal Science, scientists have developed a minimally modified version of HIV-1, the virus that causes AIDS in infected humans, that is capable of causing progressive infection and AIDS in monkeys. The advance should help create more authentic animal models of the disease and provide a potentially invaluable approach for faster and better preclinical evaluation of new drugs and vaccines.
Lead authors are Paul Bieniasz, Ph.D., Aaron Diamond AIDS Research Center and Howard Hughes Medical Institute; Jeff Lifson, M.D., AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research; Theodora Hatziioannou, Ph.D., Aaron Diamond AIDS Research Center; and Vineet KewalRamani, Ph.D., HIV Drug Resistance Program, National Cancer Institute at Frederick. [More]
The figure shows the serial passage of minimally changed HIV into a series of pigtail macaques to adapt the virus, which became capable of causing AIDS in the monkeys, beginning after the third animal-to-animal passage (“P4” in the figure). Inverted monkey icons indicate animals that succumbed to AIDS-defining conditions. The background demonstrates depletion of CD4+ T cells from gut-associated lymphoid tissues, a hallmark of AIDS virus pathogenesis.
Cell "Leading Edge Select" feature: Opening the HIV mystery box — HIV crosses the monkey barrier. Cell 158: 469, 31 July 2014.
Nature World News feature: Iacurci, J. (2014) AIDS monkey model offers promise of new treatment. Nature World News, 21 July 2014.
ScienceDaily feature: Rockefeller University. (2014) New monkey model for AIDS offers promise for medical research. ScienceDaily, 19 June 2014.
HIV DRP Publications (August – November 2014)
Afonin, K.A., Viard, M., Koyfman, A.Y., Martins, A.N., Kasprzak, W.K., Panigaj, M., Desai, R., Santhanam, A., Grabow, W.W., Jaeger, L., Heldman, E., Reiser, J., Chiu, W., Freed, E.O., and Shapiro, B.A. (2014) Multifunctional RNA nanoparticles. Nano Lett. 14: 5662-5671.
[Abstract] [PMID: 25267559]
PDF (7397 K) from publisher]
[Supporting information (1444 K)]
Archin, N.M., Bateson, R., Tripathy, M., Crooks, A.M., Yang, K.H., Dahl, N.P., Kearney,
M.F., Anderson, E.M., Coffin, J.M., Strain, M.C., Richman, D.D., Robertson, K.R., Kashuba, A.D., Bosch, R.J., Hazuda, D.J., Kuruc, J.D., Eron, J.J., and Margolis, D.M. (2014) HIV-1 expression within resting CD4 T-cells following multiple doses of vorinostat. J. Infect. Dis. 210: 728-735.
PDF (426 K) from publisher] [PMID: 24620025]
Bhardwaj, N., Maldarelli, F., Mellors, J., and Coffin, J.M. (2014) HIV-1 infection leads to increased transcription of HERV-K (HML-2) proviruses in vivo but not to increased virion production. J. Virol. 88: 11108-11120. [Abstract] [PMID: 25056891]
PDF (2222 K) from publisher] [Supplemental material (69 K)]
Bird, S.W., Kirkegaard, K., Agbandje-McKenna, M., and Freed, E.O. (2014) The ins and outs of viral infection: Keystone meeting review. Viruses 6: 3652-3662. [Abstract]
[PMID: 25256395] [Full-text
PDF (109 K) from publisher]
Chen, J., Grunwald, D., Sardo, L., Galli, A., Plisov, S., Nikolaitchik, O.A., Chen, D., Lockett, S., Larson, D.R., Pathak, V.K., and Hu, W.-S. (2014) Cytoplasmic HIV-1 RNA is mainly transported by diffusion in the presence or absence of Gag protein. Proc. Natl. Acad. Sci. USA Plus, in press. [Abstract] [Supporting information (1410 K)]
PDF (1728 K) from publisher, posted online Nov 17 ahead of print]
Cillo, A.R., Vagratian, D., Bedison, M., Anderson, E., Kearney,
M.F., Fyne, E., Koontz, D., Coffin, J.M., Piatak, M., and Mellors, J.W. (2014) Improved single-copy assays for quantification of persistent HIV-1 viremia in patients on suppressive antiretroviral therapy. J. Clin. Microbiol. 52: 3944-3951. [Abstract] [PMID: 25187636]
PDF (1013 K) from publisher] [Supplemental material (33 K)]
Del Prete, G.Q., Ailers, B., Moldt, B., Keele, B.F., Estes, J.D., Rodriguez, A., Sampias, M., Oswald, K., Fast, R., Trubey, C.M., Chertova, E., Smedley, J., LaBranche, C.C., Montefiori, D.C., Burton, D.R., Shaw, G.M., Markowitz, M., Piatak, M., Jr., KewalRamani, V.N., Bieniasz, P.D., Lifson, J.D., and Hatziioannou, T. (2014) Selection of unadapted, pathogenic SHIVs encoding newly transmitted HIV-1 envelope proteins. Cell Host Microbe 16: 412-418. [Abstract]
PDF including supplemental information (3481 K) from publisher] [PMID: 25211081]
Fraietta, J.A., Mueller, Y.M., Lozenski, K.L., Ratner, D., Boesteanu, A.C., Hancock, A.S., Lackman-Smith, C., Zentner, I.J., Chaiken, I.M., Chung, S., Le Grice, S.F.J., Snyder, B.A., Mankowski, M.K., Jones, N.M., Hope, J.L., Gupta, P., Anderson, S.H., Wigdahl, B., and Katsikis, P.D. (2014) Abasic phosphorothioate oligomers inhibit HIV-1 reverse transcription and block virus transmission across polarized ectocervical organ cultures. Antimicrob. Agents Chemother. 58: 7056-7071. [Abstract] [PMID: 25224013] [Full-text
PDF (3663 K) from publisher]
Han, L., Diehl, A., Nguyen, N.K., Korangath, P., Teo, W., Cho, S., Kominsky, S., Huso, D.L., Feigenbaum, L., Rein, A., Argani, P., Landberg, G., Gessler, M., and Sukumar, S. (2014) The Notch pathway inhibits TGFß signaling in breast cancer through HEYL-mediated crosstalk. Cancer Res. 74: 6509-6518. [Abstract] [Full-text
PDF (2474 K) from publisher]
[Supplementary data] [PMID: 25217524]
S.H. (2014) Reverse transcription of retroviruses and LTR retrotransposons. In Mobile DNA III, ASM Press, Washington, in press.
