Understanding the HIV coreceptor switch from a dynamical perspective

Abstract

Background: The entry of HIV into its target cells is facilitated by the prior binding to the cell surface molecule CD4 and a secondary coreceptor, mostly the chemokine receptors CCR5 or CXCR4. In early infection CCR5-using viruses (R5 viruses) are mostly dominant while a receptor switch towards CXCR4 occurs in about 50% of the infected individuals (X4 viruses) which is associated with a progression of the disease. There are many hypotheses regarding the underlying dynamics without yet a conclusive understanding.

Results: While it is difficult to isolate key factors in vivo we have developed a minimal in silico model based on the approaches of Nowak and May to investigate the conditions under which the receptor switch occurs. The model allows to investigate the evolution of viral strains within a probabilistic framework along the three stages of disease from primary and latent infection to the onset of AIDS with a a sudden increase in viral load which goes along with the impairment of the immune response. The model is specifically applied to investigate the evolution of the viral quasispecies in terms of R5 and X4 viruses which directly translates into the composition of viral load and consequently the question of the coreceptor switch.

Conclusion: The model can explain the coreceptor switch as a result of a dynamical change in the underlying environmental conditions in the host. The emergence of X4 strains does not necessarily result in the dominance of X4 viruses in viral load which is more likely to occur in the model after some time of chronic infection. A better understanding of the conditions leading to the coreceptor switch is especially of interest as CCR5 blockers have recently been licensed as drugs which suppress R5 viruses but do not seem to necessarily induce a coreceptor switch.

Figure 1

The course of disease in the model. Viral load of R5 viruses (blue) and X4 viruses (red) in a simulation of the model described by equations (1) and parameters as in table 2. The viral load is given in arbitrary units of viral load (VL).

Figure 2

The distribution of strains. The probability to find n^R5 R5 strains and n^X4 X4 strains in a patient at 1200 days since infection in the model with parameters as in table 2 and v_max = 500 units of viral load, the final stage of disease (absorbing state) is marked by the accumulation of probability density at the diagonal border.

Figure 3

X4 dominance and the onset of AIDS. The figure shows how the dominance of X4 viral load and the onset of AIDS depends on the number of X4 and R5 strains present in the system according to equations (3) and (7), for parameters cf. table 2.

Figure 4

Survival distribution and the coreceptor switch. The probability to have reached the final stage of disease (black) either with dominance in viral load of R5 viruses (blue) or X4 viruses (red) according to the master equation (5), the survival distribution sampled from 200 simulations of equation (1) (grey) agree well with the master equation's predictions i.e. giving support to the assumption of quasi-stationary viral populations, parameters according to table 2.