Abstract
When highly active antiretroviral therapy is administered for long periods of time to HIV-1 infected patients, most patients achieve viral loads that are “undetectable” by standard assay (i.e., HIV-1 RNA < 50 copies/ml). Yet despite exhibiting sustained viral loads below the level of detection, a number of these patients experience unexplained episodes of transient viremia or viral “blips”. We propose here that transient activation of the immune system by opportunistic infection may explain these episodes of viremia. Indeed, immune activation by opportunistic infection may spur HIV replication, replenish viral reservoirs and contribute to accelerated disease progression. In order to investigate the effects of intercurrent infection on chronically infected HIV patients under treatment with highly active antiretroviral therapy (HAART), we extend a simple dynamic model of the effects of vaccination on HIV infection [Jones, L.E., Perelson, A.S., 2002. Modeling the effects of vaccination on chronically infected HIV-positive patients. JAIDS 31, 369–377] to include growing pathogens. We then propose a more realistic model for immune cell expansion in the presence of pathogen, and include this in a set of competing models that allow low baseline viral loads in the presence of drug treatment. Programmed expansion of immune cells upon exposure to antigen is a feature not previously included in HIV models, and one that is especially important to consider when simulating an immune response to opportunistic infection. Using these models we show that viral blips with realistic duration and amplitude can be generated by intercurrent infections in HAART treated patients.
Similar content being viewed by others
References
Badovinac, V.P., Porter, B.B., Harty, J.T., 2002. Programmed contraction of CD8+ T cells after infection. Nature Immunol. 3, 619–626.
Bevan, M.J., 2004. Helping the CD8+ T-cell response. Nature Rev. Immunol. 4, 595–602.
Blattman, J.N., Antia, R., Sourdive, D.J.D., Wang, X., Kaech, S.M., Murali-Krishna, K., Altman, J.D., Ahmed, R., 2002. Estimating the precursor frequency of naive antigen-specific CD8 T cells. J. Exp. Med. 195, 657–664.
Bonhoeffer, S., Coffin, J.M., Nowak, M.A., 1997. Human immunodeficiency virus drug therapy and virus load. J. Virol. 71, 3275–3278.
Brichacek, B., Swindells, S., Janoff, E.N., Pirruccelo, S., Stevenson, M., 1996. Increased plasma human immunodeficiency virus type 1 burden following antigenic challenge with pneumoccocal vaccine. J. Infect. Dis. 174, 1191–1199.
Callaway, D.S., Perelson, A.S., 2002. HIV-1 infection and low steady state viral loads. Bull. Math. Biol. 64, 29–64.
Davenport, M.P., Ribeiro, R.M., Perelson, A.S., 2004. Kinetics of virus specific CD8+ T cells and the control of HIV infection. J. Virol. 78, 10096–10103.
De Boer, R.J., Oprea, M., Antia, R., Murali-Krishna, K., Ahmed, R., Perelson, A.S., 2001. Recruitment times, proliferation, and apoptosis rates during the CD8+ T cell response to LCMV. J. Virol. 75, 10663–10669.
De Boer, R.J., Homann, D., Perelson, A.S., 2003. Different dynamics of CD4+ and CD8+ T cell responses during and after acute lymphocytic choriomeningitis virus infection. J. Immunol. 171, 3928–3935.
De Boer, R.J., Perelson, A.S. Estimating division and death rates from CFSE data. J. Comput. Appl. Math. (in press).
Deenick, E.K., Gett, A.V., Hodgkin, P.D., 2003. Stochastic model of T cell proliferation: A calculus revealing IL-2 regulation of precursor frequencies, cell cycle time, and survival. J. Immunol. 170, 4963–4972.
Di Mascio, M., Markowitz, M., Louie, M., Hogan, C., Hurley, A., Ho, D.D., Perelson, A.S., 2003a. Viral blip dynamics during highly active antiretroviral therapy. J. Virol. 77, 12165–12172.
Di Mascio, M., Dornadula, G., Zhang, H., Sullivan, J., Xu, Y., Kulkosky, J., Pomerantz, R., Perelson, A.S., 2003b. In a subset of patients on highly active antiretroviral therapy plasma HIV-1 RNA can decay from 50 copies/ml to <5 copies/ml with a half-life of six months. J. Virol. 77, 2271–2275.
Di Mascio, M., Ribeiro, R.M., Markowitz, M., Ho, D.D., Perelson, A.S., 2004a. Modeling the long-term control of viremia in HIV-1 infected patients treated with antiretroviral therapy. Math. Biosci. 188, 47–62.
