Mathematical modeling of viral kinetics under immune control during primary HIV-1 infection.

Primary human immunodeficiency virus (HIV) infection is characterized by an initial exponential increase of viral load in peripheral blood reaching a peak, followed by a rapid decline to the viral setpoint. Although the target-cell-limited model can account for part of the viral kinetics observed early in infection [Phillips, 1996. Reduction of HIV concentration during acute infection: independence from a specific immune response. Science 271 (5248), 497-499], it frequently predicts highly oscillatory kinetics after peak viremia, which is not typically observed in clinical data. Furthermore, the target-cell-limited model is unable to predict long-term viral kinetics, unless a delayed immune effect is assumed [Stafford et al., 2000. Modeling plasma virus concentration during primary HIV infection. J. Theor. Biol. 203 (3), 285-301]. We show here that extending the target-cell-limited model, by implementing a saturation term for HIV-infected cell loss dependent upon infected cell levels, is able to reproduce the diverse observed viral kinetic patterns without the assumption of a delayed immune response. Our results suggest that the immune response may have significant effect on the control of the virus during primary infection and may support experimental observations that an anti-HIV immune response is already functional during peak viremia.

[1]  A. Perelson,et al.  HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time , 1996, Science.

[2]  R. P. Bucy.  Viral and cellular dynamics in HIV disease , 2004, Current HIV/AIDS reports.

[3]  John W. Mellors,et al.  Prognosis in HIV-1 Infection Predicted by the Quantity of Virus in Plasma , 1996, Science.

[4]  Sebastian Bonhoeffer,et al.  Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis , 1999, The Lancet.

[5]  Haihong Zhu,et al.  Parameter Identifiability and Estimation of HIV/AIDS Dynamic Models , 2008, Bulletin of mathematical biology.

[6]  A S Perelson,et al.  Modeling plasma virus concentration during primary HIV infection. , 2000, Journal of theoretical biology.

[7]  D. Montefiori,et al.  Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. , 1999, Science.

[8]  C. Apetrei,et al.  Simian immunodeficiency viruses replication dynamics in African non‐human primate hosts: common patterns and species‐specific differences , 2006, Journal of medical primatology.

[9]  L M Wahl,et al.  Viral dynamics of primary viremia and antiretroviral therapy in simian immunodeficiency virus infection , 1997, Journal of virology.

[10]  J. Mittler,et al.  Viral dynamics in primary HIV-1 infection. Karolinska Institutet Primary HIV Infection Study Group. , 2000, AIDS.

[11]  G. Pantaleo,et al.  Immunopathogenesis of HIV infection. , 1998, AIDS research and human retroviruses.

[12]  S. Rowland-Jones,et al.  Direct visualization of HIV-1-specific cytotoxic T lymphocytes during primary infection , 2000, AIDS.

[13]  B. Berkhout,et al.  In HIV-1 pathogenesis the die is cast during primary infection , 2007, AIDS.

[14]  S. Staprans,et al.  Contribution of Peaks of Virus Load to Simian Immunodeficiency Virus Pathogenesis , 2002, Journal of Virology.

[15]  S. J. Clark,et al.  Viral dynamics in primary HIV-1 infection , 1993, The Lancet.

[16]  J. Dinulos,et al.  Acute retroviral syndrome. , 2006, Dermatologic clinics.

[17]  Russell W. Anderson,et al.  Direct HIV cytopathicity cannot account for CD4 decline in AIDS in the presence of homeostasis: a worst-case dynamic analysis. , 1998, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[18]  Douglas D. Richman,et al.  Viral Dynamics of Acute HIV-1 Infection , 1999, The Journal of experimental medicine.

[19]  Beda Joos,et al.  HIV replication elicits little cytopathic effects in vivo: Analysis of surrogate markers for virus production, cytotoxic T cell response and infected cell death , 2006, Journal of medical virology.

[20]  J L Sullivan,et al.  Inappropriate model-fitting methods may lead to significant underestimates of viral decay rates in HIV dynamic studies. , 1999, Journal of acquired immune deficiency syndromes.

[21]  S. Self,et al.  Do scarce targets or T killers control primary HIV infection? , 2002, Journal of theoretical biology.

[22]  M. Somasundaran,et al.  A major mechanism of human immunodeficiency virus-induced cell killing does not involve cell fusion , 1987, Journal of virology.

[23]  H. Clifford Lane,et al.  Administration of an Anti-CD8 Monoclonal Antibody Interferes with the Clearance of Chimeric Simian/Human Immunodeficiency Virus during Primary Infections of Rhesus Macaques , 1998, Journal of Virology.

[24]  L. Weinberger,et al.  Dramatic Rise in Plasma Viremia after CD8+ T Cell Depletion in Simian Immunodeficiency Virus–infected Macaques , 1999, The Journal of experimental medicine.

[25]  J. Schmitz,et al.  Comparison of Simian Immunodeficiency Virus SIVagmVer Replication and CD4+ T-Cell Dynamics in Vervet and Sabaeus African Green Monkeys , 2006, Journal of Virology.

[26]  Andrew N. Phillips,et al.  Reduction of HIV Concentration During Acute Infection: Independence from a Specific Immune Response , 1996, Science.

[27]  D. Cooper,et al.  Patterns of viral dynamics during primary human immunodeficiency virus type 1 infection. The Sydney Primary HIV Infection Study Group. , 1998, The Journal of infectious diseases.

[28]  P. Roques,et al.  Primary Simian Immunodeficiency Virus SIVmnd-2 Infection in Mandrills (Mandrillus sphinx) , 2006, Journal of Virology.

[29]  Saroja Ramanujan,et al.  Differential Dynamics of CD4+ and CD8+ T-Lymphocyte Proliferation and Activation in Acute Simian Immunodeficiency Virus Infection , 2000, Journal of Virology.

[30]  D M Bortz,et al.  Estimating kinetic parameters from HIV primary infection data through the eyes of three different mathematical models. , 2006, Mathematical biosciences.

[31]  F. Miedema,et al.  T cell dynamics in HIV-1 infection. , 1999, Advances in immunology.

[32]  V. ter meulen,et al.  Early activation and proliferation of T cells in simian immunodeficiency virus-infected rhesus monkeys. , 2000, AIDS research and human retroviruses.

[33]  R I Shrager,et al.  HIV-1 infection kinetics in tissue cultures. , 1996, Mathematical biosciences.

[34]  F. Barré-Sinoussi,et al.  High Levels of Viral Replication Contrast with Only Transient Changes in CD4+ and CD8+ Cell Numbers during the Early Phase of Experimental Infection with Simian Immunodeficiency Virus SIVmnd-1 in Mandrillus sphinx , 2002, Journal of Virology.

[35]  Rob J. de Boer,et al.  Understanding the failure of CD8 T-cell vaccination against simian/human immunodeficiency virus , 2007 .

[36]  Peter Hunt,et al.  Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. , 2004, Blood.

[37]  D. Ho,et al.  Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome , 1994, Journal of virology.

[38]  Hal L. Smith,et al.  Virus Dynamics: A Global Analysis , 2003, SIAM J. Appl. Math..

[39]  F. Barré-Sinoussi,et al.  High Levels of Viral Replication during Primary Simian Immunodeficiency Virus SIVagm Infection Are Rapidly and Strongly Controlled in African Green Monkeys , 2000, Journal of Virology.