[Show abstract][Hide abstract] ABSTRACT: We tested if an increase of immune activation and drop of CD4+ T cells induced by different antigenic stimuli could be associated with changes in thymic function and IL-7/CD127 system.
Twenty-six HIV-infected patients under cART were randomized to receive during 12 months a complete immunization schedule (7 vaccines and 15 doses) or placebo. Thereafter, cART was interrupted 6 months. Changes in the thymic function and IL-7/CD127 system after 3 different antigenic stimuli (vaccines, episodes of low level intermittent viremia before cART interruption or viral load rebound after cART interruption) were assessed.
During the period on cART neither vaccines nor low level viremia influenced thymic function or IL-7/CD127 system parameters. Analyzing the cohort as a whole while on cART, a significant improvement was observed in thymic function as measured by an increase in the thymic volume (p=0.024), TRECs-bearing cells (p=0.012) and naive CD4+ and CD8+ T cells (p=0.069 both). No significant changes were observed in the IL-7/CD127 system. After cART interruption, a decrease of TRECs (p<0.001) and naïve CD8+ T cells (p<0.001), an increase of IL-7 and expression of CD127 on naïve and memory CD4+ T cells (p=0.028, p=0.088 and p=0.04, respectively) and a significant decrease of CD127 on naive and memory CD8+ T cells (p=0.01, p=0.006, respectively) were observed.
Low level transient antigenic stimuli during cART were not associated with changes on thymic function or IL-7/CD127 system. Conversely, viral load rebound very early after cART interruption influenced thymic function and IL-7/CD127 system.ClinicalTrials.gov number NCT00329251.
[Show abstract][Hide abstract] ABSTRACT: Most patients on suppressive ART experience improvements in CD4 T cell count. However, some patients with undetectable viral load continue to lose CD4 T cells for unknown reasons. Casp8p41 is a host derived protein fragment that is present only in productively infected cells, that causes the death of HIV-infected cells. We questioned whether ongoing CD4+ T cell losses while on suppressive ART were associated with subclinical HIV replication causing production of Casp8p41. We analyzed the association of Casp8p41 content with subsequent CD4 losses in patients on continuous suppressive ART and in patients who discontinued ART after Casp8p41 content was determined, adjusting for age, baseline CD4+ T cell count, and baseline HIV RNA level. Casp8p41 expression in memory CD4+ T cells was measured by intracellular flow cytometry and correlated with viral load and CD4+ T cell change over time. In patients who stopped therapy after Casp8p41 content was determined, baseline Casp8p41 content did not predict CD4+ T cell change. However, in patients on continuous ART, higher baseline Casp8p41 content was associated with a greater odds of a CD4+ T cell decline at 6 months (P=0.01). Therefore, patients on suppressive ART, who have ongoing production of Casp8p41, have increased risk of CD4 T cell losses, suggesting that subclinical HIV replication is driving both Casp8p41 which in turn causes CD4+ T cell decline.
AIDS research and human retroviruses 12/2013; · 2.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dendritic cells have a central role in HIV infection. On one hand, they are essential to induce strong HIV-specific CD4+ helper T-cell responses that are crucial to achieve a sustained and effective HIV-specific CD8+ cytotoxic T-lymphocyte able to control HIV replication. On the other hand, DCs contribute to virus dissemination and HIV itself could avoid a correct antigen presentation. As the efficacy of immune therapy and therapeutic vaccines against HIV infection has been modest in the best of cases, it has been hypothesized that ex vivo generated DC therapeutic vaccines aimed to induce effective specific HIV immune responses might overcome some of these problems. In fact, DC-based vaccine clinical trials have yielded the best results in this field. However, despite these encouraging results, functional cure has not been reached with this strategy in any patient. In this Commentary, we discuss new approaches to improve the efficacy and feasibility of this type of therapeutic vaccine.
Human vaccines & immunotherapeutics. 08/2013; 9(11).
[Show abstract][Hide abstract] ABSTRACT: Background: The reduction of risk of non-AIDS events after antiretroviral therapy (cART) initiation and the crude incidence rate (CIR) of these events in patients who control the viral load without cART (controllers) in a cohort of 574 antiretroviral naïve patients with a baseline CD4 T cell count above 500 cells/mm3 were assessed. Methods: Non-AIDS severe events were defined as a first admission to the hospital due to non-AIDS-defining malignancies, cardiovascular, neuropsychiatric, liver-related or end-stage renal disease events. Potential determinants of non-AIDS/death events were studied using Cox regression models. Results: Eighty-five non-AIDS/death events occurred during 6062 persons-years of follow-up with a CIR of 1.4 per-100-PYFU. Factors associated with non-AIDS/death event were age (HR 3.4; 95%CI:1.6-6.9), nadir CD4 below 350 cells/mm3 (HR 2.5; 95%CI:1.4-4.6) and a last determination of viral load above the median (HR 1.9; 95%CI:1.0-3.3). The CIR of non-AIDS/death events was 2.1 and 1.8 per-100-PYFU before and after cART in patients who started cART (n=446). A reduction of CIR of non-AIDS events after cART initiation was only observed in patients with a nadir of CD4 above 350 cells/mm3 (2.5 vs 0.6 per-100-PYFU P= 0.004 and remained stable after cART in patients with a median nadir of CD4 below 350 cells/mm3. CIR was similar in elite, viremic and non controllers (1.1, 1.0 and 1.5 per-100-PYFU, respectively, P=0.25). Conclusions: Reduction of CIR of non-AIDS events after cART initiation depends on nadir CD4 T cell count. Most of the controllers patients had a CIR similar to non-controllers. These data support the early initiation of cART in HIV infected patients.
