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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, M.F., 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.

Related Articles:

Cohen, J.  (2014)  Cancer genes help HIV persist, complicating cure efforts.  Science 343: 1188.

Saey, T.H.  (2014)  HIV hides in growth-promoting genes.  ScienceNews, June 26.

Margolis, D., and Bushman, F.  (2014)  Persistence by proliferation?  Science 345: 143-144.

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.

Damania, B.  (2014)  F1000Prime recommendation of [Maldarelli F et al., Science 2014, 345(6193):179-83].  F1000Prime, 21 Jul 2014.

Graphic of HIV-infected cells clonally expanding - figure 1

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.


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]

Graphic of AIDS and monkeys

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.


Recent HIV DRP Publications (April – July 2014)

Abram, M.E., Ferris, A.L., Das, K., Quinoñes, O., Shao, W., Tuske, S., Alvord, W.G., Arnold, E., and Hughes, S.H.  (2014)  Mutations in HIV-1 reverse transcriptase affect the errors made in a single cycle of viral replication.  J. Virol. 88: 7589-7601.     [Abstract]     [PMID: 24760888]
[Full-text PDF (727 K) from publisher]     [Supplemental material]

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., in press.
[Abstract]     [Full-text PDF (401 K) from publisher, posted online Mar 11 ahead of print]
[PMID: 24620025]

Chen, A.K., Sengupta, P., Waki, K., Van Engelenburg, S.B., Ochiya, T., Ablan, S.D., Freed, E.O., and Lippincott-Schwartz, J.  (2014)  MicroRNA binding to the HIV-1 Gag protein inhibits Gag assembly and virus production.  Proc. Natl. Acad. Sci. USA 111: E2676-E2683.
[Abstract]     [Supporting information (1172 K)]     [PMID: 24938790]
[Full-text PDF (1247 K) from publisher, posted online June 17 ahead of print]

Costi, R., Métifiot, M., Chung, S., Cuzzucoli Crucitti, G., Maddali, K., Pescatori, L., Messore, A., Madia, V.N., Pupo, G., Scipione, L., Tortorella, S., Di Leva, F.S., Cosconati, S., Marinelli, L., Novellino, E., Le Grice, S.F.J., Corona, A., Pommier, Y., Marchand, C., and Di Santo, R.  (2014)  Basic quinolinonyl diketo acid derivatives as inhibitors of HIV integrase and their activity against RNase H function of reverse transcriptase.  J. Med. Chem. 57: 3223-3234.
[Abstract]     [Full-text PDF (3176 K) from publisher]     [PMID: 24684270]
[Supporting information]

De Ravin, S.S., Su, L., Theobald, N., Choi, U., Macpherson, J.L., Poidinger, M., Symonds, G., Pond, S.M., Ferris, A.L., Hughes, S.H., Malech, H.L., and Wu, X.  (2014)  Enhancers are major targets for murine leukemia virus vector integration.  J. Virol. 88: 4504-4513.     [Abstract]
[Full-text PDF (2378 K) from publisher]      [Supplemental material]     [PMID: 24501411]

Grohman, J.K., Gorelick, R.J., Kottegoda, S., Allbritton, N.L., Rein, A. and Weeks, K.M.  (2014)  An immature retroviral RNA genome resembles a kinetically trapped intermediate state.  J. Virol. 88: 6061-6068.     [Abstract]     [PMID: 24623442]     [Full-text PDF (395 K) from publisher]

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)  HIV-1–induced AIDS in monkeys.  Science 344: 1401-1405.     [Abstract]     [Full-text PDF (1394 K) from publisher]
[Supplementary materials]     [PMID: 24948736]

Ivetac, A., Swift, S.E., Boyer, P.L., Diaz, A., Naughton, J., Young, J.A., Hughes, S.H., and McCammon, J.A.  (2014)  Discovery of novel inhibitors of HIV-1 reverse transcriptase through virtual screening of experimental and theoretical ensembles.  Chem. Biol. Drug Des. 83: 521-531.     [Abstract]     [Full-text PDF (1611 K) from publisher]     [PMID: 24405985]

Kuo, L., and Freed, E.O.  (2014)  HIV-1 assembly cofactors.  In Encyclopedia of AIDS, Springer, in press.

Kuzembayeva, M., Dilley, K., Sardo, L., and Hu, W.-S.  (2014)  Life of Psi: How full-length HIV-1 RNAs become packaged genomes in the viral particles.  Virology 454–455: 362–370.
[Abstract]    [Full-text PDF (915 K) from publisher]    [PMID: 24530126]

Lau, C.Y., Maldarelli, F., Eckelman, W.C., and Neumann, R.D.  (2014)  Rational development of radiopharmaceuticals for HIV-1.  Nucl. Med. Biol. 41: 299-308.     [Abstract]
[Full-text PDF (1305 K) from publisher]     [PMID: 24607432]

Le Grice, S.F.J., and Nowotny, M.  (2014)  Reverse transcriptases.  In Nucleic Acid Polymerases (K. Murakami and M. Takselis, eds.), Springer Publishing, New York, pp. 189-214.

