HIV-1 Dynamics IN VIVO Under Drug Therapy

Wei-Yin Chen and Revanth B. Mutyala

Department of Chemical Engineering
The University of Mississippi
University, MS 38677

ABSTRACT

Recent development of nonlinear science renders it possible to analyze and simulate the
dynamic features of the HIV-1 virus and its interactions with the cells in vivo. The
current study extends the historical work of Perelson and Nelson (1999) and Murray
(2002). Perelson and Nelson mathematically interpreted Ho et al.s observation in 1995
that the HIV viruses undergo a two-phase decline, a rapid phase followed by a slow
phase, after the initiation of combination antiretroviral therapy. By using a four-equation
model that included the concentrations of uninfected T-cells, productively infected T-
cells, infectious viruses and noninfectious viruses, they demonstrated that an additional
source of virus production is a plausible explanation for the slow, secondary decay in the
sum of infectious and noninfectious virus concentrations. They further demonstrated
that, by including the effects of another pool of cells that are long-lived and susceptible to
HIV-1 infection, such as macrophages (M), the resultant six-equation model correlates
remarkably well with the experimentally observed two-staged virus populations. Their
analysis was based on the assumptions that the two types of drugs, reverse-transcriptase
inhibitor (rt) and protease inhibitor (p), are completely effective. In reality, the drugs are
not completely effective, and the population of the infectious virus does not decrease to
zero. To take into account the effectiveness of the drugs, Murray conducted detailed
stability and bifurcation analyses to Perelson and Nelsons four-equation model, and
concluded that there is a transcritical bifurcation when the effectiveness of the two drugs,
0
rtT
and 0
pT
, vary between 0 and 1.

The current work takes into account both the effectiveness of the drugs and the
populations of uninfected and productively infected macrophages. The dynamical system
includes six equations for the populations of six species and four parameters: the
effectiveness of protease and reverse transcriptase on each of T and M cells. Due to the
nonlinearity of the process, the drug effectiveness may or may not be directly
proportional to the amount of dosage. It may even be related to the type of drug itself.
Although the exact nature of M cells is not known, macrophages are victims of HIV-1
and are assumed to be the representative M cells. The effects of the four parameters have
been systematically investigated, i.e., from the selected two-parameter to the complete
four-parameter systems. The number and stability of steady states, and bifurcation and
phase plane characteristics have been examined in detail by numerical analysis in Matlab
environment.

It has been found that, for all cases, there are only two steady states, the infected and
uninfected steady states. The boundary separating the regions of stable and unstable
infected steady state, i.e., the bifurcation curve or surface, is numerically determined as
the effectiveness of the drugs varies. The boundaries of these regions are determined by
examining the signs and the nature of the eigenvalues of the J acobian matrix of the
system. In a region where the infected state is unstable, any perturbation caused by
antiretroviral drugs from the infected steady state will lead to an uninfected stable steady
state, or the healthy state. For a two-parameter system, i.e., taking drug effectiveness on
the productively infected T cells only, the bifurcation curve is a line function, (1 - 0
rtT
)(1 -
0
pT
) =c where c is a constant. By keeping the fourth parameter constant for a four-
parameter system, this curve extends into a three-dimension space as surface functions.
By increasing the fourth parameter, 0
pM
, this surface function moves downward. In the
region above this surface, the treatment will cause an increase in the numbers of T and M
cells and also a decrease in the number of HIV inside the body. Consequently, the effects
of HIV inside the body are minimized and the immunity is improved. Continuous
administration of the combination drug may stabilize the T and M cells to the normal
range.