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.
In the absence of antiretroviral therapy (ART), a relatively stable level of plasma viremia emerges after the resolution of primary HIV-1 infection. This set-point plasma virus load (VL) is usually maintained over a period of several years, and its level is a prognostic indicator for the rate of progression to disease (1). Both viral and host factors govern the set-point VL (reviewed in refs. 2 and 3). Among the latter factors, HIV-specific cellular immune responses and host genetic factors are major players (reviewed in refs. 4 and 5).
The availability of ART has provided the means with which to manipulate the set-point plasma VL. In a majority of patients, ART reduces plasma viremia to undetectable levels. However, ART is not able to eradicate HIV from an infected host (6–8). Further, long-term therapy is not devoid of adverse effects such as drug toxicities, costs, and the selection of drug-resistant variant viruses in partially adherent patients (9–11). ART also impinges on cellular immunity; prolonged control of viral replication is associated with a beneficial increase in CD4+ T cell counts (12), but also with decreasing HIV-specific cellular immune responses in patients with chronic HIV-1 infection (13, 14). In contrast, in patients who initiated ART during acute primary HIV-1 infection, HIV-specific cellular immune responses are preserved despite drug-mediated control of viremia (15, 16).
Discontinuation of treatment in chronic HIV patients generally results in rapid viral rebound followed by stabilization to levels comparable to pretreatment VL (17). However, in a few case studies, treatment interruptions of limited duration were followed by improved virological control in the absence of ART (18, 19). These reports spawned the idea that repeated exposures of short duration to autologous virus might boost HIV-specific immunity such that it would achieve a resetting of the viral set point at lower levels. This hypothesis was tested by structured treatment interruptions (STIs) in chronically infected HIV patients in a series of pilot studies (reviewed in ref. 20). In some of these preliminary studies, HIV-specific CD8+ T cell responses were boosted by reexposure to autologous virus; in the case of HIV-specific CD4+ T cell responses, such increases were transient. However, marked interpatient heterogeneity and small cohort sizes reached inconclusive and conflicting results and precluded statistically meaningful analysis (21–25). In contrast, STI after ART initiated during primary HIV-1 infection seems to have a beneficial effect on viremic control when ART is subsequently withdrawn (15).
Here, we present a detailed analysis investigating the impact of STI on HIV-specific cellular immunity and on the ensuing level of viral control performed in a large prospective study of STI involving 97 patients with chronic HIV-1 infection. We addressed several questions: (i) Does STI boost HIV-specific cellular immunity? (ii) Is STI able to lower set point VL? (iii) Is there a correlation between changes in HIV-specific cellular immunity and the set point that emerges after STI? (iv) Which parameters best predict the set point VL after STI?
Materials and Methods
Inclusion and Exclusion Criteria.
According to the Swiss-Spanish Intermittent Therapy Trial (SSITT) protocol (C.F., A.O., H.G., F.G., G. Mestre, M. Le Braz, M. Battegay, H. Furrer, P. Vernazza, E. Bernasconi, A. Telenti, R.W., D. Leduc, S. Yerly, D.A.P., S.J.D., T. Klimkait, T. V. Perneger, A.M., B. Clotet, J. M. Gatell, L.P., M.P., R.P., and B.H., unpublished work) patients were on continuous ART, with plasma VL <50 copies per ml for a minimum of 6 months and CD4 count >300 cells per mm3 at enrollment.
Treatment Schedule.
According to the SSITT treatment schedule, ART was stopped at week 0 for 2 weeks, and resumed thereafter for 8 weeks (week 2 to week 10). This cycle was repeated four times. Patients resumed continuous therapy between weeks 0 and 40 if their VL remained >50 copies per ml after retreatment. ART was also continued beyond week 40 if CD4 T cell counts were <400 per mm3. Otherwise, at week 40, ART was stopped for 3 months and was resumed only if symptoms of acute infection occurred, or if VL exceeded 50,000 copies per ml three times, 100,000 copies per ml twice, or 500,000 copies per ml once.
Patient Cohort.
Men (92) and women (41) were recruited for SSITT. Most (83%) had always been asymptomatic with a median pretreatment CD4 count of 398 (range 1–1,892) per mm3, and a median pretreatment VL of 4.5 (range 2.2–6.2) log10 (copies per ml). The median duration of ART at study entry was 26 months (range 8.5–44.5) with plasma VL <50 copies per ml for a median of 21 months (range 6–43). At the start of SSITT, the median CD4 T cell count was 740 (range 318–1,909). In 80 patients, a viral subtype analysis was performed based on a reverse transcriptase (RT) sequence and 80% were in subtype B. Virological and immunological responses were analyzed in all patients who were recruited in Switzerland (97 of 133).
Quantification of Plasma VL.
Plasma VL was quantified from cryopreserved plasma by using the regular or the ultrasensitive (for measurements taken on ART) Roche HIV Monitor assay (Roche Diagnostics, Rotkreuz, Switzerland; limit of detection 200 and ≤50 copies per ml).
HLA Genotyping.
The HLA class I and II genotypes were determined by PCR, using sequence-specific primers (PCR-SSP) (26).
IFN-γ Enzyme-Linked Immunospot (ELISPOT) Analysis.
All analysis was performed on cryopreserved peripheral blood lymphocytes (PBLs). For analysis of CD8+ T cell frequencies, PBLs were stimulated directly ex vivo with peptides corresponding to HLA class I-restricted cytotoxic T lymphocyte (CTL) epitopes at 2 μM in IFN-γ ELISPOT assays as described (16, 27). According to the HLA genotype, each patient was screened with a median of 16 (range 2–32) different peptide epitopes. For HIV-specific CD4+ T cell frequencies, PBLs were depleted of CD8+ T cells before IFN-γ ELISPOT analysis by using anti-CD8 conjugated Dynabeads (Dynal Biotech, Bromborough, U.K.). Pooled overlapping peptides spanning the HIV Gag p24 (National Institute for Biological Standards and Control, Potters Bar, U.K.) were used at 5 μg/ml (16). For both assays, phytohemagglutinin stimulation (5 μg/ml) was used as a positive control, and RPMI 1640, 10% FCS, glutamine, and antibiotics as a negative control. Results are expressed as spot-forming cells (SFC) per total or 106 CD8-depleted PBL. Background values were subtracted from the specific response before normalization. A positive response was more than three standard deviations above background. All assays were performed in duplicate.
Statistics.
Data were analyzed by using minitab statistical software, Release 13 [(2000) Minitab Statistical Software, State College, PA].
Results and Discussion
Pretreatment Plasma VL and Off-Treatment Viral Rebound Rate Are Independent Predictors of Plateau VL After STI.
To test for virological predictors of the plateau VL reached after the final cessation of ART, we compared each individual's pretreatment VL with his or her plateau VL. For each patient, plateau VL was defined as the average VL over all measurements available from week 50 to week 96 (median number of measurements, 9; range 1–13). Furthermore, for each patient, an individual viral growth rate at the final cessation of ART was calculated by regression through VL measurements between weeks 39 and 44. Both pretreatment VL and viral growth rate were highly significant predictors of plateau VL (P < 0.001). This result is shown in Fig. 1, where patients were divided into four equal groups according to their pretreatment plasma VL. Plateau VL is plotted against the viral upslope for each of the four patient groups. The plot is an illustration of the statistical result described above. Patients with faster viral rebound rates had higher plateau viral loads (the upward slope of the lines is significant), and patients with higher pretreatment viral loads also had higher plateau viral loads (the increasing height of the intercept of the lines is significant). Further, we found a significant correlation between each patient's average peak viremia reached during the 2-week treatment interruptions and the pretreatment VL and plateau VL (P = 0.002). A comparison of plateau VL to pretreatment VL showed that plateau VL was significantly lower than pretreatment VL (P = 0.005, paired t test); however, this difference was small (mean log10 pretreatment VL = 4.2826 and mean log10 plateau VL = 3.869).
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.
Our results corroborate and extend previous findings from STI pilot studies, which showed that, with some variation, VL levels reached 3 months after final cessation of therapy approximated to pre-ART VL levels (25). This result is comparable to studies of single treatment interruptions where the ensuing plasma VL was similar to pretreatment VL (17, 28).
In a few studies, STI has been shown to have an overall effect on viral doubling times; with increasing rounds of treatment interruption showing an increase in viral doubling times (21, 22). In a substudy of SSITT, including 13 patients with frequent sampling, such an increase in doubling times was also seen (29).
Impact of STI on HIV-Specific CD8+ T Cell Frequencies: Heterogeneous Patterns.
We followed HIV-specific CD8+ T cell responses over the four cycles of treatment interruption and after the final cessation of therapy by direct ex vivo IFN-γ ELISPOT analysis. For each patient, quantification of HIV-specific CD8+ T cell responses was performed at baseline (week 0), at weeks 9, 19, 29, and 39 (i.e., after 7 weeks of retreatment in each cycle), and at multiple time points after the final cessation of therapy. A heterogeneous picture was observed, and representative examples are shown in Fig. 2.
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.
Patients 1 and 2 showed an immediate and substantial increase in HIV-specific CD8+ T cell frequencies after their first treatment interruption (Fig. 2 A and B). This increase was mainly confined to a single epitope in patient 1; in patient 2, multiple responses were enhanced. For patients 3 and 4, the kinetics of HIV-specific CD8+ T cell enhancement was slower and substantial boosting was observed only after three treatment interruptions (Fig. 2 C and D). Enhancement was even further delayed to the final cessation of therapy in patients 5 and 6 (Fig. 2 E and F). These two patients did not show viral rebounds during the 2-week treatment interruptions, which might explain the initial lack of stimulation. No overall induction of HIV-specific CD8+ T cell responses was observed in patients 7 and 8, despite a very transient response in patient 7, which was observed at one time point after the final cessation of therapy (Fig. 2 G and H). A random picture with respect to HIV-specific CD8+ T cell frequencies was observed in patients 9 and 10, although significant responses to various epitopes were detectable at most time points (Fig. 2 I and J). All patients with sufficient data were classified according to these five patterns: 19/76 patients fell into the response pattern shown in Fig. 2 A and B; 15/76 into the response pattern shown in Fig. 2 C and D; 15/76 into the response pattern shown in Fig. 2 E and F; 8/76 into the response pattern shown in Fig. 2 G and H; and 19/76 into the response pattern shown in Fig. 2 I and J. Great individual variability was also observed for off-treatment plasma VLs. Based on this heterogeneity, a large cohort of patients had to be analyzed to draw general conclusions as to whether STI boosts cellular immunity.
Impact of STI on HIV-Specific CD8+ T Cell Frequencies: Overall Effects on Magnitude and Breadth of the Response.
Analysis of the compiled data on HIV-specific CD8+ T cell responses on all patients for whom data were available at least until week 52 showed a significant increase in the median frequency of total HIV-specific CD8+ T cells (defined as the sum of individual responses per patient) from baseline to weeks 39 and 52 (P = 0.002, <0.0001, respectively, Mann–Whitney U test). If CTL responses were grouped according to their HIV protein specificity, we observed significant increases for responses directed against HIV-Gag, Nef, and Env epitopes (P = 0.003, P = 0.001, and P = 0.039, respectively, Mann–Whitney U test) and a smaller increase in responses directed against Pol epitopes (not significant). Further, the number of recognized epitopes per patient increased slightly but significantly from baseline to week 52 (P = 0.0349), but not from baseline to week 39 (P = 0.1256, Mann–Whitney U test).
Before SSITT commenced, at week 0, the strongest CD8+ T cell response specific for an individual peptide represented an average of 57% of the total response. There was a trend for this percentage to decrease after SSITT and during the final off-treatment period (52% at wk 39, 48% at wk 52, not significant). Such a change is to be expected because patients were acquiring new responses over the period of observation.
These observations demonstrate that, in general, the pattern of HIV-specific CD8+ T cell responses within one individual is rather rigid and is maintained over the consecutive periods of STI. To address the question as to whether the responses observed during and after STI were related to responses before any treatment, or whether a qualitatively different response was induced by STI, we compared the pattern of pretreatment responses (0–124 days before first initiation of ART) to responses observed during and after STI in a subset of patients (Fig. 3). Importantly, this subset analysis revealed that the CTL epitope recognition profile was very similar in pretreatment samples and those analyzed during and after STI, indicating that STI largely restored the pretherapy response and did not significantly alter the recognition profile within a patient.
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.
This finding is in contrast to patients who initiated STIs after primary HIV-1 infection, where treatment interruptions significantly changed the recognition profile. Every treatment interruption induced, on average, one previously undetectable HIV-specific CD8+ T cell response (30).
Good and Poor Immunological Responders at Baseline Remain So After STI.
Comparison of the magnitude and number of recognized epitopes for each patient between baseline, week 39, and week 52 showed that these parameters were positively correlated. This indicates that: (i) patients with higher frequencies of HIV-specific CD8+ T cells exhibited broader epitope recognition; (ii) patients with higher frequencies of HIV-specific CD8+ T cells at baseline had higher frequencies at weeks 39 and 52; and (iii) patients with a broader range of epitope recognition at baseline exhibited broader recognition at weeks 39 and 52. Regression analysis between the variables “total HIV-specific CD8+ T cell frequencies at week 0, 39, and 52,” “number of recognized epitopes at week 0, 39, and 52,” “pretreatment plasma VL,” and “post-STI plateau VL” is shown in Table 1.
Table 1.
Pairwise correlations between immunological and/or virological parameters before, during, and after STI
| SFC wk 0 (n = 89) | SFC wk 39 (n = 64) | SFC wk 52 (n = 53) | No. of responses wk 0 (n = 89) | No. of responses wk 39 (n = 64) | No. of responses wk 52 (n = 53) | Pre-ART VL (n = 97) | |
|---|---|---|---|---|---|---|---|
| SFC wk 39 | C = 0.456 | ||||||
| P = 0.001 | |||||||
| SFC wk 52 | C = 0.332 | C = 0.609 | |||||
| P = 0.027 | P < 0.0001 | ||||||
| No. of responses wk 0 | C = 0.768 | C = 0.377 | C = 0.404 | ||||
| P < 0.0001 | P = 0.004 | P = 0.005 | |||||
| No. of responses wk 39 | C = 0.345 | C = 0.745 | C = 0.490 | C = 0.453 | |||
| P = 0.008 | P < 0.0001 | P = 0.001 | P < 0.0001 | ||||
| No. of responses wk 52 | C = 0.460 | C = 0.507 | C = 0.692 | C = 0.583 | C = 0.733 | ||
| P = 0.001 | P < 0.0001 | P < 0.0001 | P < 0.0001 | P < 0.0001 | |||
| Pre-ART VL | C = −0.371 | C = −0.302 | NS | C = −0.235 | C = −0.239 | NS | |
| P = 0.001 | P = 0.020 | P = 0.027 | P = 0.058 | ||||
| Plateau VL (n = 55) | NS | NS | C = 0.275 | C = 0.327 | NS | NS | C = 0.556 |
| P = 0.075 | P = 0.018 | P < 0.0001 |
Pre-ART VL, pretreatment plasma VL; Plateau VL, median VL after week 50; SFC, total spot-forming cells per 106 PBLs; No. of responses, number of recognized epitopes; C, Pearson correlation coefficient; P, P value; NS, not significant.
