Figure 2.

Duration of therapy during primary infection required to successfully establish CTL memory in dependence of host and viral parameters. The same relationships hold true for the duration of the secondary phase of therapy in the asymptomatic period required to re-establish CTL memory (Fig. 3). The arrows with an infinity sign denote parameter thresholds beyond which establishment of CTL memory becomes impossible, regardless of the duration of treatment. (i) Start of therapy in primary infection or after the drug holiday during the asymptomatic period. Treatment should be started when virus load has replicated to a level sufficient to stimulate specific CTLp. Starting too early may result in treatment failure because the immune system has not been boosted enough. On the other hand, if the virus has replicated to sufficiently high levels, delaying the onset of therapy results in an increased duration of treatment required for the establishment of CTL memory. If treatment is started too late, control of the virus becomes impossible. (ii) A fast replication rate of the virus, β, results in a decreased availability of functional T helper cells. Consequently, if β lies above a threshold, immunological control of the virus is impossible. On the other hand, if the virus replicates relatively slowly and β lies below a threshold, virus-induced immune impairment is minimal and the immune system may control the virus without the need for any therapy. For intermediate values of β, immune impairment interferes with the generation of memory, but therapy may restore it, resulting in long-term immunological control of the virus. In this parameter region, the duration of therapy required to establish CTL memory increases with a faster replication rate of the virus (β). (iii) The lower the immune responsiveness of the host (c), the longer the duration of treatment required to establish CTL memory. If the immune responsiveness lies below a threshold, treatment cannot result in the establishment of CTL memory. On the other hand, if the immune responsiveness lies above a threshold and is sufficiently high to overcome virus-induced immune impairment, CTL memory is established and the virus is controlled without the need for therapy. (iv) The rate of CD4⁺ T cell production (λ), and thus the initial CD4⁺ T cell count at the start of therapy, is an important parameter for successful treatment. The lower the rate of CD4⁺ T cell production, the longer the duration of treatment required to establish CTL memory. If the rate of CD4⁺ cell production has fallen below a threshold, therapy cannot result in the establishment of CTL memory. (v) The lower the efficacy of the drug (1-s), the longer the duration of therapy required to establish CTL memory. If the efficacy of the drugs lies below a threshold, therapy cannot result in the establishment of CTL memory. Baseline parameters were chosen as follows: λ = 1; d = 0.1; β = 0.5; a = 0.2; p = 1; c = 0.1; b = 0.01; q = 0.5; h = 0.1; s = 0.0042.