Di Mascio, M., Markowitz, M., Louie, M., Hurley, A., Hogan, C., Simon, V., Follman, D., Ho, D.D., Perelson, A.S., 2004b. 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.
Donovan, R.M., Bush, C.E., Markowitz, N.P., Baxa, D.M., Saravolatz, L.D., 1996. Changes in virus load markers during AIDS-associated opportunistic diseases in human-immunodeficiency virus-infected persons. J. Infect. Dis. 174, 401–403.
Dornadula, G., Zhang, H., VanUitert, B., Stern, J., Livornese Jr., L., Ingerman, M.J., Witek, J., Kedanis, R.J., Natkin, J., DeSimone, J., Pomerantz, R.J., 1999. Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. J. Amer. Med. Assoc. 282, 1627–1632.
Ferguson, N.M., de Wolf, F., Ghani, A.C., Fraser, C., Donnelly, C.A., Reiss, P., Lange, J.M.A., Danner, S.A., Garnett, G.P., Goudsmit, J., Anderson, R.M., 1999. Antigen-driven CD4+ T-cell and HIV-1 dynamics: residual viral replication under highly active antiretroviral therapy. Proc. Natl. Acad. Sci. USA 96, 15167–15172.
Fraser, C., Ferguson, N.M., de Wolf, F., Anderson, R.M., 2001a. The role of antigenic stimulation and cytotoxic T cell activity in regulating long-term immunopathogenesis of HIV: mechanisms and clinical implications. Proc. R. Soc. Lond. B. 268, 2085–2095.
Fraser, C., Ferguson, N.M., Anderson, R.M., 2001b. Quantification of intrinsic residual viral replication in treated HIV-infected patients. Proc. Natl. Acad. Sci. USA 98, 15167–15172.
Gett, A.V., Hodgkin, P.D., 2000. A cellular calculus for signal integration by T cells. Nature Immunol. 1, 239–244.
Holte, S.A., Melvin, A., Mullins, J., Frenkel, L., 2001. Density-dependent decay in HIV dynamics after HAART (Abstract 394). In: 8th Conference on Retroviruses and Opportunistic Infections. Foundation for Retrovirology and Human Health, Alexandria, VA, USA.
Jones, L.E., Perelson, A.S., 2002. Modeling the effects of vaccination on chronically infected HIV-positive patients. JAIDS 31, 369–377.
Kaech, S.M., Ahmed, R., 2001. Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nature Immunol. 2, 415–422.
Kaufmann, D.E., Bailey, P.M., Sidney, J., Wagner, B., Norris, P.J., Johnston, M.N., Cosimi, L.A., Addo, M.M., Lichterfeld, M., Altfeld, M., Frahm, N., Brander, C., Sette, A., Walker, B.D., Rosenberg, E.S., 2004. Comprehensive analysis of human immunodeficiency virus type 1-specific CD4 responses reveals marked immunodominance of gag and nef and the presence of broadly recognized peptides. J. Virol. 78, 4463–4477.
Kim, R.B., Fromm, M.F., Wandel, C., Leake, B., Wood, A.J., Roden, D.M., Wilkinson, G.R., 1998. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J. Clin. Invest. 101, 289–294.
Lee, W.T., Pasos, G., Cecchini, L., Mittler, J.N., 2002. Continued antigen stimulation is not required during CD4+ T cell clonal expansion. J. Immunol. 168, 1682–1689.
McLean, A.R., Nowak, M.A., 1992. Models of interactions between HIV and other pathogens. J. Theor. Biol. 155, 69–102.
Meaden, E.R., Hoggard, P.G., Newton, P., Tjia, J.F., Aldam, D., Cornforth, D., Lloyd, J., Williams, I., Back, D.J., Khoo, S.H., 2002. P-glycoprotein and MRP1 expression and reduced ritonavir and saquinavir accumulation in HIV-infected individuals. J. Antimicrob. Chemother. 50, 583–588.
Mohri, H., Bonhoeffer, S., Monard, S., Perelson, A.S., Ho, D.D., 1998. Rapid turnover of T-lymphocytes in SIV-infected rhesus macaques. Science 279, 1223–1227.
Murali-Krishna, K., Altman, J.D., Suresh, M., Sourdive, D., Zajac, A., Miller, J.D., Slansky, J., Ahmed, R., 1998a. Counting antigen-specific CD8 T cells: a reevaluation of the bystander activation during viral infection. Immunity 8, 177–187.