These observations demonstrate that STI, initiated during chronic HIV infection, did not turn poor HIV-specific immunological responders into good responders. STI preserved and enhanced the HIV-specific cellular immunological patterns that were largely established at week 0. Importantly, comparison of the post-STI responses with responses present before the first initiation of therapy showed that pretherapy responses were equal if not slightly stronger than post-STI responses (Fig. 3), indicating that STI seems to restore rather than to improve pretherapy HIV-specific CD8+ T cell responses.
Lack of Correlation Between Plateau VL and Magnitude of HIV-Specific CD8+ T Cell Responses.
We compared the frequencies of HIV-specific CD8+ T cells and the number of recognized epitopes per patient at baseline, week 39, and week 52 with pretreatment VL and plateau VL. No correlation between the magnitude of the HIV-specific CD8+ T cell response at week 0, 39, or 52 with plateau VL was observed (Table 1). However, the frequency of HIV-specific CD8+ T cells measured at week 0 or 39, i.e., at time points where viremia was drug-controlled, correlated inversely with pretreatment pVL (Table 1). This inverse correlation was not observed at week 52, where patients were off-treatment, and hence, viremic. HIV-specific CD8+ T cells measured at week 52 showed a trend toward a positive correlation with plateau VL that could be a direct reflection of an antigenic drive. Likewise, the number of recognized epitopes per patient measured at week 0 correlated inversely with pretreatment VL; this was not the case at week 52.
Based on previous suggestions from STI pilot studies (22, 23) we initially hypothesized that the increase in HIV-specific CD8+ T cell frequencies over the course of four STIs would correlate with improved virological control after the final cessation of therapy. In our study we found only a very small improvement of virological control after STI as compared with pretreatment, and it remains to be shown whether this small improvement is maintained over time. Our data did not reveal a correlation between virological improvement and the increase of HIV-specific CD8+ T cell frequencies, and there was no immunological parameter that accurately predicted the individual's plateau VL. However, it remains to be determined whether there might be beneficial long-term consequences of STI-boosted CD8+ T cell responses.
There are several potential explanations for the lack of a linear correlation between virological and immunological parameters. First, the magnitude and breadth of the individual's HIV-specific CD8+ T cell response might have been suboptimally defined by screening with a panel of HIV clade B-derived, HLA-matched CTL epitopes. However, this screening approach was much broader than previous approaches where correlations between CTL frequencies and plasma VL were observed (31). Second, it might be too simple to postulate that frequencies of HIV-specific CD8+ T cells are a direct inverse correlate of HIV-1 replication in vivo. In the absence of treatment, different levels of viremia establish which probably represent different levels of antigenic stimulation on one hand, whereas increased frequencies of effective HIV-specific CD8+ T cells may control viral replication on the other hand. These complex interactions between VL and CTL frequencies might preclude the detection of straightforward correlations (14, 32, 33). Third, it is likely that the amount of viral replication is controlled by the synergistic action of multiple immunological effector arms, including CD8+ T cells (by means of cytolytic and noncytolytic mechanisms), CD4+ T cells, antiviral neutralizing antibodies, and natural killer cells. Moreover, nonimmunological parameters such as host and virus genotype are known to influence the level of viral replication in vivo (2, 3).
HIV-Specific CD4+ T Cell Responses.
