Distinct effects of protease and reverse transcriptase inhibition in an immunological model of HIV-1 infection with impulsive drug effects

Smith, R.J.; Wahl, L.M.
September 2004
Bulletin of Mathematical Biology;Sep2004, Vol. 66 Issue 5, p1259
Academic Journal
We present an immunological model that considers the dynamics of CD4+ T cells interacting with free virions, reverse transcriptase inhibiting drugs and protease inhibiting drugs. We divide the T cells into multiple classes and use impulsive differential equations to describe the drug activity. As expected, we find that insufficient dosing of either drug corresponds to high viral load and a large population of infectious T cells. The model further predicts that, in the absence of physiological limits on tolerable drug concentrations, sufficiently frequent dosing with the reverse transcriptase inhibitor alone could theoretically maintain the CD4+ T cell count arbitrarily close to the T cell count in the uninfected immune system. However, for frequent dosing of the protease inhibitor alone, the limiting T cell populations may not be enough to maintain the immune system. Furthermore, frequent dosing of both drugs has the same net effect on the T cell population as frequent dosing of the reverse transcriptase inhibitor only. Thus, the two drug classes can have fundamentally different effects on the long-term dynamics and the reverse transcriptase inhibitor, in particular, plays a crucial role in maintaining the immune system. We also provide estimates for the dosing intervals of each drug that could theoretically sustain the T cell population at a desired level.


Related Articles

  • Broad Nucleoside Reverse-Transcriptase Inhibitor Cross-Resistance in Human Immunodeficiency Virus Type 1 Clinical Isolates. Whitcomb, Jeannette M.; Parkin, Neil T.; Chappey, Colombe; Hellmann, Nicholas S.; Petropoulos, Christos J. // Journal of Infectious Diseases;10/1/2003, Vol. 188 Issue 7, p992 

    Characterizes patterns of cross-resistance among all nucleoside reverse-transcriptase inhibitors (NRTI) in HIV type 1 clinical isolates. Association of an increasing number of thymidine-analogue mutations with a progressive reduction in drug susceptibility for all NRTIs.

  • Evidence that HIV-1 restriction factor SAMHD1 facilitates differentiation of myeloid THP-1 cells. Dragin, Loic; Munir-Matloob, Soundasse; Froehlich, Jeanne; Morel, Marina; Sourisce, Adèle; Lahouassa, Hichem; Bailly, Karine; Mangeney, Marianne; Ramirez, Bertha Cecilia; Margottin-Goguet, Florence // Virology Journal;11/25/2015, Vol. 12 Issue 1, p1 

    Background: SAMHD1 counteracts HIV-1 or HIV-2/SIVsmm that lacks Vpx by depleting the intracellular pool of nucleotides in myeloid cells and CD4+ quiescent T cells, thereby inhibiting the synthesis of retroviral DNA by reverse transcriptase. Depletion of nucleotides has been shown to underline...

  • CD8+ T lymphocyte responses target functionally important regions of Protease and Integrase in HIV-1 infected subjects. Rodriguez, William R.; Addo, Marylyn M.; Rathod, Almas; Fitzpatrick, Cecily A.; Yu, Xu G.; Perkins, Beth; Rosenberg, Eric S.; Altfeld, Marcus; Walker, Bruce D. // Journal of Translational Medicine;2004, Vol. 2, p15 

    Background: CD8+ T cell responses are known to be important to the control of HIV-1 infection. While responses to reverse transcriptase and most structural and accessory proteins have been extensively studied, CD8 T cell responses specifically directed to the HIV-1 enzymes Protease and Integrase...

  • Monitoring of Human Immunodeficiency Virus Infection in Resource-Constrained Countries. Crowe, Suzanne; Turnbull, Shannon; Oelrichs, Robert; Dunne, Amanda // Clinical Infectious Diseases;7/1/2003 Supplement 1, Vol. 37, pS25 

    The reference standards used to monitor human immunodeficiency virus (HIV) infection are flow cytometric analysis of T lymphocyte subsets to provide the CD4[SUP+] T cell count and molecular assays to quantify plasma HIV load. Few laboratories in resource-constrained countries can afford to...

  • SAMHD1: a new contributor to HIV-1 restriction in resting CD4+ T-cells. Li Wu // Retrovirology;2012, Vol. 9 Issue 1, p88 

    Resting CD4+ T-cells are critical for establishing HIV-1 reservoirs. It has been known for over two decades that resting CD4+ T-cells are refractory to HIV-1 infection, but the underlying mechanisms are not fully understood. Compared with activated CD4+ T-cells that support HIV-1 infection,...

  • The triple combination of tenofovir, emtricitabine and efavirenz shows synergistic anti-HIV-1 activity in vitro: a mechanism of action study. Feng, Joy Y.; Ly, John K.; Myrick, Florence; Goodman, Derrick; White, Kirsten L.; Svarovskaia, Evguenia S.; Borroto-Esoda, Katyna; Miller, Michael D. // Retrovirology;2009, Vol. 6, p1 

    Background: Tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and efavirenz (EFV) are the three components of the once-daily, single tablet regimen (Atripla) for treatment of HIV-1 infection. Previous cell culture studies have demonstrated that the double combination of tenofovir (TFV),...

  • Variation of Human Immunodeficiency Virus Type-1 Reverse Transcriptase within the Simian Immunodeficiency Virus Genome of RT-SHIV. Wadford, Debra A.; Kauffman, Robert C.; Deere, Jesse D.; Aoki, Scott T.; Stanton, Richard A.; Higgins, Joanne; Van Rompay, Koen K. A.; Villalobos, Andradi; Nettles, James H.; Schinazi, Raymond F.; Pedersen, Niels C.; North, Thomas W. // PLoS ONE;Jan2014, Vol. 9 Issue 1, p1 

    RT-SHIV is a chimera of simian immunodeficiency virus (SIV) containing the reverse transcriptase (RT)-encoding region of human immunodeficiency virus type 1 (HIV-1) within the backbone of SIVmac239. It has been used in a non-human primate model for studies of non-nucleoside RT inhibitors (NNRTI)...

  • HIV tropism and CD4+ T-cell depletion. Hellerstein, Marc // Nature Medicine;Jun2002, Vol. 8 Issue 6, p537 

    Discusses the critical role of immune activation in HIV-1 pathogenesis. Analysis of conclusions of the study conducted by Gossman et al.; Destruction of CD4[sup+] T-cells by HIV-1; Emphasis on the study of phenotype of HIV-1 strains that are present in infected humans; Reasons for understanding...

  • A Review of Recent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Research Activity. Corbett, Jeffrey W. // Current Medicinal Chemistry - Anti-Infective Agents;Apr2002, Vol. 1 Issue 2, p119 

    This non-nucleoside reverse transcriptase inhibitor review covers the patent and published literature from January, 1998-August, 2001. Major advances have been made in the past decade in discovering non-nucleoside reverse transcriptase inhibitors that are effective in inhibiting replication of...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics