Computer Simulations of Slow Progression of Human Immunodeficiency Virus Infection and Relapse during Anti‐HIV Treatment with Reverse Transcriptase Inhibitors and Protease Inhibitors

Abstract

Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) have been serious problems since the 1980s. Although the progression of HIV infection into AIDS can be controlled well with the use of reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs) (40), the long-term efficacy of such treatment is not known. Furthermore, since recent clinical data have suggested that the dynamics of HIV infection is more complex than had been thought, more studies on HIV are required.Since we consider it important to understand the interactions among HIV, immunity and anti-HIV drugs, we propose new mathematical models of HIV infection. In modeling HIV infection, we paid attention to the following facts: 1) lymphoid organs are major reservoirs for HIV virions (13, 18, 26 28, 39), 2) the viral load in lymphoid organs does not necessarily correspond with that in blood (28, 39), 3) lymphoid organs contain 98% of the total lymphocyte pool (25,36,45), 4) changes in the lymphocyte count and the CD4/CD8 ratio in lymphoid organs do not necessarily correspond with those in blood (25, 36), and 5) relations between stimuli and responses are nonlinear (9, 20). Thus we assumed that the interactions occur in lymphoid organs. We also defined a function to calculate the nonlinear relations.In this study, we present three models of HIV infecMicrobiol. Immunol., 46(6), 397 407, 2002 397Abbreviations: AIDS, acquired immunodeficiency syndrome; CTL, cytotoxic T lymphocyte; HIV, human immunodeficiency virus; liCD4, latently infected CD4 T cell; niCD4, non-infected CD4 T cell; npiCD4, non-productively infected CD4 T cell; PI, protease inhibitor; piCD4, productively infected CD4 T cell; RTI, reverse transcriptase inhibitor. Abstract: Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) have been very serious problems since the 1980s. The progression of HIV infection into AIDS can be suppressed to some extent with reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs); however, there are some serious problems with treatments using the anti-HIV drugs (e.g. very high expense, complicated administration, and drug resistance). Hence, more studies on HIV and the development of more effective anti-HIV treatments are required. We consider it important to understand the complex dynamics involved in HIV infection, and we therefore propose new mathematical models of HIV infection. In the modeling, we have paid attention to the nonlinear relations between stimuli and responses (i.e., when responses are plotted against the logarithm of stimuli, a sigmoid curve is obtained), and to lymphoid organs which seem more important than the blood compartment (i.e., lymphoid organs are major reservoirs of HIV virions and contain most of the lymphocytes). Using the models, we have found that viral antigenic mutation plays an important role in the slow progression in the chronic phase of HIV infection. We have also found that viral antigenic mutation can cause relapse of HIV in...