×

Modeling HIV persistence, the latent reservoir, and viral blips. (English) Zbl 1402.92409

Summary: HIV-1 eradication from infected individuals has not been achieved with the prolonged use of highly active antiretroviral therapy (HAART). The cellular reservoir for HIV-1 in resting memory CD4\(^+\) T cells remains a major obstacle to viral elimination. The reservoir does not decay significantly over long periods of time but is able to release replication-competent HIV-1 upon cell activation. Residual ongoing viral replication may likely occur in many patients because low levels of virus can be detected in plasma by sensitive assays and transient episodes of viremia, or HIV-1 blips, are often observed in patients even with successful viral suppression for many years. Here we review our current knowledge of the factors contributing to viral persistence, the latent reservoir, and blips, and mathematical models developed to explore them and their relationships. We show how mathematical modeling has helped improve our understanding of HIV-1 dynamics in patients on HAART and of the quantitative events underlying HIV-1 latency, reservoir stability, low-level viremic persistence, and emergence of intermittent viral blips. We also discuss treatment implications related to these studies.

MSC:

92D30 Epidemiology
92C60 Medical epidemiology
92-02 Research exposition (monographs, survey articles) pertaining to biology

References:

[1] Adams, B.M.; Banks, H.T.; Davidian, M.; Rosenberg, E.S., Estimation and prediction with HIV-treatment interruption data, Bull. math. biol., 69, 563-584, (2007) · Zbl 1139.92304
[2] Ahmed, R.; Gray, D., Immunological memory and protective immunity: understanding their relation, Science, 272, 54-60, (1996)
[3] Bailey, J.R.; Sedaghat, A.R.; Kieffer, T.; Brennan, T.; Lee, P.K.; Wind-Rotolo, M.; Haggerty, C.M.; Kamireddi, A.R.; Liu, Y.; Lee, J.; Persaud, D.; Gallant, J.E.; Cofrancesco, J.; Quinn, T.C.; Wilke, C.O.; Ray, S.C.; Siliciano, J.D.; Nettles, R.E.; Siliciano, R.F., Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating \(\operatorname{CD} 4 +\) T cells, J. virol., 80, 6441-6457, (2006)
[4] Bajaria, S.H.; Webb, G.; Kirschner, D.E., Predicting differential responses to structured treatment interruptions during HAART, Bull. math. biol., 66, 1093-1118, (2004) · Zbl 1334.92224
[5] Benson, C.A., Structured treatment interruptions—new findings, Top. HIV med., 14, 107-111, (2006)
[6] Birk, M.; Aleman, S.; Visco-Comandini, U.; Sonnerborg, A., Proviral HIV-1 dynamics and evolution in patients receiving efficient long-term antiretroviral combination therapy, HIV med., 1, 205-211, (2000)
[7] Blankson, J.N.; Finzi, D.; Pierson, T.C.; Sabundayo, B.P.; Chadwick, K.; Margolick, J.B.; Quinn, T.C.; Siliciano, R.F., Biphasic decay of latently infected \(\operatorname{CD} 4 +\) T cells in acute human immunodeficiency virus type 1 infection, J. infect. dis., 182, 1636-1642, (2000)
[8] Blankson, J.N.; Persaud, D.; Siliciano, R.F., The challenge of viral reservoirs in HIV-1 infection, Annu. rev. med., 53, 557-593, (2002)
[9] Blankson, J.N.; Siliciano, J.D.; Siliciano, R.F., The effect of early treatment on the latent reservoir of HIV-1, J. infect. dis., 191, 1394-1396, (2005)
[10] Bonhoeffer, S.; Coffin, J.M.; Nowak, M.A., Human immunodeficiency virus drug therapy and virus load, J. virol., 71, 3275-3278, (1997)
[11] Bonhoeffer, S.; May, R.M.; Shaw, G.M.; Nowak, M.A., Virus dynamics and drug therapy, Proc. natl. acad. sci. USA, 94, 6971-6976, (1997)
[12] Bonhoeffer, S.; Nowak, M.A., Pre-existence and emergence of drug resistance in HIV-1 infection, Proc. R. soc. London B, 264, 631-637, (1997)
[13] Bucy, R.P., Immune clearance of HIV type 1 replication-active cells: a model of two patterns of steady state HIV infection, AIDS res. hum. retroviruses, 15, 223-227, (1999)
[14] Callaway, D.S.; Perelson, A.S., HIV-1 infection and low steady state viral loads, Bull. math. biol., 64, 29-64, (2002) · Zbl 1334.92227
[15] Chang, J.T.; Palanivel, V.R.; Kinjyo, I.; Schambach, F.; Intlekofer, A.M.; Banerjee, A.; Longworth, S.A.; Vinup, K.E.; Mrass, P.; Oliaro, J.; Killeen, N.; Orange, J.S.; Russell, S.M.; Weninger, W.; Reiner, S.L., Asymmetric T lymphocyte division in the initiation of adaptive immune responses, Science, 315, 1687-1691, (2007)
[16] Chen, H.Y.; Di Mascio, M.; Perelson, A.S.; Ho, D.D.; Zhang, L., Determination of virus burst size in vivo using a single-cycle SIV in rhesus macaques, Proc. natl. acad. sci. USA, 104, 19079-19084, (2007)
[17] Ching, N.; Yang, O.O.; Deville, J.G.; Nielsen-Saines, K.; Ank, B.J.; Sim, M.S.; Bryson, Y.J., Pediatric HIV-1-specific cytotoxic T-lymphocyte responses suggesting ongoing viral replication despite combination antiretroviral therapy, Pediatr. res., 61, 692-697, (2007)
[18] Chomont, N., et al., 2009. HIV reservoir size and persistence are driven by T-cell survival and homeostatic proliferaiton. Nat. Med., in press, doi:10.1038/nm.1972.; Chomont, N., et al., 2009. HIV reservoir size and persistence are driven by T-cell survival and homeostatic proliferaiton. Nat. Med., in press, doi:10.1038/nm.1972.
[19] Chun, T.W.; Carruth, L.; Finzi, D.; Shen, X.; DiGiuseppe, J.A.; Taylor, H.; Hermankova, M.; Chadwick, K.; Margolick, J.; Quinn, T.C.; Kuo, Y.H.; Brookmeyer, R.; Zeiger, M.A.; Barditch-Crovo, P.; Siliciano, R.F., Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection, Nature, 387, 183-188, (1997)
[20] Chun, T.W.; Stuyver, L.; Mizell, S.B.; Ehler, L.A.; Mican, J.A.; Baseler, M.; Lloyd, A.L.; Nowak, M.A.; Fauci, A.S., Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy, Proc. natl. acad. sci. USA, 94, 13193-13197, (1997)
[21] Chun, T.W.; Davey, R.T.; Engel, D.; Lane, H.C.; Fauci, A.S., Re-emergence of HIV after stopping therapy, Nature, 401, 874-875, (1999)
[22] Chun, T.W.; Engel, D.; Mizell, S.B.; Hallahan, C.W.; Fischette, M.; Park, S.; Davey, R.T.; Dybul, M.; Kovacs, J.A.; Metcalf, J.A.; Mican, J.M.; Berrey, M.M.; Corey, L.; Lane, H.C.; Fauci, A.S., Effect of interleukin-2 on the pool of latently infected, resting \(\operatorname{CD} 4 +\) T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy, Nat. med., 5, 651-655, (1999)
[23] Chun, T.W.; Davey, R.T.; Ostrowski, M.; Shawn Justement, J.; Engel, D.; Mullins, J.I.; Fauci, A.S., Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia after discontinuation of highly active anti-retroviral therapy, Nat. med., 6, 757-761, (2000)
[24] Chun, T.W.; Engel, D.; Berrey, M.M.; Shea, T.; Corey, L.; Fauci, A.S., Early establishment of a pool of latently infected, resting \(\operatorname{CD} 4(+)\) T cells during primary HIV-1 infection, Proc. natl. acad. sci. USA, 95, 8869-8873, (1998)
[25] Chun, T.W.; Engel, D.; Mizell, S.B.; Ehler, L.A.; Fauci, A.S., Induction of HIV-1 replication in latently infected \(\operatorname{CD} 4 +\) T cells using a combination of cytokines, J. exp. med., 188, 83-91, (1998)