Luttge, B.G., Panchal, P., Puri, V., Checkley, M.A., and Freed, E.O.  (2014)  Mutations in the feline immunodeficiency virus envelope glycoprotein confer resistance to a dominant-negative fragment of Tsg101 by enhancing infectivity and cell-to-cell virus transmission.  Biochim. Biophys. Acta 1838: 1143-1152.     [Abstract]     [Full-text PDF (1367 K) from publisher]
[PMID: 24036228]

Maldarelli, F., Wu, X., Su, L., Simonetti, F.R., Shao, W., Hill, S., Spindler, J., Ferris, A.L., Mellors, J.W., Kearney, M.F., Coffin, J.M., and Hughes, S.H.  (2014)  Specific HIV integration sites are linked to clonal expansion and persistence of infected cells.  Science 345: 179-183.
[Abstract]     [Full-text PDF (1183 K) from publisher]     [Supplementary materials]
[PubMed citation: PMID 24968937]

National Cancer Institute press release about this paper:
NCI News Note — Where HIV genetic information is inserted into host DNA is linked to clonal growth and persistence of infected cells, 26 June 2014

"News & Analysis" commentary in Science:
Cohen, J.  (2014)  Cancer genes help HIV persist, complicating cure efforts.  Science 343: 1188.

"Perspectives" commentary in Science:
Margolis, D., and Bushman, F.  (2014)  Persistence by proliferation?  Science 345: 143-144.

News feature about this paper:
Saey, T.H.  (2014)  HIV hides in growth-promoting genes.  ScienceNews, June 26.

National Cancer Institute "In the Journals" summary of this paper:
HIV integration at certain sites in host DNA is linked to the expansion and persistence of infected cells, July 2014.

F1000Prime recommendation of this paper:
Damania, B.  (2014)  F1000Prime recommendation of [Maldarelli F et al., Science 2014, 345(6193):179-83].  F1000Prime, 21 Jul 2014.

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., in press.
[Abstract]     [PMID: 25018022]

Nair, S., Sanchez-Martinez, S., Ji, X., and Rein, A.  (2014)  Biochemical and biological studies of mouse APOBEC3.  J. Virol. 88: 3850-3860.     [Abstract]     [PMID: 24453360]
[Full-text PDF (2477 K) from publisher]

Nikolaitchik, O., and Hu, W.-S.  (2014)  Deciphering the role of the Gag-Pol ribosomal frameshift signal in HIV-1 RNA genome packaging.  J. Virol. 88: 4040-4046.     [Abstract]
[Full-text PDF (468 K) from publisher]     [PMID: 24453371]

Nowak, E., Miller, J.T., Bona, M.K., Studnicka, J., Szczepanowski, R.H., Jurkowski, J., Le Grice, S.F.J., and Nowotny, M.  (2014)  Ty3 reverse transcriptase complexed with an RNA-DNA hybrid shows structural and functional asymmetry.  Nat. Struct. Mol. Biol. 21: 389-396.
[Abstract]     [Full-text PDF (1309 K) from publisher]     [Supplementary information]
[Center for Cancer Research (CCR) "In the Journals" Feature]     [PMID: 24608367]

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]
[Full-text PDF (819 K) from publisher]     [PMID: 24681054]

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., in press.     [Abstract]     [Full-text PDF (2327 K) from publisher, posted online June 18 ahead of print]     [PMID: 24942576]

Smith, S.J., and Hughes, S.H.  (2014)  Rapid screening of HIV reverse transcriptase and integrase inhibitors.  J. Vis. Exp. 86: e51400.     [Abstract]     [Video link]
[Full-text PDF (714 K) from publisher]     [PMID: 24747880]

Sztuba-Solinska, J., and Le Grice, S.F.J.  (2014)  Insights into secondary and tertiary interactions of dengue virus RNA by SHAPE.  Methods Mol. Biol. 1138: 225-239.
[Abstract]     [Full-text PDF (1543 K) from publisher]     [PMID: 24696340]

Sztuba-Solinska, J., Shenoy, S.R., Gareiss, P., Krumpe, L.R., Le Grice, S.F.J., O'Keefe, B.R., and Schneekloth, J.S., Jr.  (2014)  Identification of biologically active, HIV TAR RNA-binding small molecules using small molecule microarrays.  J. Am. Chem. Soc. 136: 8402–8410.
[Abstract]     [Full-text PDF (2027 K) from publisher]     [PMID: 24820959]
[Supporting information]

Tedbury, P.R., and Freed, E.O.  (2014)  The role of matrix in HIV-1 envelope glycoprotein incorporation.  Trends Microbiol. 22: 372-378.
[Abstract]     [Full-text PDF (1692 K) from publisher]     [PMID: 24933691]

Tedbury, P., and Freed, E.O.  (2014)  Virus assembly.  In Encyclopedia of AIDS, Springer, in press.

Wei, D.G., Chiang, V., Fyne, E., Balakrishnan, M., Barnes, T., Graupe, M., Hesselgesser, J., Irrinki, I., Murry, J.P., Stepan, G., Stray, K.M., Tsai, A., Yu, H., Spindler, J., Kearney, M., Spina, C.A., McMahon, D., Lalezari, J., Sloan, D., Mellors, J., Geleziunas, R., and Cihlar, T.  (2014)  Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing.  PLoS Pathog. 10(4): e1004071.     [Abstract]     [Full-text PDF (1269 K) from publisher]

Wiegand, A., and Maldarelli, F.  (2014)  Single-copy quantification of HIV-1 in clinical samples.  In Human Retroviruses: Methods and Protocols (E. Vicenzi and G. Poli, eds.), Methods in Molecular Biology, Vol. 1087, Springer Science+Business Media, pp. 251-260.
[Abstract]     [PMID: 24158828]     [Full-text PDF (297 K) from publisher]

Zhao, X.Z., Smith, S.J., Métifiot, M., Marchand, C., Boyer, P.L., Pommier, Y., Hughes, S.H., and Burke, T.R., Jr.  (2014)  4-Amino-1-hydroxy-2-oxo-1,8-naphthyridine-containing compounds having high potency against raltegravir-resistant integrase mutants of HIV-1.  J. Med. Chem. 57: 5190-5202.      [Abstract]     [Full-text PDF (3309 K) from publisher]     [PMID: 24901667]


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Last modified: 21 July 2014

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