Kuo, L., and Freed, E.O. (2014) HIV-1 assembly cofactors. In Encyclopedia of AIDS, Springer, in press.
Miller, J., and Le Grice, S.F.J. (2014) Reverse transcription. In Encyclopedia of AIDS (T. Hope, D. Richman, and M. Stevenson, eds.), Springer, New York, in press.
Nair, S., and Rein, A. (2014) Antiretroviral restriction factors in mice. Virus Res. 193: 130-134.
PDF (687 K) from publisher] [PMID: 25018022]
Nair, S., and Rein, A. (2014)
In vitro assay for cytidine deaminase activity of APOBEC3 protein. bio-protocol 4(20): e1266. [Full-text
article from publisher]
O'Carroll, I.P., and Rein, A. (2014) Viral nucleic acids. In Bradshaw, R.A., and Stahl, P.D. (eds.), Encyclopedia of Cell Biology, Elsevier, Oxford, in press.
Park, S.-Y., Waheed, A.A., Zhang, Z.R., Freed, E.O., and Bonifacino, J.S. (2014) HIV-1 Vpu induces caspase-mediated cleavage of IRF3. J. Biol. Chem., in press. [Abstract]
PDF (2709 K) from publisher, posted online Oct 28 ahead of print] [PMID: 25352594]
Pilkington, G.R., Purzycka, K.J., Bear, J., Le Grice, S.F.J., and Felber, B.K. (2015) Gammaretrovirus mRNA expression is mediated by a novel, bipartite post-transcriptional regulatory element. Nucleic Acids Res. 42: 11092-11106. [Abstract] [PMID: 25190459]
PDF (4091 K) from publisher] [Supplementary data]
Rausch, J.W., Sztuba-Solinska, J., Lusvarghi, S., and Le Grice, S.F.J. (2014) Novel biochemical tools for probing HIV RNA structure. Methods Mol. Biol., in press.
Sato, K., Takeuchi, J.S., Misawa, N., Izumi, T., Kobayashi, T., Kimura, Y., Iwami, S., Takaori-Kondo, A., Hu, W.-S., Aihara, K., Ito, M., An, D.S., Pathak, V.K., and Koyanagi, Y. (2014) APOBEC3D and APOBEC3F potently promote HIV-1 diversification and evolution in humanized mouse model. PLoS Pathog. 10(10): e1004453. [Abstract]
(3032 K) from NIH Public Access] [PMID: 25330146; PMCID: PMC4199767]
Shao, W., Kearney,
M.F., Boltz, V.F., Spindler, J.E., Mellors, J.W., Maldarelli, F., and Coffin, J.M. (2014) PAPNC, a novel method to calculate nucleotide diversity from large scale next generation sequencing data. J. Virol. Methods 203C: 73-80. [Abstract]
PDF (819 K) from publisher] [PMID: 24681054]
Sheng-Fowler, L., Tu, W., Fu, H., Murata, H., Lanning, L., Foseh, G., Macauley, J., Blair, D., Hughes,
S.H., Coffin, J.M., Lewis, A.M., Jr., and Peden, K. (2014) A mouse strain defective in both T cells and NK cells has enhanced sensitivity to tumor induction by plasmid DNA expressing both activated H-ras and c-myc. PLoS One 9: e108926. [Abstract]
PDF (1404 K) from NIH Public Access] [PMID: 25302710; PMCID: PMC4193875]
Smith, J.L., Izumi, T., Borbet, T.C., Hagedorn, A.N., and Pathak, V.K. (2014) HIV-1 and HIV-2 Vif interact with human APOBEC3 proteins using completely different determinants. J. Virol. 88: 9893-9908. [Abstract] [Full-text
PDF (1818 K) from publisher] [PMID: 24942576]
Tedbury, P., and Freed, E.O. (2014) The cytoplasmic tail of retroviral envelope glycoproteins. In The Molecular Basis of Viral Infection; Progress in Molecular Biology and Translational Science, in press.
Tedbury, P., and Freed, E.O. (2014) Virus assembly. In Encyclopedia of AIDS, Springer, in press.
Waheed, A.A., Kuruppu, N.D., Felton, K.L., D'Souza, D., and Freed, E.O. (2014) In COS cells Vpu can both stabilize tetherin expression and counteract its antiviral activity. PLoS One 9(10): e111628. [Abstract] [Full-text
PDF (1552 K) from publisher] [PMID: 25360760]
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modified: 18 November 2014