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 DRP 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 (November 2015 – February 2016)
Asher, I., Guri, K.M., Elbirt, D., Bezalel, S.R., Maldarelli, F., Mor, O., Grossman, Z., and Sthoeger, Z.M. (2016) Characteristics and outcome of patients diagnosed with HIV at older age. Medicine 95(1): e2327.
PDF (254 K) from publisher] [PMID: 26735534]
Boyer, P.L., Das, K., Arnold, E., and Hughes,
S.H. (2015) Analysis of the zidovudine resistance mutations T215Y, M41L, and L210W in HIV-1 reverse transcriptase. Antimicrob. Agents Chemother. 59: 7184-7196. [Abstract] [Full-text
PDF (3170 K) from publisher]
[Supplemental material] [PMID: 26324274]
Chen, J., Rahman, S.A., Nikolaitchik, O.A., Grunwald, D., Sardo, L., Burdick, R.C., Plisov, S., Liang, E., Tai, S., Pathak, V.K., and Hu, W.-S. (2016) HIV-1 RNA genome dimerizes on the plasma membrane in the presence of Gag protein. Proc. Natl. Acad. Sci. USA 113: E201-E208.
PDF (1633 K) from publisher] [Supporting information]
Datta, S.A.K., Clark, P.K., Fan, L., Ma, B., Harvin, D.P., Sowder, R.C. II, Nussinov, R., Wang, Y.-X., and Rein, A. (2016) Dimerization of the SP-1 region of HIV-1 Gag induces a helical conformation and association into helical bundles: Implications for particle assembly. J. Virol. 90: 1773-1787. [Abstract] [Full-text
PDF (2977 K) from publisher] [PMID: 26637452]
Fontana, J., Keller, P., Urano, E., Ablan, S.D., Steven, A.C., and Freed, E.O. (2015) Identification of an HIV-1 mutation in spacer peptide 1 that stabilizes the immature CA-SP1 lattice. J. Virol. 90: 972-978. [Abstract] [PMID: 26537676]
PDF (1532 K) from publisher]
M.F., Anderson, E.M., Coomer, C., Smith, L., Shao, W., Johnson, N., Kline, C., Spindler, J., Mellors, J.W., Coffin, J.M., and Ambrose, Z. (2015) Well-mixed plasma and tissue viral populations in RT-SHIV-infected macaques implies a lack of viral replication in the tissues during antiretroviral therapy. Retrovirology 12: 93. [Abstract]
PDF (2160 K) from NIH Public Access] [Supplemental figures]
[PMID: 26559632; PMCID: PMC4642622]
Kearney, M.F., Wiegand, A., Shao, W., Coffin, J.M., Mellors, J.W., Lederman, M., Gandhi, R.T., Keele, B.F., and Li, J.Z. (2016) Origin of rebound plasma HIV includes cells with identical proviruses that are transcriptionally active before stopping antiretroviral therapy. J. Virol. 90: 1369-1376. [Abstract] [Full-text
PDF (1469 K) from publisher]
Macatangay, B.J.C., Riddler, S.A., Wheeler, N.D., Spindler, J., Lawani, M., Hong, F., Buffo, M.J., Whiteside, T.L., Kearney, M.F., Mellors, J.W., and Rinaldo, C.R. (2016) Therapeutic vaccination with dendritic cells loaded with autologous HIV type 1-infected apoptotic cells. J. Infect. Dis., in press. [Abstract] [Supplementary data]
PDF (754 K) from publisher, posted online Dec 8 ahead of print] [PMID: 26647281]
Maldarelli, F. (2016) The role of HIV integration in viral persistence: no more whistling past the proviral graveyard. J. Clin. Invest. 126: 438-447. [Abstract]
PDF (763 K) from publisher] [PMID: 26829624]
O'Carroll, I.P., and Rein, A. (2016) Viral nucleic acids. In Bradshaw, R.A., and Stahl, P.D. (eds.), Encyclopedia of Cell Biology, Vol. 1, Academic Press, Waltham, MA, pp. 517-524.