[26] Chun, T.W.; Fauci, A.S., Latent reservoirs of HIV: obstacles to the eradication of virus, Proc. natl. acad. sci. USA, 96, 10958-10961, (1999)
[27] Chun, T.W.; Finzi, D.; Margolick, J.; Chadwick, K.; Schwartz, D.; Siliciano, R.F., In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency, Nat. med., 1, 1284-1290, (1995)
[28] Chun, T.W.; Justement, J.S.; Moir, S.; Hallahan, C.W.; Maenza, J.; Mullins, J.I.; Collier, A.C.; Corey, L.; Fauci, A.S., Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: implications for eradication of virus, J. infect. dis., 195, 1762-1764, (2007)
[29] Chun, T.W.; Justement, J.S.; Pandya, P.; Hallahan, C.W.; McLaughlin, M.; Liu, S.; Ehler, L.A.; Kovacs, C.; Fauci, A.S., Relationship between the size of the human immunodeficiency virus type 1 (HIV-1) reservoir in peripheral blood \(\operatorname{CD} 4 +\) T cells and \(\operatorname{CD} 4 +\):\(\operatorname{CD} 8 +\) T cell ratios in aviremic HIV-1-infected individuals receiving long-term highly active antiretroviral therapy, J. infect. dis., 185, 1672-1676, (2002)
[30] Chun, T.W.; Nickle, D.C.; Justement, J.S.; Large, D.; Semerjian, A.; Curlin, M.E.; O’Shea, M.A.; Hallahan, C.W.; Daucher, M.; Ward, D.J.; Moir, S.; Mullins, J.I.; Kovacs, C.; Fauci, A.S., HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir, J. clin. invest., 115, 3250-3255, (2005)
[31] Clavel, F.; Hance, A.J., HIV drug resistance, N. engl. J. med., 350, 1023-1035, (2004)
[32] Cocohoba, J.; Dong, B.J., Raltegravir: the first HIV integrase inhibitor, Clin. ther., 30, 1747-1765, (2008)
[33] Coffin, J.M., HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy, Science, 267, 483-489, (1995)
[34] Cohen Stuart, J.W.; Wensing, A.M.; Kovacs, C.; Righart, M.; de Jong, D.; Kaye, S.; Schuurman, R.; Visser, C.J.; Boucher, C.A., Transient relapses (“blips”) of plasma HIV RNA levels during HAART are associated with drug resistance, J. acquir. immune defic. syndr., 28, 105-113, (2001)
[35] Collier, A.C.; Coombs, R.W.; Schoenfeld, D.A.; Bassett, R.L.; Timpone, J.; Baruch, A.; Jones, M.; Facey, K.; Whitacre, C.; McAuliffe, V.J.; Friedman, H.M.; Merigan, T.C.; Reichman, R.C.; Hooper, C.; Corey, L., Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine, N. engl. J. med., 334, 1011-1017, (1996)
[36] Davey, R.T.; Bhat, N.; Yoder, C.; Chun, T.W.; Metcalf, J.A.; Dewar, R.; Natarajan, V.; Lempicki, R.A.; Adelsberger, J.W.; Miller, K.D.; Kovacs, J.A.; Polis, M.A.; Walker, R.E.; Falloon, J.; Masur, H.; Gee, D.; Baseler, M.; Dimitrov, D.S.; Fauci, A.S.; Lane, H.C., HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression, Proc. natl. acad. sci. USA, 96, 15109-15114, (1999)
[37] De Boer, R.J., Understanding the failure of \(\operatorname{CD} 8 +\) T-cell vaccination against Simian/human immunodeficiency virus, J. virol., 81, 2838-2848, (2007)
[38] De Boer, R.J.; Ganusov, V.V.; Milutinovic, D.; Hodgkin, P.D.; Perelson, A.S., Estimating lymphocyte division and death rates from CFSE data, Bull. math. biol., 68, 1011-1031, (2006) · Zbl 1334.92112
[39] De Boer, R.J.; Homann, D.; Perelson, A.S., Different dynamics of \(\operatorname{CD} 4 +\) and \(\operatorname{CD} 8 +\) T cell responses during and after acute lymphocytic choriomeningitis virus infection, J. immunol., 171, 3928-3935, (2003)
[40] De Boer, R.J.; Oprea, M.; Antia, R.; Murali-Krishna, K.; Ahmed, R.; Perelson, A.S., Recruitment times, proliferation, and apoptosis rates during the \(\operatorname{CD} 8(+)\) T-cell response to lymphocytic choriomeningitis virus, J. virol., 75, 10663-10669, (2001)
[41] De Boer, R.J.; Perelson, A.S., Target cell limited and immune control models of HIV infection: a comparison, J. theor. biol., 190, 201-214, (1998)
[42] De Boer, R.J.; Perelson, A.S., Estimating division and death rates from CFSE data, J. comput. appl. math., 184, 140-164, (2005) · Zbl 1074.92016
[43] Deeks, S.G.; Wrin, T.; Liegler, T.; Hoh, R.; Hayden, M.; Barbour, J.D.; Hellmann, N.S.; Petropoulos, C.J.; McCune, J.M.; Hellerstein, M.K.; Grant, R.M., Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia, N. engl. J. med., 344, 472-480, (2001)
[44] Devereux, H.L.; Youle, M.; Johnson, M.A.; Loveday, C., Rapid decline in detectability of HIV-1 drug resistance mutations after stopping therapy, Aids, 13, 123-127, (1999)
[45] Di Mascio, M.; Markowitz, M.; Louie, M.; Hogan, C.; Hurley, A.; Chung, C.; Ho, D.D.; Perelson, A.S., Viral blip dynamics during highly active antiretroviral therapy, J. virol., 77, 12165-12172, (2003)
[46] Di Mascio, M.; Markowitz, M.; Louie, M.; Hurley, A.; Hogan, C.; Simon, V.; Follmann, D.; Ho, D.D.; Perelson, A.S., Dynamics of intermittent viremia during highly active antiretroviral therapy in patients who initiate therapy during chronic versus acute and early human immunodeficiency virus type 1 infection, J. virol., 78, 10566-10573, (2004)
[47] Di Mascio, M.; Percus, J.K.; Percus, O.E.; Markowitz, M.; Ho, D.D.; Perelson, A.S., Duration of an intermittent episode of viremia, Bull. math. biol., 67, 885-900, (2005) · Zbl 1334.92245
[48] Di Mascio, M.; Ribeiro, R.M.; Markowitz, M.; Ho, D.D.; Perelson, A.S., Modeling the long-term control of viremia in HIV-1 infected patients treated with antiretroviral therapy, Math. biosci., 188, 47-62, (2004) · Zbl 1034.92014
[49] Dimitrov, D.S.; Willey, R.L.; Sato, H.; Chang, L.J.; Blumenthal, R.; Martin, M.A., Quantitation of human immunodeficiency virus type 1 infection kinetics, J. virol., 67, 2182-2190, (1993)
[50] Dinoso, J.B.; Kim, S.Y.; Wiegand, A.M.; Palmer, S.E.; Gange, S.J.; Cranmer, L.; O’Shea, A.; Callender, M.; Spivak, A.; Brennan, T.; Kearney, M.F.; Proschan, M.A.; Mican, J.M.; Rehm, C.A.; Coffin, J.M.; Mellors, J.W.; Siliciano, R.F.; Maldarelli, F., Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy, Proc. natl. acad. sci. USA, 106, 9403-9408, (2009)
[51] Dornadula, G.; Zhang, H.; VanUitert, B.; Stern, J.; Livornese, L.; Ingerman, M.J.; Witek, J.; Kedanis, R.J.; Natkin, J.; DeSimone, J.; Pomerantz, R.J., Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy, Jama, 282, 1627-1632, (1999)
[52] Duh, E.J.; Maury, W.J.; Folks, T.M.; Fauci, A.S.; Rabson, A.B., Tumor necrosis factor alpha activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-kappa B sites in the long terminal repeat, Proc. natl. acad. sci. USA, 86, 5974-5978, (1989)
[53] Dybul, M.; Daucher, M.; Jensen, M.A.; Hallahan, C.W.; Chun, T.W.; Belson, M.; Hidalgo, B.; Nickle, D.C.; Yoder, C.; Metcalf, J.A.; Davey, R.T.; Ehler, L.; Kress-Rock, D.; Nies-Kraske, E.; Liu, S.; Mullins, J.I.; Fauci, A.S., Genetic characterization of rebounding human immunodeficiency virus type 1 in plasma during multiple interruptions of highly active antiretroviral therapy, J. virol., 77, 3229-3237, (2003)