In 30 patients we measured HIV Gag p24-specific CD4+ T cell responses at baseline, week 39, and at one time point after the final cessation of therapy (Fig. 4). We divided the 30 patients into two groups according to their median pretreatment VL (30,976 copies per ml). In both groups of patients, an increase in HIV p24-specific CD4+ T cell frequencies was observed between baseline and week 39. After the cessation of therapy, HIV p24-specific CD4+ T cell frequencies were not maintained in the group with the higher pretreatment VL. Such transient increases in HIV-specific CD4+ T cell responses have also been described in other studies of STI (21, 24, 34, 35). This result is in contrast to the patient group with lower pretreatment VL who maintained, and even increased, levels of HIV p24-specific CD4+ T cells after the cessation of therapy. Consequently, HIV p24-specific CD4+ T cell frequencies after the cessation of therapy were significantly different between the two groups of patients (P = 0.018, Mann–Whitney U test). This result was true despite comparable total CD4 T cell counts at any of the three time points of analysis. In line with observations for the entire patient cohort (Fig. 1), the patient group with lower pretreatment VL exhibited significantly lower VL after cessation of therapy than the group with higher pretreatment VL. This lower VL might be the cause, or the consequence, of elevated HIV-specific CD4+ T cell frequencies. If elevated HIV-specific CD4+ T cell frequencies were the cause of better virological control, their antiviral effect would most likely be mediated indirectly by means of activation of antigen-presenting cells (APCs), local cytokine secretion, and cognate help to HIV-specific B cells. Alternatively, elevated HIV-specific CD4+ T cell frequencies might be the consequence of better virological control, implying that higher levels of HIV replication are detrimental for the maintenance of HIV-specific CD4+ T cell frequencies (36). Higher levels of HIV replication may induce higher numbers of activated HIV-specific CD4+ T cells which have been shown to be preferential targets for infection (37).
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.
Summary
Here we analyzed the impact of controlled viral recrudescence on virological and immunological parameters in a large prospective study of STI. Plateau VL reached after STI was strongly correlated with pretreatment VL, and was slightly lower than, but within 0.4 log10 units of, the pretreatment VL. This small virological improvement was not explained by STI-induced increases in either the magnitude or breadth of the HIV-specific CD8+ T cell response. Patterns of HIV-specific CD8+ T cell responses were maintained over STI, in that individuals with strong and broad HIV-specific CD8+ T cell responses at baseline retained these characteristics after STI. Moreover, the quantity and quality of post-STI HIV-specific CD8+ T cell responses were comparable, if not slightly below the level of responses observed before any therapy was commenced, suggesting that STI restored, rather than improved, established HIV-specific CD8+ T cell responses. HIV-specific CD4+ T cell responses increased over STI but were maintained at elevated levels only in patients with lower VL. These findings demonstrate that STI initiated during chronic HIV-1 infection is generally unable to significantly alter the individual preexisting equilibrium between cellular immunity and viral replication nor is it able to significantly lower the set-point VL. This result is in contrast to STI initiated during primary infection where a certain degree of modulation of the ensuing set-point VL has been observed (15).
Supplementary Material
Acknowledgments
We thank the patients for their commitment, M. LeBraz, C. Schneider, R. Hafner, M. Battegay, E. Beransconi, and P. Vernazza for excellent patient care, and S. Yerly, F. Burgener, E. Schlaepfer, and D. Russenberger for laboratory support. This work was supported by the Schweizerische Stiftung für Medizinisch Biolgische Stipendien (SSMBS) (A.O.), the Wellcome Trust (R.E.P., S.J.D., and A.M.), and the Medical Research Council (D.A.P.). Further, this study has been financed by the Swiss National Science Foundation (Grant 3345-062041), Swiss HIV Cohort Study (SHCS) Grant 290 (to H.F.G.), a research grant from the Kanton of Zürich, and in part by the Fund for the Improvement of Postsecondary Education (FIPSE), Grant 3118/00 (FIPSE is a nonprofit foundation that includes the following: The Spanish Ministry of Health, Abbott Laboratories, Boehringer Ingelheim, Bristol–Myers Squibb, GlaxoSmithKline, Merck Sharp, Dohme, and Roche).
Abbreviations
- ART
antiretroviral therapy
- STI
structured therapeutic interruption
- VL
virus load
- PBL
peripheral blood lymphocyte
- CTL
cytotoxic T lymphocyte
- SSITT
Swiss-Spanish Intermittent Therapy Trial
- ELISPOT
enzyme-linked immunospot
- SFCs
spot-forming cells
Footnotes
This paper was submitted directly (Track II) to the PNAS office.
See commentary on page 13377.
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