Sardo, L., Hatch, S.C., Chen, J., Nikolaitchik, O., Burdick, R.C., Chen, D., Westlake, C.J., Lockett, S., Pathak, V.K., and Hu, W.-S. (2015) Dynamics of HIV-1 RNA near the plasma membrane during virus assembly. J. Virol. 89: 10832-10840. [Abstract] [PMID: 26292321]
PDF (486 K) from publisher]
Simonetti, F.R., Sobolewski, M.D., Fyne, E., Shao, W., Spindler, J., Hattori, J., Anderson, E.M., Watters, S.A., Hill, S., Wu, X., Wells, D., Su, L., Luke, B.T., Halvas, E.K., Besson, G., Penrose, K.J., Yang, Z., Kwan, R.W., Van Waes, C., Uldrick, T., Citrin, D., Kovacs, J., Polis, M.A., Rehm, C.A., Gorelick, R., Piatak, M., Keele, B.F., Kearney, M.F., Coffin, J.M., Hughes,
S.H., Mellors, J.W., and Maldarelli, F. (2016) Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo. Proc. Natl. Acad. Sci. USA, in press. [Abstract] [Supporting information]
PDF (1104 K) from publisher, posted online Feb 8 ahead of print]
Kim, M., and R.F. Siliciano. (2016) Commentary: Reservoir expansion by T-cell proliferation may be another barrier to curing HIV infection. Proc. Natl. Acad. Sci. USA, in press (posted online Feb 9 ahead of print).
Singh, P.K., Plumb, M.R., Ferris, A.L., Iben, J.R., Wu, X., Fadel, H.J., Luke, B.T., Esnault, C., Poeschla, E.M., Hughes,
S.H., Kvaratskhelia, M., and Levin, H.L. (2015) LEDGF/p75 interacts with mRNA splicing factors and targets HIV-1 integration to
highly spliced genes. Genes Dev. 29: 2287-2297. [Abstract] [Full-text
PDF (3087 K) from publisher]
[Supplemental material] [PMID: 26545813]
Smith, S.J., Pauly, G.T., Akrim, A., Melody, K., Raj, G., Maloney, D.J., Ambrose, Z., Thomas, C.J., Schneider, J.T., and Hughes,
S.H. (2016) Rilpivirine analogs potently inhibit drug-resistant HIV-1 mutants. Retrovirology, in press.
Tedbury, P.R., and Freed, E.O. (2015) HIV-1 Gag: An emerging target for antiretroviral therapy. Curr. Top. Microbiol. Immunol. 389: 171-201. [Abstract]
PDF (857 K) from publisher]
Tedbury, P.R., Novikova, M., Ablan, S.D., and Freed, E.O. (2016) Biochemical evidence of a role for matrix trimerization in HIV-1 envelope glycoprotein incorporation. Proc. Natl. Acad. Sci. USA 113: E182-E190. [Abstract] [Full-text
PDF (1632 K) from publisher]
[Supporting information] [PMID: 26711999]
Zhao, X.Z., Métifiot, M., Smith, S.J., Maddali, K., Marchand, C., Hughes,
S.H., Pommier, Y., and Burke, T.R., Jr. (2016) 6,7-Dihydroxyisoindolin-1-one and 7,8-dihydroxy-3,4-dihydroisoquinolin-1(2H)-one based HIV-1 integrase inhibitors. Curr. Top. Med. Chem. 16: 435-440.
[Abstract] [PMID: 26268341]
Zhao, X.Z., Smith, S.J., Maskell, D.P., Métifiot, M., Pye, V.E., Fesen, K., Marchand, C., Pommier, Y., Cherepanov, P., Hughes,
S.H., and Burke, T.R., Jr. (2016) HIV-1 integrase strand transfer inhibitors with reduced susceptibility to drug resistant mutant integrases. ACS Chem. Biol., in press.
PDF (4939 K) from publisher, posted online Jan 25 ahead of print]
These links are provided as a service to visitors of the HIV Dynamics and Replication
Program (HIV DRP) website. The HIV DRP is not responsible for the availability or
content of these external sites, nor does the HIV DRP endorse, warrant, or guarantee the products, services, or information described or offered at these other
modified: 10 February 2016