[54] Ferguson, N.M.; deWolf, F.; Ghani, A.C.; Fraser, C.; Donnelly, C.A.; Reiss, P.; Lange, J.M.; Danner, S.A.; Garnett, G.P.; Goudsmit, J.; Anderson, R.M., Antigen-driven \(\operatorname{CD} 4 +\) T cell and HIV-1 dynamics: residual viral replication under highly active antiretroviral therapy, Proc. natl. acad. sci. USA, 96, 15167-15172, (1999)
[55] Finzi, D.; Blankson, J.; Siliciano, J.D.; Margolick, J.B.; Chadwick, K.; Pierson, T.; Smith, K.; Lisziewicz, J.; Lori, F.; Flexner, C.; Quinn, T.C.; Chaisson, R.E.; Rosenberg, E.; Walker, B.; Gange, S.; Gallant, J.; Siliciano, R.F., Latent infection of \(\operatorname{CD} 4 +\) T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy, Nat. med., 5, 512-517, (1999)
[56] Finzi, D.; Hermankova, M.; Pierson, T.; Carruth, L.M.; Buck, C.; Chaisson, R.E.; Quinn, T.C.; Chadwick, K.; Margolick, J.; Brookmeyer, R.; Gallant, J.; Markowitz, M.; Ho, D.D.; Richman, D.D.; Siliciano, R.F., Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy, Science, 278, 1295-1300, (1997)
[57] Finzi, D.; Siliciano, R., Viral dynamics in HIV-1 infection, Cell, 93, 665-671, (1998)
[58] Fischer, M.; Hafner, R.; Schneider, C.; Trkola, A.; Joos, B.; Joller, H.; Hirschel, B.; Weber, R.; Gunthard, H.F., HIV RNA in plasma rebounds within days during structured treatment interruptions, Aids, 17, 195-199, (2003)
[59] Fraser, C.; Ferguson, N.M.; Anderson, R.M., Quantification of intrinsic residual viral replication in treated HIV-infected patients, Proc. natl. acad. sci. USA, 98, 15167-15172, (2001)
[60] Fraser, C.; Ferguson, N.M.; de Wolf, F.; Anderson, R.M., The role of antigenic stimulation and cytotoxic T cell activity in regulating the long-term immunopathogenesis of HIV: mechanisms and clinical implications, Proc. biol. sci., 268, 2085-2095, (2001)
[61] Fraser, J.D.; Proft, T., The bacterial superantigen and superantigen-like proteins, Immunol. rev., 225, 226-243, (2008)
[62] Frenkel, L.M.; Wang, Y.; Learn, G.H.; McKernan, J.L.; Ellis, G.M.; Mohan, K.M.; Holte, S.E.; De Vange, S.M.; Pawluk, D.M.; Melvin, A.J.; Lewis, P.F.; Heath, L.M.; Beck, I.A.; Mahalanabis, M.; Naugler, W.E.; Tobin, N.H.; Mullins, J.I., Multiple viral genetic analyses detect low-level human immunodeficiency virus type 1 replication during effective highly active antiretroviral therapy, J. virol., 77, 5721-5730, (2003)
[63] Furtado, M.R.; Callaway, D.S.; Phair, J.P.; Kunstman, K.J.; Stanton, J.L.; Macken, C.A.; Perelson, A.S.; Wolinsky, S.M., Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy, N. engl. J. med., 340, 1614-1622, (1999)
[64] Geeraert, L.; Kraus, G.; Pomerantz, R.J., Hide-and-seek: the challenge of viral persistence in HIV-1 infection, Annu. rev. med., 59, 215-229, (2008)
[65] Gett, A.V.; Hodgkin, P.D., A cellular calculus for signal integration by T cells, Nat. immunol., 1, 239-244, (2000)
[66] Greub, G.; Cozzi-Lepri, A.; Ledergerber, B.; Staszewski, S.; Perrin, L.; Miller, V.; Francioli, P.; Furrer, H.; Battegay, M.; Vernazza, P.; Bernasconi, E.; Gunthard, H.F.; Hirschel, B.; Phillips, A.N.; Telenti, A., Intermittent and sustained low-level HIV viral rebound in patients receiving potent antiretroviral therapy, Aids, 16, 1967-1969, (2002)
[67] Grossman, Z.; Feinberg, M.; Kuznetsov, V.; Dimitrov, D.; Paul, W., HIV infection: how effective is drug combination treatment?, Immunol. today, 19, 528-532, (1998)
[68] Grossman, Z.; Polis, M.; Feinberg, M.B.; Grossman, Z.; Levi, I.; Jankelevich, S.; Yarchoan, R.; Boon, J.; de Wolf, F.; Lange, J.M.; Goudsmit, J.; Dimitrov, D.S.; Paul, W.E., Ongoing HIV dissemination during HAART, Nat. med., 5, 1099-1104, (1999)
[69] Gulick, R.M., Structured treatment interruption in patients infected with HIV, Drugs, 62, 245-253, (2002)
[70] Gulick, R.M.; Lalama, C.M.; Ribaudo, H.J.; Shikuma, C.M.; Schackman, B.R.; Schouten, J.; Squires, K.E.; Koletar, S.L.; Pilcher, C.D.; Reichman, R.C.; Klingman, K.L.; Kuritzkes, D.R., Intensification of a triple-nucleoside regimen with tenofovir or efavirenz in HIV-1-infected patients with virological suppression, Aids, 21, 813-823, (2007)
[71] Gulick, R.M.; Mellors, J.W.; Havlir, D.; Eron, J.J.; Gonzalez, C.; McMahon, D.; Richman, D.D.; Valentine, F.T.; Jonas, L.; Meibohm, A.; Emini, E.A.; Chodakewitz, J.A., Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy, N. engl. J. med., 337, 734-739, (1997)
[72] Gunthard, H.F.; Frost, S.D.; Leigh-Brown, A.J.; Ignacio, C.C.; Kee, K.; Perelson, A.S.; Spina, C.A.; Havlir, D.V.; Hezareh, M.; Looney, D.J.; Richman, D.D.; Wong, J.K., Evolution of envelope sequences of human immunodeficiency virus type 1 in cellular reservoirs in the setting of potent antiviral therapy, J. virol., 73, 9404-9412, (1999)
[73] Gunthard, H.F.; Wong, J.K.; Ignacio, C.C.; Guatelli, J.C.; Riggs, N.L.; Havlir, D.V.; Richman, D.D., Human immunodeficiency virus replication and genotypic resistance in blood and lymph nodes after a year of potent antiretroviral therapy, J. virol., 72, 2422-2428, (1998)
[74] Gunthard, H.F.; Wong, J.K.; Spina, C.A.; Ignacio, C.; Kwok, S.; Christopherson, C.; Hwang, J.; Haubrich, R.; Havlir, D.; Richman, D.D., Effect of influenza vaccination on viral replication and immune response in persons infected with human immunodeficiency virus receiving potent antiretroviral therapy, J. infect. dis., 181, 522-531, (2000)
[75] Haase, A.T.; Henry, K.; Zupancic, M.; Sedgewick, G.; Faust, R.A.; Melroe, H.; Cavert, W.; Gebhard, K.; Staskus, K.; Zhang, Z.Q.; Dailey, P.J.; Balfour, H.H.; Erice, A.; Perelson, A.S., Quantitative image analysis of HIV-1 infection in lymphoid tissue, Science, 274, 985-989, (1996)
[76] Haggerty, C.M.; Pitt, E.; Siliciano, R.F., The latent reservoir for HIV-1 in resting \(\operatorname{CD} 4 +\) T cells and other viral reservoirs during chronic infection: insights from treatment and treatment-interruption trials, Curr. opin. HIV AIDS, 1, 62-68, (2006)
[77] Hall, P.A.; Watt, F.M., Stem cells: the generation and maintenance of cellular diversity, Development, 106, 619-633, (1989)
[78] Hammer, S.M.; Squires, K.E.; Hughes, M.D.; Grimes, J.M.; Demeter, L.M.; Currier, J.S.; Eron, J.J.; Feinberg, J.E.; Balfour, H.H.; Deyton, L.R.; Chodakewitz, J.A.; Fischl, M.A., A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS clinical trials group 320 study team, N. engl. J. med., 337, 725-733, (1997)
[79] Han, Y.; Lassen, K.; Monie, D.; Sedaghat, A.R.; Shimoji, S.; Liu, X.; Pierson, T.C.; Margolick, J.B.; Siliciano, R.F.; Siliciano, J.D., Resting \(\operatorname{CD} 4 +\) T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals carry integrated HIV-1 genomes within actively transcribed host genes, J. virol., 78, 6122-6133, (2004)
[80] Havlir, D.V.; Bassett, R.; Levitan, D.; Gilbert, P.; Tebas, P.; Collier, A.C.; Hirsch, M.S.; Ignacio, C.; Condra, J.; Günthard, H.F.; Richman, D.D.; Wong, J.K., Prevalence and predictive value of intermittent viremia with combination HIV therapy, Jama, 286, 171-179, (2001)
[81] Havlir, D.V.; Strain, M.C.; Clerici, M.; Ignacio, C.; Trabattoni, D.; Ferrante, P.; Wong, J.K., Productive infection maintains a dynamic steady state of residual viremia in human immunodeficiency virus type 1-infected persons treated with suppressive antiretroviral therapy for five years, J. virol., 77, 11212-11219, (2003)
[82] Hawkins, E.D.; Turner, M.L.; Dowling, M.R.; van Gend, C.; Hodgkin, P.D., A model of immune regulation as a consequence of randomized lymphocyte division and death times, Proc. natl. acad. sci. USA, 104, 5032-5037, (2007)
[83] Hermankova, M.; Ray, S.C.; Ruff, C.; Powell-Davis, M.; Ingersoll, R.; D’Aquila, R.T.; Quinn, T.C.; Siliciano, J.D.; Siliciano, R.F.; Persaud, D., HIV-1 drug resistance profiles in children and adults with viral load of \(< 50 \operatorname{copies} / \operatorname{ml}\) receiving combination therapy, Jama, 286, 196-207, (2001)
[84] Hermankova, M.; Siliciano, J.D.; Zhou, Y.; Monie, D.; Chadwick, K.; Margolick, J.B.; Quinn, T.C.; Siliciano, R.F., Analysis of human immunodeficiency virus type 1 gene expression in latently infected resting \(\operatorname{CD} 4 +\) T lymphocytes in vivo, J. virol., 77, 7383-7392, (2003)
[85] Hlavacek, W.S.; Stilianakis, N.I.; Notermans, D.W.; Danner, S.A.; Perelson, A.S., Influence of follicular dendritic cells on decay of HIV during antiretroviral therapy, Proc. natl. acad. sci. USA, 97, 10966-10971, (2000)
[86] Hlavacek, W.S.; Stilianakis, N.I.; Perelson, A.S., Influence of follicular dendritic cells on HIV dynamics, Philos. trans. R. soc. London B biol. sci., 355, 1051-1058, (2000)
[87] Hlavacek, W.S.; Wofsy, C.; Perelson, A.S., Dissociation of HIV-1 from follicular dendritic cells during HAART: mathematical analysis, Proc. natl. acad. sci. USA, 96, 14681-14686, (1999) · Zbl 0983.92014
[88] Ho, D.D., Viral counts count in HIV infection, Science, 272, 1124-1125, (1996)
[89] Ho, D.D., Toward HIV eradication or remission: the tasks ahead, Science, 280, 1866-1867, (1998)
[90] Ho, D.D.; Neumann, A.U.; Perelson, A.S.; Chen, W.; Leonard, J.M.; Markowitz, M., Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection, Nature, 373, 123-126, (1995)
[91] Ho, D.; Rota, T.; Hirsch, M., Infection of monocyte/macrophages by human T lymphotropic virus type III, J. clin. invest., 77, 1712-1715, (1986)
[92] Hockett, R.D.; Kilby, J.M.; Derdeyn, C.A.; Saag, M.S.; Sillers, M.; Squires, K.; Chiz, S.; Nowak, M.A.; Shaw, G.M.; Bucy, R.P., Constant Mean viral copy number per infected cell in tissues regardless of high, low, or undetectable plasma HIV RNA, J. exp. med., 189, 1545-1554, (1999)
[93] Holte, S.E.; Melvin, A.J.; Mullins, J.I.; Tobin, N.H.; Frenkel, L.M., Density-dependent decay in HIV-1 dynamics, J. acquir. immune defic. syndr., 41, 266-276, (2006)
[94] Homann, D.; Teyton, L.; Oldstone, M.B., Differential regulation of antiviral T-cell immunity results in stable \(\operatorname{CD} 8 +\) but declining \(\operatorname{CD} 4 +\) T-cell memory, Nat. med., 7, 913-919, (2001)
[95] Horvitz, H.R.; Herskowitz, I., Mechanisms of asymmetric cell division: two Bs or not two Bs, that is the question, Cell, 68, 237-255, (1992)
[96] Imamichi, H.; Crandall, K.A.; Natarajan, V.; Jiang, M.K.; Dewar, R.L.; Berg, S.; Gaddam, A.; Bosche, M.; Metcalf, J.A.; Davey, R.T.; Lane, H.C., Human immunodeficiency virus type 1 quasi species that rebound after discontinuation of highly active antiretroviral therapy are similar to the viral quasi species present before initiation of therapy, J. infect. dis., 183, 36-50, (2001)
[97] Jan, Y.N.; Jan, L.Y., Asymmetric cell division, Nature, 392, 775-778, (1998)
[98] Jeffrey, A.M.; Xia, X., Identifiability of HIV/AIDS model, () · Zbl 1268.92092
[99] Jones, L.E.; Perelson, A.S., Modeling the effects of vaccination on chronically infected HIV-positive patients, J. acquir. immune defic. syndr., 31, 369-377, (2002)
[100] Jones, L.E.; Perelson, A.S., Opportunistic infection as a cause of transient viremia in chronically infected HIV patients under treatment with HAART, Bull. math. biol., 67, 1227-1251, (2005) · Zbl 1334.92407
[101] Jones, L.E.; Perelson, A.S., Transient viremia, plasma viral load, and reservoir replenishment in HIV-infected patients on antiretroviral therapy, J. acquir. immune defic. syndr., 45, 483-493, (2007)
[102] Jordan, A.; Bisgrove, D.; Verdin, E., HIV reproducibly establishes a latent infection after acute infection of T cells in vitro, Embo j., 22, 1868-1877, (2003)
[103] Kaech, S.M.; Ahmed, R., Memory \(\operatorname{CD} 8 +\) T cell differentiation: initial antigen encounter triggers a developmental program in naive cells, Nat. immunol., 2, 415-422, (2001)
[104] Kao, S.Y.; Calman, A.F.; Luciw, P.A.; Peterlin, B.M., Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product, Nature, 330, 489-493, (1987)
[105] Kepler, T.B.; Perelson, A.S., Drug concentration heterogeneity facilitates the evolution of drug resistance, Proc. natl. acad. sci. USA, 95, 11514-11519, (1998) · Zbl 0919.92023
[106] Kieffer, T.L.; Finucane, M.M.; Nettles, R.E.; Quinn, T.C.; Broman, K.W.; Ray, S.C.; Persaud, D.; Siliciano, R.F., Genotypic analysis of HIV-1 drug resistance at the limit of detection: virus production without evolution in treated adults with undetectable HIV loads, J. infect. dis., 189, 1452-1465, (2004)
[107] Kim, H.; Perelson, A.S., Viral and latent reservoir persistence in HIV-1-infected patients on therapy, Plos comput. biol., 2, e135, (2006)
[108] Kim, H.; Perelson, A.S., Dynamic characteristics of HIV-1 reservoirs, Curr. opin. HIV AIDS, 1, 152-156, (2006)
[109] Kirschner, D.E.; Webb, G.F., Understanding drug resistance for montherapy treatment of HIV infection, Bull. math. biol., 59, 763-786, (1997) · Zbl 0922.92011
[110] Kolber, M.A.; Campo, R.E.; Dickinson, G.M., Development of anti-retroviral resistance of HIV-1 infected individuals on therapy: is it inevitable?, IUBMB life, 56, 301-307, (2004)
[111] Korin, Y.D.; Brooks, D.G.; Brown, S.; Korotzer, A.; Zack, J.A., Effects of prostratin on T-cell activation and human immunodeficiency virus latency, J. virol., 76, 8118-8123, (2002)
[112] Krakovska, O.; Wahl, L.M., Drug-sparing regimens for HIV combination therapy: benefits predicted for “drug coasting”, Bull. math. biol., 69, 2627-2647, (2007) · Zbl 1245.92031
[113] Kulkosky, J.; Culnan, D.M.; Roman, J.; Dornadula, G.; Schnell, M.; Boyd, M.R.; Pomerantz, R.J., Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART, Blood, 98, 3006-3015, (2001)
[114] Kupfer, B.; Matz, B.; Daumer, M.P.; Roden, F.; Rockstroh, J.K.; Qurishi, N.; Spengler, U.; Kaiser, R., Frequent detection of cell-associated HIV-1 RNA in patients with plasma viral load \(< 50 \operatorname{copies} / \operatorname{ml}\), J. med. virol., 79, 1440-1445, (2007)
[115] Lafeuillade, A.; Poggi, C.; Chadapaud, S.; Hittinger, G.; Chouraqui, M.; Pisapia, M.; Delbeke, E., Pilot study of a combination of highly active antiretroviral therapy and cytokines to induce HIV-1 remission, J. acquir. immune defic. syndr., 26, 44-55, (2001)
