Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection

Abstract

Potent antiretroviral therapy (ART) suppresses HIV-1 viral replication and results in decreased morbidity and mortality. However, prolonged treatment is associated with drug-induced toxicity, emergence of drug-resistant viral strains, and financial constraints. Structured therapeutic interruptions (STIs) have been proposed as a strategy that could boost HIV-specific immunity, through controlled exposure to autologous virus over limited time periods, and subsequently control viral replication in the absence of ART. Here, we analyzed the impact of repeated STIs on virological and immunological parameters in a large prospective STI study. We show that: (i) the plateau virus load (VL) reached after STIs correlated with pretreatment VL, the amount of viral recrudescence during the treatment interruptions, and the off-treatment viral rebound rate; (ii) the magnitude and the breadth of the HIV-specific CD8(+) T lymphocyte response, despite marked interpatient variability, increased overall with STI. However, the quantity and quality of the post-STI response was comparable to the response observed before any therapy; (iii) individuals with strong and broad HIV-specific CD8(+) T lymphocyte responses at baseline retained these characteristics during and after STI; (iv) the increase in HIV-specific CD8(+) T lymphocyte frequencies induced by STI was not correlated with decreased viral set point after STI; and (v) HIV-specific CD4(+) T lymphocyte responses increased with STI, but were subsequently maintained only in patients with low pretreatment and plateau VLs. Overall, these data indicate that STI-induced quantitative boosting of HIV-specific cellular immunity was not associated with substantial change in viral replication and that STI was largely restoring pretherapy CD8(+) T cell responses in patients with established infection.

Figure 1

Pretreatment VL and the off-treatment rebound rate are independent predictors of plateau VL. For all patients with available VL data up to week 52 (n = 53), pretreatment VL, plateau VL, and off-treatment viral growth rate were compared in an analysis of covariance. Pretreatment VL is treated as a categorical variable by dividing patient groups into quartiles (in order of increasing pretreatment VL: ♦, ●, ▴, and ■. The y axis represents log₁₀ (plateau VL), and the x axis represents the off-treatment viral growth rate. The lines represent the best fitting relationship between off-treatment viral growth rate and plateau VL for the four patient groups. The lines with increasing intercepts represent the patient groups with increasing pretreatment VL.

Figure 2

Evolution of VL and HIV-specific CD8⁺ T cell frequencies in 10 patients during and after four consecutive 2-week treatment interruptions. The left y axis refers to the magnitude of epitope-specific CD8⁺ T cell frequencies (SFC/10⁶ PBL). For each patient, frequencies of CD8⁺ T cell responses are shown only for epitopes that induced consistently or transiently measurable responses (for lines without symbols, each line represents a different epitope). The right y axis refers to the plasma VL, represented by ●. White areas represent time periods on ART, and gray areas represent time periods off-treatment. The x axis refers to the weeks after the first treatment interruption.

Figure 3

Assessment of HIV-specific CD8⁺ T cell responses before the first initiation of ART, during STI, and after the final cessation of therapy. The y axis refers to the magnitude of HIV-specific CD8⁺ T cell responses. Frequencies of CD8⁺ T cell responses are shown only for epitopes that consistently or transiently induced a response. Gray areas represent time periods off-treatment. The numbers above each graph show the plasma VL (copies per ml) at the indicated time points off-treatment. The x axis refers to the weeks after the initial treatment interruption. For each pre-ART sample, the time before the initiation of ART is given in days, and the initiation of ART with respect to week 0 of the SSITT trial is given in weeks. Peptide sequences inducing measurable responses are presented in Table 2, which is published as supporting information on the PNAS web site, www.pnas.org.

Figure 4

HIV-specific CD4⁺ T cell responses. HIV Gag p24-specific CD4⁺ T cell frequencies were determined at baseline (wk 0), at week 39 (wk 39), and at a time point after the final cessation of therapy (off) in 30 patients. Patients were divided into two groups according to the median of their pretreatment VL (Upper, lower pretreatment VL; Lower, higher pretreatment VL). (Left) The frequency of HIV Gag p24-specific CD4⁺ T cells. (Right) Plasma VL, including the pretreatment pVL (pre). Each circle represents a single patient. Bars represent median values.