Murali-Krishna, K., Altman, J.D., Suresh, M., Sourdive, D., Zajac, A., Ahmed, R., 1998b. In vivo dynamics of antiviral CD8+ T cell responses to different epitopes: an evaluation of bystander activation in primary and secondary responses to viral infection. Adv. Exp. Med. Biol. 452, 123–142.
Nowak, M.A., Bangham, C.R.M., 1996. Population dynamics of immune responses to persistent viruses. Science 272, 74–79.
Nowak, M.A., May, R.M., 2000. Virus dynamics: Mathematical Principles of Immunology and Virology. Oxford University Press, Oxford.
O’Brien, W.A., Grovit-Ferbas, K., Namazi, A., Ovcak-Derzic, S., Wang, H.J., Park, J., Yeramian, C., Mao, S.H., Zack, J.A., 1995. Human immunodeficiency virus type 1 replication can be increased in the peripheral blood of seropositive patients after influenza vaccination. Blood 86, 1982–1089.
Perelson, A.S., Neumann, A.U., Markowitz, M., Leonard, J.M., Ho, D.D., 1996. HIV-1 dynamics in vivo: Virion clearance rate, infected cell lifespan, and viral generation time. Science 271, 1582–1586.
Perelson, A.S., Essunger, P., Cao, Y., Vesanen, M., Hurley, A., Saksela, K., Markowitz, M., Ho, D.D., 1997. Decay characteristics of HIV-1 infected compartments during combination therapy. Nature 271, 1582–1586.
Perelson, A.S., 2002. Modelling viral and immune system dynamics. Nature Rev. Immunol. 2, 28–36.
Perno, C., Newcombe, F.M., Davis, D., Aquaro, S., Humphrey, R.W., Calio, R., Yarchoan, R., 1998. Relative potency of protease inhibitors in monocytes/macrophages acutely and chronically infected with human immunodeficiency virus. J. Infect. Dis. 178, 413–422.
Puddu, P., Fais, S., Luciani, F., Gherardi, G., Dupuis, M.L., Romagnioli, G., Ramoni, C., Cianfriglia, M., Gessani, S., 1999. Interferon-γ up-regulates expression and activity of P-glycoprotein in human peripheral blood monocyte-derived macrophages. Lab. Invest. 79, 1299–1309.
Revy, P., Sospedra, M., Barbour, B., Trautman, A., 2001. Functional antigen-independent synapses formed between T-cells and dendritic cells. Nature Immunol. 2, 925–931.
Sachsenberg, N., Perelson, A.S., Yerly, S., Schockmel, G.A., Leduc, D., Hirschel, B., Perrin, L., 1998. Turnover of CD4+ and CD8+ T Lymphocytes in HIV-1 Infection as Measured by Ki-67 Antigen. J. Exp. Med. 187, 1295–1303.
Stanley, S.K., Ostrowski, M.A., Justement, J.S., Gantt, K., Hedayati, S., Mannix, M., Roche, K., Schwartzentruber, D., Fox, C.H., Fauci, A.S., 1996. 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.
Staprans, S.I., Hamilton, B., Follansbee, S., Elbeik, T., Barbosa, P., Grant, R., Feinberg, M., 1995. Activation of virus replication after vaccination of HIV-1 infected individuals. J. Exp. Med. 182, 1727–1737.
Sun, J.C., Williams, M.A., Bevan, M.J., 2004. CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nature Immunol. 5, 927–933.
Van Stipdonk, M.J., Lemmons, E.E., Schoenberger, S.P., 2001. Naive CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation. Nature Immunol. 21, 29–70.
Wodarz, D., Nowak, M.A., 2000. CD8 escape, immunodominance, and antigenic escape. Eur. J. Immunol. 30, 2704–2712.
Wodarz, D., May, R.M., Nowak, M.A., 2000. The role of antigen-independent persistence of memory cytotoxic T lymphocytes. Int. Immunol. 12, 467–477.
Wong, P., Pamer, E.G., 2003. CD8 T-cell responses to infectious pathogens. Ann. Rev. Immunol. 21, 29–70.
Zhang, Z.Q., Wietgrefe, S.W., Li, Q., Shore, M.D., Duan, L., Reilly, C., Lifson, J.D., Haase, A.T., 2004. Roles of substrate activity and infection of resting and activated CD4+ T cells in transmission and acute simian immunodeficiency virus infection. Proc. Natl. Acad. Sci. USA 101, 5640–5645.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jonesa, 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). https://doi.org/10.1016/j.bulm.2005.01.006
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1016/j.bulm.2005.01.006