[116] Lambotte, O.; Chaix, M.L.; Gubler, B.; Nasreddine, N.; Wallon, C.; Goujard, C.; Rouzioux, C.; Taoufik, Y.; Delfraissy, J.F., The lymphocyte HIV reservoir in patients on long-term HAART is a memory of virus evolution, Aids, 18, 1147-1158, (2004)
[117] Langford, D.; Marquie-Beck, J.; de Almeida, S.; Lazzaretto, D.; Letendre, S.; Grant, I.; McCutchan, J.A.; Masliah, E.; Ellis, R.J., Relationship of antiretroviral treatment to postmortem brain tissue viral load in human immunodeficiency virus-infected patients, J. neurovirol., 12, 100-107, (2006)
[118] Lassen, K.; Han, Y.; Zhou, Y.; Siliciano, J.; Siliciano, R.F., The multifactorial nature of HIV-1 latency, Trends mol. med., 10, 525-531, (2004)
[119] Lawrence, J.; Hullsiek, K.H.; Thackeray, L.M.; Abrams, D.I.; Crane, L.R.; Mayers, D.L.; Jones, M.C.; Saldanha, J.M.; Schmetter, B.S.; Baxter, J.D., Disadvantages of structured treatment interruption persist in patients with multidrug-resistant HIV-1: final results of the CPCRA 064 study, J. acquir. immune defic. syndr., 43, 169-178, (2006)
[120] Layne, S.P., Factors underlying spontaneous inactivation and susceptibility to neutralization of human immunodeficiency virus, Virology, 189, 695-714, (1992)
[121] Lee, H.Y.; Perelson, A.S., Modeling T cell proliferation and death in vitro based on labeling data: generalizations of the smith – martin cell cycle model, Bull. math. biol., 70, 21-44, (2008) · Zbl 1281.92020
[122] Lee, P.K.; Kieffer, T.L.; Siliciano, R.F.; Nettles, R.E., HIV-1 viral load blips are of limited clinical significance, J. antimicrob. chemother., 57, 803-805, (2006)
[123] Lehrman, G.; Hogue, I.B.; Palmer, S.; Jennings, C.; Spina, C.A.; Wiegand, A.; Landay, A.L.; Coombs, R.W.; Richman, D.D.; Mellors, J.W.; Coffin, J.M.; Bosch, R.J.; Margolis, D.M., Depletion of latent HIV-1 infection in vivo: a proof-of-concept study, Lancet, 366, 549-555, (2005)
[124] Little, S.J.; McLean, A.R.; Spina, C.A.; Richman, D.D.; Havlir, D.V., Viral dynamics of acute HIV-1 infection, J. exp. med., 190, 841-850, (1999)
[125] Liu, S.L.; Rodrigo, A.G.; Shankarappa, R.; Learn, G.H.; Hsu, L.; Davidov, O.; Zhao, L.P.; Mullins, J.I., HIV quasispecies and resampling, Science, 273, 415-416, (1996)
[126] Lori, F.; Foli, A.; Lisziewicz, J., Structured treatment interruptions as a potential alternative therapeutic regimen for HIV-infected patients: a review of recent clinical data and future prospects, J. antimicrob. chemother., 50, 155-160, (2002)
[127] Lori, F.; Jessen, H.; Lieberman, J.; Finzi, D.; Rosenberg, E.; Tinelli, C.; Walker, B.; Siliciano, R.F.; Lisziewicz, J., Treatment of human immunodeficiency virus infection with hydroxyurea, didanosine, and a protease inhibitor before seroconversion is associated with normalized immune parameters and limited viral reservoir, J. infect. dis., 180, 1827-1832, (1999)
[128] Lori, F.; Lisziewicz, J., Structured treatment interruptions for the management of HIV infection, Jama, 286, 2981-2987, (2001)
[129] MacArthur, R.D.; Novak, R.M., Reviews of anti-infective agents: maraviroc: the first of a new class of antiretroviral agents, Clin. infect. dis., 47, 236-241, (2008)
[130] Macias, J.; Palomares, J.C.; Mira, J.A.; Torres, M.J.; Garcia-Garcia, J.A.; Rodriquez, J.M.; Vergera, S.; Pineda, J.A., Transient rebounds of HIV plasma viremia are associated with the emergence of drug resistance mutations in patients on highly active antiretroviral therapy, J. infect., 51, 195-200, (2005)
[131] Maldarelli, F.; Palmer, S.; King, M.S.; Wiegand, A.; Polis, M.A.; Mican, J.; Kovacs, J.A.; Davey, R.T.; Rock-Kress, D.; Dewar, R.; Liu, S.; Metcalf, J.A.; Rehm, C.; Brun, S.C.; Hanna, G.J.; Kempf, D.J.; Coffin, J.M.; Mellors, J.W., ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia, Plos pathog., 3, e46, (2007)
[132] Margolis, D.M.; Archin, N.M., Eliminating persistent HIV infection: getting to the end of the rainbow, J. infect. dis., 195, 1734-1736, (2007)
[133] Markowitz, M.; Jin, X.; Hurley, A.; Simon, V.; Ramratnam, B.; Louie, M.; Deschenes, G.R.; Ramanathan, M.; Barsoum, S.; Vanderhoeven, J.; He, T.; Chung, C.; Murray, J.; Perelson, A.S.; Zhang, L.; Ho, D.D., Discontinuation of antiretroviral therapy commenced early during the course of human immunodeficiency virus type 1 infection, with or without adjunctive vaccination, J. infect. dis., 186, 634-643, (2002)
[134] Markowitz, M., Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study, J. acquir. immune defic. syndr., 46, 125-133, (2007)
[135] Marsden, M.D.; Zack, J.A., Eradication of HIV: current challenges and new directions, J. antimicrob. chemother., 63, 7-10, (2009)
[136] Martinez, M.A.; Cabana, M.; Ibanez, A.; Clotet, B.; Arno, A.; Ruiz, L., Human immunodeficiency virus type 1 genetic evolution in patients with prolonged suppression of plasma viremia, Virology, 256, 180-187, (1999)
[137] Martinez, V.; Marcelin, A.G.; Morini, J.P.; Deleuze, J.; Krivine, A.; Gorin, I.; Yerly, S.; Perrin, L.; Peytavin, G.; Calvez, V.; Dupin, N., HIV-1 intermittent viraemia in patients treated by non-nucleoside reverse transcriptase inhibitor-based regimen, Aids, 19, 1065-1069, (2005)
[138] Martinez-Picado, J.; DePasquale, M.P.; Kartsonis, N.; Hanna, G.J.; Wong, J.; Finzi, D.; Rosenberg, E.; Gunthard, H.F.; Sutton, L.; Savara, A.; Petropoulos, C.J.; Hellmann, N.; Walker, B.D.; Richman, D.D.; Siliciano, R.; D’Aquila, R.T., Antiretroviral resistance during successful therapy of HIV type 1 infection, Proc. natl. acad. sci. USA, 97, 10948-10953, (2000)
[139] McCormick, J.K.; Yarwood, J.M.; Schlievert, P.M., Toxic shock syndrome and bacterial superantigens: an update, Annu. rev. microbiol., 55, 77-104, (2001)
[140] McLean, A.R.; Michie, C.A., In vivo estimates of division and death rates of human T lymphocytes, Proc. natl. acad. sci. USA, 92, 3707-3711, (1995)
[141] McLean, A.R.; Nowak, M.A., Competition between zidovudine-sensitive and zidovudine-resistant strains of HIV, Aids, 6, 71-79, (1992)
[142] McLean, A.R.; Nowak, M.A., Models of interactions between HIV and other pathogens, J. theor. biol., 155, 69-86, (1992)
[143] Mellors, J.W.; Rinaldo, C.R.; Gupta, P.; White, R.M.; Todd, J.A.; Kingsley, L.A., Prognosis in HIV-1 infection predicted by the quantity of virus in plasma, Science, 272, 1167-1170, (1996)
[144] Michie, C.A.; Mclean, A.R.; Alcock, C.; Beverley, P.C., Lifespan of human lymphocyte subsets defined by CD45 isoforms, Nature, 360, 264-265, (1992)
[145] Miller, V.; Sabin, C.; Hertogs, K.; Bloor, S.; Martinez-Picado, J.; D’Aquila, R.; Larder, B.; Lutz, T.; Gute, P.; Weidmann, E.; Rabenau, H.; Phillips, A.; Staszewski, S., Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure, Aids, 14, 2857-2867, (2000)
[146] Mira, J.A.; Macias, J.; Nogales, C.; Fernandez-Rivera, J.; Garcia-Garcia, J.A.; Ramos, A.; Pineda, J.A., Transient rebounds of low-level viraemia among HIV-infected patients under HAART are not associated with virological or immunological failure, Antivir. ther., 7, 251-256, (2002)
