Specific therapy regimes could lead to long-term immunological control of HIV

Abstract

We use mathematical models to study the relationship between HIV and the immune system during the natural course of infection and in the context of different antiviral treatment regimes. The models suggest that an efficient cytotoxic T lymphocyte (CTL) memory response is required to control the virus. We define CTL memory as long-term persistence of CTL precursors in the absence of antigen. Infection and depletion of CD4(+) T helper cells interfere with CTL memory generation, resulting in persistent viral replication and disease progression. We find that antiviral drug therapy during primary infection can enable the development of CTL memory. In chronically infected patients, specific treatment schedules, either including deliberate drug holidays or antigenic boosts of the immune system, can lead to a re-establishment of CTL memory. Whether such treatment regimes would lead to long-term immunologic control deserves investigation under carefully controlled conditions.

Figure 1

Primary HIV infection. Shading indicates drug therapy. (i) Basic dynamics. The virus population replicates up to a peak and subsequently settles to a stable equilibrium. The memory CTLp initially expand, but subsequently are exhausted because of HIV-induced impairment of the T helper cell response. Note that we only take into account an efficient memory CTL response, dependent on CD4 cell help. The model considers a simplified scenario, excluding less efficient CTL responses that may be independent of CD4 cell help and that may not control the virus in the long term. Hence, virus load does not fall by a very large amount after the peak, and the memory CTLp response declines to low levels. The depicted scenario may correspond to fast progressing disease. (ii) Effect of drug therapy. Administration of antiretroviral drugs during the primary phase of the infection minimizes the degree of HIV-induced immune impairment. Consequently, CTL memory becomes established in response to the increased viral load. Once CTL memory has been established, it may control HIV in the long term in the absence of continued therapy. 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.

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.

Figure 3

Asymptomatic period of the infection. Shading indicates drug therapy. (i) Efficient drug therapy reduces virus load to low levels. However, if the drugs are withdrawn, virus load re-emerges to pretreatment levels. Although the rise in virus load boosts the immune system, virus-induced immune impairment prevents the development of CTL memory. Note again, that we only consider memory CTLp as defined in the text, dependent on the presence of CD4 cell help. Hence, before therapy, the figure does not show persistence of less efficient CTL at higher levels that may not control the infection in the long term and that may be maintained by continuous viral replication in HIV-infected patients. (ii) Treatment regime required to re-establish CTL memory. It consists of four phases: The first phase of treatment reduces virus load to low levels, which is followed by a drug holiday allowing the virus to replicate, thereby boosting the immune system. While virus load increases, the secondary phase of therapy is initiated. This phase suppresses the amount of virus-induced immune impairment and allows the establishment of CTL memory in response to the increased virus load. Finally, drug therapy can be stopped for good once CTL memory has been generated. The virus now is controlled in the long term by the immune system. Note that after the second phase of therapy virus load transiently rises and oscillates before being controlled by CTL memory, because during the second phase of therapy the CTL effector response will have declined to low levels, allowing the virus to initially attain a positive growth rate. However, this does not indicate failure of the treatment regime. Furthermore, it is important to point out that the secondary phase of treatment reduces virus load to lower levels in a shorter period of time than the primary phase of treatment, because the secondary phase of treatment is associated with a rising CTL memory response that accelerates the death rate and consequently the decay rate of infected cells during therapy. This finding underlines the notion that the effect of drug treatment on virus load is enhanced by the presence of an efficient CTL response (41). 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.

Figure 4

Modifications of the basic treatment window regime resulting in the re-establishment of CTL memory during the asymptomatic period of the infection. Again, only memory CTL responses generated in the presence of CD4 cell help are considered. Because we assume that CD4 cell help is significantly impaired, these CTL are at low levels before start of therapy. Shading indicates drug therapy. (i) Multiple drug windows. In low immune responders and in patients with advanced HIV disease, the basic drug window treatment regime may result only in partial establishment of CTL memory and failure to control the virus. Further phases of drug therapy separated by treatment windows may successively boost the CTL response, resulting in the eventual generation of efficient CTL memory and long-term control of HIV. Parameters were chosen as follows: λ = 1; d = 0.1; β = 0.5; a = 0.2; p = 1; c = 0.027; b = 0.001; q = 0.5; h = 0.1; s = 0.0042. (ii) Drug therapy in conjunction with vaccination with persisting antigen. Although virus load is kept at low levels because of antiviral therapy, the patient is vaccinated with a mixture of immunogenic HIV peptides. This boost induces the establishment of CTL memory whereas drug treatment keeps HIV-induced immune impairment to a minimum. During the generation of CTL memory, HIV load sharply drops to very low levels, because the CTL response is boosted in the absence of HIV replication, allowing the rising CTL to reduce virus load to ever decreasing values. This process theoretically could clear the infection. However, the presence of latently infected cells and reservoirs inaccessible to CTL renders this goal difficult to achieve. Thus, when drug treatment is stopped, virus load is likely to transiently increase before being controlled in the long term by CTL memory. Vaccination with a recombinant virus vector expressing HIV-specific proteins was modeled according to the basic virus infection model (38). Denoting uninfected target cells for the vector as x₂, and vector-infected cells by y₂, the model is given by ẋ₂ = λ₂− d_2x2 − β_2x2y2; ẏ₂ = β_2x2y2 − a_2y2 − p_2y2z. The CTL response is equally stimulated both by HIV and the vaccine. Parameters were chosen as follows: λ = 1; d = 0.1; β = 0.5; a = 0.2; p = 1; c = 0.1; b = 0.001; q = 0.5; h = 0.1; s = 0.0042; λ₂ = 1; d₂ = 0.1; β₂ = 0.5; a₂ = 0.2.