[147] Mittler, J.E.; Markowitz, M.; Ho, D.D.; Perelson, A.S., Refined estimates for HIV-1 clearance rate and intracellular delay, Aids, 13, 1415-1417, (1999)
[148] Monie, D.; Simmons, R.P.; Nettles, R.E.; Kieffer, T.L.; Zhou, Y.; Zhang, H.; Karmon, S.; Ingersoll, R.; Chadwick, K.; Zhang, H.; Margolick, J.B.; Quinn, T.C.; Ray, S.C.; Wind-Rotolo, M.; Miller, M.; Persaud, D.; Siliciano, R.F., A novel assay allows genotyping of the latent reservoir for human immunodeficiency virus type 1 in the resting \(\operatorname{CD} 4 +\) T cells of viremic patients, J. virol., 79, 5185-5202, (2005)
[149] Muller, V.; Vigueras-Gomez, J.F.; Bonhoeffer, S., Decelerating decay of latently infected cells during prolonged therapy for human immunodeficiency virus type 1 infection, J. virol., 76, 8963-8965, (2002)
[150] Murphy, E.L.; Collier, A.C.; Kalish, L.A.; Assmann, S.F.; Para, M.F.; Flanigan, T.P.; Kumar, P.N.; Mintz, L.; Wallach, F.R.; Nemo, G.J., Highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced HIV disease, Ann. intern. med., 135, 17-26, (2001)
[151] Murray, J.M.; Emery, S.; Kelleher, A.D.; Law, M.; Chen, J.; Hazuda, D.J.; Nguyen, B.Y.; Teppler, H.; Cooper, D.A., Antiretroviral therapy with the integrase inhibitor raltegravir alters decay kinetics of HIV, significantly reducing the second phase, Aids, 21, 2315-2321, (2007)
[152] Murray, J.M.; Perelson, A.S., Human immunodeficiency virus: quasi-species and drug resistance, Multiscale model. simul., 3, 300-311, (2005) · Zbl 1068.92027
[153] Nabel, G.; Baltimore, D., An inducible transcription factor activates expression of human immunodeficiency virus in T cells, Nature, 326, 711-713, (1987)
[154] Natarajan, V.; Bosche, M.; Metcalf, J.A.; Ward, D.J.; Lane, H.C.; Kovacs, J.A., HIV-1 replication in patients with undetectable plasma virus receiving HAART, Lancet, 353, 119-120, (1999)
[155] Nelson, P.W.; Perelson, A.S., Mathematical analysis of delay differential equation models of HIV-1 infection, Math. biosci., 179, 73-94, (2002) · Zbl 0992.92035
[156] Nettles, R.E.; Kieffer, T.L.; Kwon, P.; Monie, D.; Han, Y.; Parsons, T.; Cofrancesco, J.; Gallant, J.E.; Quinn, T.C.; Jackson, B.; Flexner, C.; Carson, K.; Ray, S.; Persaud, D.; Siliciano, R.F., Intermittent HIV-1 viremia (blips) and drug resistance in patients receiving HAART, Jama, 293, 817-829, (2005)
[157] Nettles, R.E.; Kieffer, T.L.; Simmons, R.P.; Cofrancesco, J.; Moore, R.D.; Gallant, J.E.; Persaud, D.; Siliciano, R.F., Genotypic resistance in HIV-1-infected patients with persistently detectable low-level viremia while receiving highly active antiretroviral therapy, Clin. infect. dis., 39, 1030-1037, (2004)
[158] Noë, A.; Plum, J.; Verhofstede, C., The latent HIV-1 reservoir in patients undergoing HAART: an archive of pre-HAART drug resistance, J. antimicrob. chemother., 55, 410-412, (2005)
[159] Nowak, M.A.; Bangham, C.R., Population dynamics of immune responses to persistent viruses, Science, 272, 74-79, (1996)
[160] Nowak, M.A.; Bonhoeffer, S.; Shaw, G.M.; May, R.M., Anti-viral drug treatment: dynamics of resistance in free virus and infected cell populations, J. theor. biol., 184, 203-217, (1997)
[161] Nowak, M.A.; May, R.M., Virus dynamics: mathematical principles of immunology and virology, (2000), Oxford University Press Oxford · Zbl 1101.92028
[162] Oxenius, A.; Price, D.A.; Easterbrook, P.J.; O’Callaghan, C.A.; Kelleher, A.D.; Whelan, J.A.; Sontag, G.; Sewell, A.K.; Phillips, R.E., Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of \(\operatorname{CD} 8 +\) and \(\operatorname{CD} 4 +\) T lymphocytes, Proc. natl. acad. sci. USA, 97, 3382-3387, (2000)
[163] Palmer, S.; Maldarelli, F.; Wiegand, A.; Bernstein, B.; Hanna, G.J.; Brun, S.C.; Kempf, D.J.; Mellors, J.W.; Coffin, J.M.; King, M.S., Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy, Proc. natl. acad. sci. USA, 105, 3879-3884, (2008)
[164] Palmer, S.; Wiegand, A.P.; Maldarelli, F.; Bazmi, H.; Mican, J.M.; Polis, M.; Dewar, R.L.; Planta, A.; Liu, S.; Metcalf, J.A.; Mellors, J.W.; Coffin, J.M., New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma, J. clin. microbiol., 41, 4531-4536, (2003)
[165] Parera, M.; Ibanez, A.; Clotet, B.; Martinez, M.A., Lack of evidence for protease evolution in HIV-1-infected patients after 2 years of successful highly active antiretroviral therapy, J. infect. dis., 189, 1444-1451, (2004)
[166] Pariente, N.; Pernas, M.; de la Rosa, R.; Gomez-Mariano, G.; Fernandez, G.; Rubio, A.; Lopez, M.; Benito, J.M.; Lopez-Galindez, C.; Leal, M.; Domingo, E.; Martinez, M.A.; Mas, A., Long-term suppression of plasma viremia with highly active antiretroviral therapy despite virus evolution and very limited selection of drug-resistant genotypes, J. med. virol., 73, 350-361, (2004)
[167] Patterson, B.K.; McCallister, S.; Schutz, M.; Siegel, J.N.; Shults, K.; Flener, Z.; Landay, A., Persistence of intracellular HIV-1 mrna correlates with HIV-1-specific immune responses in infected subjects on stable HAART, Aids, 15, 1635-1641, (2001)
[168] Percus, J.K.; Percus, O.E.; Markowitz, M.; Ho, D.D.; Di Mascio, M.; Perelson, A.S., The distribution of viral blips observed in HIV-1 infected patients treated with combination antiretroviral therapy, Bull. math. biol., 65, 263-277, (2003) · Zbl 1334.92238
[169] Perelson, A.S., Modelling viral and immune system dynamics, Nat. rev. immunol., 2, 28-36, (2002)
[170] Perelson, A.S.; Essunger, P.; Cao, Y.; Vesanen, M.; Hurley, A.; Saksela, K.; Markowitz, M.; Ho, D.D., Decay characteristics of HIV-1-infected compartments during combination therapy, Nature, 387, 188-191, (1997)
[171] Perelson, A.S.; Essunger, P.; Ho, D.D., Dynamics of HIV-1 and \(\operatorname{CD} 4 +\) lymphocytes in vivo, Aids, 11, Suppl. A, S17-S24, (1997)
[172] Perelson, A.S.; Nelson, P.W., Mathematical analysis of HIV-1 dynamics in vivo, SIAM rev., 41, 3-44, (1999) · Zbl 1078.92502
[173] Perelson, A.S.; Neumann, A.U.; Markowitz, M.; Leonard, J.M.; Ho, D.D., HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time, Science, 271, 1582-1586, (1996)
[174] Persaud, D.; Ray, S.C.; Kajdas, J.; Ahonkhai, A.; Siberry, G.K.; Ferguson, K.; Ziemniak, C.; Quinn, T.C.; Casazza, J.P.; Zeichner, S.; Gange, S.J.; Watson, D.C., Slow human immunodeficiency virus type 1 evolution in viral reservoirs in infants treated with effective antiretroviral therapy, AIDS res. hum. retroviruses, 23, 381-390, (2007)
[175] Persaud, D.; Siberry, G.K.; Ahonkhai, A.; Kajdas, J.; Monie, D.; Hutton, N.; Watson, D.C.; Quinn, T.C.; Ray, S.C.; Siliciano, R.F., Continued production of drug-sensitive human immunodeficiency virus type 1 in children on combination antiretroviral therapy who have undetectable viral loads, J. virol., 78, 968-979, (2004)
[176] Persaud, D.; Zhou, Y.; Siliciano, J.M.; Siliciano, R.F., Latency in human immunodeficiency virus type 1 infection: no easy answers, J. virol., 77, 1659-1665, (2003)
[177] Peterson, S.; Reid, A.P.; Kim, S.; Siliciano, R.F., Treatment implications of the latent reservoir for HIV-1, Adv. pharmacol., 55, 411-425, (2007)
[178] Phillips, A.N., Reduction of HIV concentration during acute infection: independence from a specific immune response, Science, 271, 497-499, (1996)
[179] Piatak, M.; Saag, M.S.; Yang, L.C.; Clark, S.J.; Kappes, J.C.; Luk, K.C.; Hahn, B.H.; Shaw, G.M.; Lifson, J.D., High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR, Science, 259, 1749-1754, (1993)
[180] Pierson, T.; McArthur, J.; Siliciano, R.F., Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy, Annu. rev. immunol., 18, 665-708, (2000)
[181] Pilyugin, S.S.; Ganusov, V.V.; Murali-Krishna, K.; Ahmed, R.; Antia, R., The rescaling method for quantifying the turnover of cell populations, J. theor. biol., 225, 275-283, (2003) · Zbl 1464.92089
[182] Poveda, E.; Briz, V.; Soriano, V., Enfuvirtide, the first fusion inhibitor to treat HIV infection, AIDS rev., 7, 139-147, (2005)
[183] Prins, J.M., Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy, Aids, 13, 2405-2410, (1999)
[184] Ramratnam, B.; Mittler, J.E.; Zhang, L.; Boden, D.; Hurley, A.; Fang, F.; Macken, C.A.; Perelson, A.S.; Markowitz, M.; Ho, D.D., The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy, Nat. med., 6, 82-85, (2000)
[185] Ramratnam, B.; Ribeiro, R.; He, T.; Chung, C.; Simon, V.; Vanderhoeven, J.; Hurley, A.; Zhang, L.; Perelson, A.S.; Ho, D.D.; Markowitz, M., Intensification of antiretroviral therapy accelerates the decay of the HIV-1 latent reservoir and decreases, but does not eliminate, ongoing virus replication, J. acquir. immune defic. syndr., 35, 33-37, (2004)
[186] Regoes, R.R.; Wodarz, D.; Nowak, M.A., Virus dynamics: the effect of target cell limitation and immune responses on virus evolution, J. theor. biol., 191, 451-462, (1998)
[187] Ribeiro, R.M.; Bonhoeffer, S., Production of resistant HIV mutants during antiretroviral therapy, Proc. natl. acad. sci. USA, 97, 7681-7686, (2000) · Zbl 0956.92022
[188] Richman, D.D., Antiviral drug resistance, Antiviral res., 71, 117-121, (2006)
[189] Richman, D.D.; Margolis, D.M.; Delaney, M.; Greene, W.C.; Hazuda, D.; Pomerantz, R.J., The challenge of finding a cure for HIV infection, Science, 323, 1304-1307, (2009)
[190] Rong, L.; Feng, Z.; Perelson, A.S., Emergence of HIV-1 drug resistance during antiretroviral treatment, Bull. math. biol., 69, 2027-2060, (2007) · Zbl 1298.92053
[191] Rong, L.; Feng, Z.; Perelson, A.S., Mathematical analysis of age-structured HIV-1 dynamics with combination antiretroviral therapy, SIAM J. appl. math., 67, 731-756, (2007) · Zbl 1121.92043
[192] Rong, L.; Gilchrist, M.A.; Feng, Z.; Perelson, A.S., Modeling within-host HIV-1 dynamics and the evolution of drug resistance: trade-offs between viral enzyme function and drug susceptibility, J. theor. biol., 247, 804-818, (2007) · Zbl 1455.92087
[193] Rong, L.; Perelson, A.S., Asymmetric division of activated latently infected cells may explain the decay kinetics of the HIV-1 latent reservoir and intermittent viral blips, Math. biosci., 217, 77-87, (2009) · Zbl 1158.92028
[194] Rong, L., Perelson, A.S., 2009b. Modeling latently infected cell activation: viral and latent reservoir persistence, and viral blips in HIV-1 infected patients on potent therapy. Submitted.; Rong, L., Perelson, A.S., 2009b. Modeling latently infected cell activation: viral and latent reservoir persistence, and viral blips in HIV-1 infected patients on potent therapy. Submitted.
[195] Ruff, C.T.; Ray, S.C.; Kwon, P.; Zinn, R.; Pendleton, A.; Hutton, N.; Ashworth, R.; Gange, S.; Quinn, T.C.; Siliciano, R.F.; Persaud, D., Persistence of wild-type virus and lack of temporal structure in the latent reservoir for human immunodeficiency virus type 1 in pediatric patients with extensive antiretroviral exposure, J. virol., 76, 9481-9492, (2002)
[196] Schrager, L.K.; D’Souza, M.P., Cellular and anatomical reservoirs of HIV-1 in patients receiving potent antiretroviral combination therapy, Jama, 280, 67-71, (1998)
[197] Sedaghat, A.R.; Dinoso, J.B.; Shen, L.; Wilke, C.O.; Siliciano, R.F., Decay dynamics of HIV-1 depend on the inhibited stages of the viral life cycle, Proc. natl. acad. sci. USA, 105, 4832-4837, (2008)
[198] Sedaghat, A.R.; Siliciano, J.D.; Brennan, T.P.; Wilke, C.O.; Siliciano, R.F., Limits on replenishment of the resting \(\operatorname{CD} 4 +\) T cell reservoir for HIV in patients on HAART, Plos pathog., 3, e122, (2007)
[199] Sharkey, M.E.; Teo, I.; Greenough, T.; Sharova, N.; Luzuriaga, K.; Sullivan, J.L.; Bucy, R.P.; Kostrikis, L.G.; Haase, A.; Veryard, C.; Davaro, R.E.; Cheeseman, S.H.; Daly, J.S.; Bova, C.; Ellison, R.T.; Mady, B.; Lai, K.K.; Moyle, G.; Nelson, M.; Gazzard, B.; Shaunak, S.; Stevenson, M., Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy, Nat. med., 6, 76-81, (2000)
[200] Sharkey, M.; Triques, K.; Kuritzkes, D.R.; Stevenson, M., In vivo evidence for instability of episomal human immunodeficiency virus type 1 cdna, J. virol., 79, 5203-5210, (2005)
[201] Siliciano, J.D.; Kajdas, J.; Finzi, D.; Quinn, T.C.; Chadwick, K.; Margolick, J.B.; Kovacs, C.; Gange, S.J.; Siliciano, R.F., Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting \(\operatorname{CD} 4 +\) T cells, Nat. med., 9, 727-728, (2003)
[202] Siliciano, J.D.; Lai, J.; Callender, M.; Pitt, E.; Zhang, H.; Margolick, J.B.; Gallant, J.E.; Cofrancesco, J.; Moore, R.D.; Gange, S.J.; Siliciano, R.F., Stability of the latent reservoir for HIV-1 in patients receiving valproic acid, J. infect. dis., 195, 833-836, (2007)
[203] Siliciano, J.D.; Siliciano, R.F., A long-term latent reservoir for HIV-1: discovery and clinical implications, J. antimicrob. chemother., 54, 6-9, (2004)
[204] Siliciano, R.F., Scientific rationale for antiretroviral therapy in 2005: viral reservoirs and resistance evolution, Top. HIV med., 13, 96-100, (2005)
[205] Simon, V.; Ho, D.D., HIV-1 dynamics in vivo: implications for therapy, Nat. rev. microbiol., 1, 181-190, (2003)
[206] Sklar, P.A.; Ward, D.J.; Baker, R.K.; Wood, K.C.; Gafoor, Z.; Alzola, C.F.; Moorman, A.C.; Holmberg, S.D., Prevalence and clinical correlates of HIV viremia (‘blips’) in patients with previous suppression below the limits of quantification, Aids, 16, 2035-2041, (2002)
[207] Smith, R.J., Adherence to antiretroviral HIV drugs: how many doses can you miss before resistance emerges?, Proc. R. soc. B, 273, 617-624, (2006)
[208] Smith, R.J.; Wahl, L.M., Drug resistance in an immunological model of HIV-1 infection with impulsive drug effects, Bull. math. biol., 67, 783-813, (2005) · Zbl 1334.92240
[209] Sprent, J.; Surh, C.D., T cell memory, Annu. rev. immunol., 20, 551-579, (2002)
[210] Stafford, M.A.; Corey, L.; Cao, Y.; Daar, E.S.; Ho, D.D.; Perelson, A.S., Modeling plasma virus concentration during primary HIV infection, J. theor. biol., 203, 285-301, (2000)
[211] Stanley, S.K.; Ostrowski, M.A.; Justement, J.S.; Gantt, K.; Hedayati, S.; Mannix, M.; Roche, K.; Schwartzentruber, D.J.; Fox, C.H.; Fauci, A.S., Effect of immunization with a common recall antigen on viral expression in patients infected with human immunodeficiency virus type 1, N. engl. J. med., 334, 1222-1230, (1996)
[212] Staszewski, S.; Morales-Ramirez, J.; Tashima, K.T.; Rachlis, A.; Skiest, D.; Stanford, J.; Stryker, R.; Johnson, P.; Labriola, D.F.; Farina, D.; Manion, D.J.; Ruiz, N.M., Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults, N. engl. J. med., 341, 1865-1873, (1999)
[213] Stevenson, M., HIV-1 pathogenesis, Nat. med., 9, 853-860, (2003)
[214] Strain, M.C.; Gunthard, H.F.; Havlir, D.V.; Ignacio, C.C.; Smith, D.M.; Leigh-Brown, A.J.; Macaranas, T.R.; Lam, R.Y.; Daly, O.A.; Fischer, M.; Opravil, M.; Levine, H.; Bacheler, L.; Spina, C.A.; Richman, D.D.; Wong, J.K., Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: intrinsic stability predicts lifelong persistence, Proc. natl. acad. sci. USA, 100, 4819-4824, (2003)
[215] Strain, M.C.; Little, S.J.; Daar, E.S.; Havlir, D.V.; Gunthard, H.F.; Lam, R.Y.; Daly, O.A.; Nguyen, J.; Ignacio, C.C.; Spina, C.A.; Richman, D.D.; Wong, J.K., Effect of treatment, during primary infection, on establishment and clearance of cellular reservoirs of HIV-1, J. infect. dis., 191, 1410-1418, (2005)
[216] Tobin, N.H.; Learn, G.H.; Holte, S.E.; Wang, Y.; Melvin, A.J.; McKernan, J.L.; Pawluk, D.M.; Mohan, K.M.; Lewis, P.F.; Mullins, J.I.; Frenkel, L.M., Evidence that low-level viremias during effective highly active antiretroviral therapy result from two processes: expression of archival virus and replication of virus, J. virol., 79, 9625-9634, (2005)
[217] Tough, D.F.; Sprent, J., Turnover of naive- and memory-phenotype T cells, J. exp. med., 179, 1127-1135, (1994)
[218] Unutmaz, D.; Pileri, P.; Abrignani, S., Antigen-independent activation of naive and memory resting T cells by a cytokine combination, J. exp. med., 180, 1159-1164, (1994)
[219] Verhofstede, C.; Noë, A.; Demecheleer, E.; De Cabooter, N.; Van Wanzeele, F.; Van Der Gucht, B.; Vogelaers, D.; Plum, J., Drug-resistant variants that evolve during nonsuppressive therapy persist in HIV-1-infected peripheral blood mononuclear cells after long-term highly active antiretroviral therapy, J. acquir. immune defic. syndr., 35, 473-483, (2004)
[220] Verhofstede, C.; Wanzeele, F.V.; Van Der Gucht, B.; De Cabooter, N.; Plum, J., Interruption of reverse transcriptase inhibitors or a switch from reverse transcriptase to protease inhibitors resulted in a fast reappearance of virus strains with a reverse transcriptase inhibitor-sensitive genotype, Aids, 13, 2541-2546, (1999)
[221] Wahl, L.M.; Nowak, M.A., Adherence and drug resistance: predictions for therapy outcome, Proc. R. soc. London B, 267, 835-843, (2000)
[222] Wei, X.; Ghosh, S.K.; Taylor, M.E.; Johnson, V.A.; Emini, E.A.; Deutsch, P.; Lifson, J.D.; Bonhoeffer, S.; Nowak, M.A.; Hahn, B.H.; Saag, M.S.; Shaw, G.M., Viral dynamics in human-immunodeficiency-virus type-1 infection, Nature, 373, 117-122, (1995)
[223] Weinberger, L.S.; Burnett, J.C.; Toettcher, J.E.; Arkin, A.P.; Schaffer, D.V., Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 tat fluctuations drive phenotypic diversity, Cell, 122, 169-182, (2005)
[224] Wodarz, D., Killer cell dynamics: mathematical and computational approaches to immunology, (2007), Springer Berlin · Zbl 1125.92032
[225] Wodarz, D.; May, R.M.; Nowak, M.A., The role of antigen-independent persistence of memory cytotoxic T lymphocytes, Int. immunol., 12, 467-477, (2000)
[226] Wodarz, D.; Nowak, M.A., CD8 memory, immunodominance, and antigenic escape, Eur. J. immunol., 30, 2704-2712, (2000)
[227] Wodarz, D.; Nowak, M.A., Mathematical models of HIV pathogenesis and treatment, Bioessays, 24, 1178-1187, (2002)
[228] Wong, J.K.; Hezareh, M.; Günthard, H.F.; Havlir, D.V.; Ignacio, C.C.; Spina, C.A.; Richman, D.D., Recovery of replication-competent HIV despite prolonged suppression of plasma viremia, Science, 278, 1291-1295, (1997)
[229] Wu, H.; Huang, Y.; Acosta, E.P.; Rosenkranz, S.L.; Kuritzkes, D.R.; Eron, J.J.; Perelson, A.S.; Gerber, J.G., Modeling long-term HIV dynamics and antiretroviral response: effects of drug potency, pharmacokinetics, adherence, and drug resistance, J. acquir. immune defic. syndr., 39, 272-283, (2005)
[230] Wu, H.; Zhu, H.; Miao, H.; Perelson, A.S., Parameter identifiability and estimation of HIV/AIDS dynamic models, Bull. math. biol., 70, 785-799, (2008) · Zbl 1146.92021
[231] Ylisastigui, L.; Archin, N.M.; Lehrman, G.; Bosch, R.J.; Margolis, D.M., Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression, Aids, 18, 1101-1108, (2004)
[232] Zhang, L.; Chung, C.; Hu, B.S.; He, T.; Guo, Y.; Kim, A.J.; Skulsky, E.; Jin, X.; Hurley, A.; Ramratnam, B.; Markowitz, M.; Ho, D.D., Genetic characterization of rebounding HIV-1 after cessation of highly active antiretroviral therapy, J. clin. invest., 106, 839-845, (2000)
[233] Zhang, H.; Dornadula, G.; Beumont, M.; Livornese, L.; Van Uitert, B.; Henning, K.; Pomerantz, R.J., Human immunodeficiency virus type 1 in the semen of men receiving highly active antiretroviral therapy, N. engl. J. med., 339, 1803-1809, (1998)
[234] Zhang, Z.Q.; Notermans, D.W.; Sedgewick, G.; Cavert, W.; Wietgrefe, S.; Zupancic, M.; Gebhard, K.; Henry, K.; Boies, L.; Chen, Z.; Jenkins, M.; Mills, R.; McDade, H.; Goodwin, C.; Schuwirth, C.M.; Danner, S.A.; Haase, A.T., Kinetics of \(\operatorname{CD} 4 +\) T cell repopulation of lymphoid tissues after treatment of HIV-1 infection, Proc. natl. acad. sci. USA, 95, 1154-1159, (1998)
[235] Zhang, L.; Ramratnam, B.; Tenner-Racz, K.; He, Y.; Vesanen, M.; Lewin, S.; Talal, A.; Racz, P.; Perelson, A.S.; Korber, B.T.; Markowitz, M.; Ho, D.D., Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy, N. engl. J. med., 340, 1605-1613, (1999)
[236] Zhang, Z., Sexual transmission and propagation of SIV and HIV in resting and activated \(\operatorname{CD} 4^+\) T cells, Science, 286, 1353-1357, (1999)
[237] Zhu, T.; Muthui, D.; Holte, S.; Nickle, D.; Feng, F.; Brodie, S.; Hwangbo, Y.; Mullins, J.I.; Corey, L., Evidence for human immunodeficiency virus type 1 replication in vivo in \(\operatorname{CD} 14(+)\) monocytes and its potential role as a source of virus in patients on highly active antiretroviral therapy, J. virol., 76, 707-716, (2002)
This reference list is based on information provided by the publisher or from digital mathematics libraries. Its items are heuristically matched to zbMATH identifiers and may contain data conversion errors. In some cases that data have been complemented/enhanced by data from zbMATH Open. This attempts to reflect the references listed in the original paper as accurately as possible without claiming completeness or a perfect matching.