AIDS research and human retroviruses 03/2013; · 2.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Combination antiretroviral therapy (cART) greatly improves survival and quality of life of HIV-1-infected patients; however, cART must be continued indefinitely to prevent viral rebound and associated disease progression. Inducing HIV-1-specific immune responses with a therapeutic immunization has been proposed to control viral replication after discontinuation of cART as an alternative to "cART for life." We report safety, tolerability, and immunogenicity results associated with a control of viral replication for a therapeutic vaccine using autologous monocyte-derived dendritic cells (MD-DCs) pulsed with autologous heat-inactivated whole HIV. Patients on cART with CD4(+) >450 cells/mm(3) were randomized to receive three immunizations with MD-DCs or with nonpulsed MD-DCs. Vaccination was feasible, safe, and well tolerated and shifted the virus/host balance. At weeks 12 and 24 after cART interruption, a decrease of plasma viral load setpoint ≥1 log was observed in 12 of 22 (55%) versus 1 of 11 (9%) and in 7 of 20 (35%) versus 0 of 10 (0%) patients in the DC-HIV-1 and DC-control groups, respectively. This significant decrease in plasma viral load observed in immunized recipients was associated with a consistent increase in HIV-1-specific T cell responses. These data suggest that HIV-1-specific immune responses elicited by therapeutic DC vaccines could significantly change plasma viral load setpoint after cART interruption in chronic HIV-1-infected patients treated in early stages. This proof of concept supports further investigation of new candidates and/or new optimized strategies of vaccination with the final objective of obtaining a functional cure as an alternative to cART for life.
Science translational medicine 01/2013; 5(166):166ra2. · 10.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Generation of new reagents that can be used to screen or monitor HIV-1-specific responses constituted an interesting field in the development of HIV vaccines to improve their efficacy.
We have evaluated the specific T cell response against different types of NL4-3 virions (including NL4-3 aldrithiol-2 treated, NL4-3/ΔRT and R5 envelopes: NL4-3/ΔRT/ΔEnv[AC10] and NL4-3/ΔRT/ΔEnv[Bal]) and against pools of overlapping peptides (15 mer) encompassing the HIV-1 Gag and Nef regions. Cryopreserved PBMC from a subset of 69 chronic asymptomatic HIV positive individuals have been employed using different techniques including IFN-γ ELISPOT assay, surface activation markers and intracellular cytokine staining (ICS) by flow cytometry.
The differential response obtained against NL4-3 aldrithiol-2 treated and NL4-3/ΔRT virions (25% vs 55%, respectively) allow us to divide the population in three groups: "full-responders" (positive response against both viral particles), "partial-responders" (positive response only against NL4-3/ΔRT virions) and "non-responders" (negative responses). There was no difference between X4 and R5 envelopes. The magnitude of the total responses was higher against NL4-3/ΔRT and was positively correlated with gender and inverse correlated with viral load. On the contrary CD4+ T cell count was not associated with this response. In any case responses to the viruses tended to be lower in magnitude than those detected by the overlapping peptides tested. Finally we have found an increased frequency of HLA-B27 allele (23% vs 9%) and a significant reduction in some activation markers (CD69 and CD38) on T cells surface in responders vs non-responders individuals.
In summary these virions could be considered as alternative and useful reagents for screening HIV-1-specific T cell responses in HIV exposed uninfected people, HIV infected patients and to assess immunogenicity of new prototypes both in vitro and in vaccine trials, by a feasible, simply, effective and low cost assay.
PLoS ONE 01/2013; 8(3):e58927. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Several potential immunological benefits have been observed during treatment with the CC chemokine receptor 5 (CCR5) antagonist maraviroc, in addition to its antiviral effect. Our objective was to analyse the in vitro effects of CCR5 blockade on T lymphocyte function and homeostasis. METHODS: Peripheral blood mononuclear cells (PBMCs) from both HIV-negative (n = 28) and treated HIV-positive (n = 27) individuals were exposed in vitro to different concentrations of maraviroc (0.1-100 μM). Effects on T cell activation were analysed by measuring the expression of the CD69, CD38, HLA-DR and CD25 receptors as well as CCR5 density using flow cytometry. Spontaneous and chemokine-induced chemotaxis were measured by transwell migration assays, and polyclonal-induced proliferation was assessed by a lymphoproliferation assay and carboxyfluorescein succinimidyl ester staining. RESULTS: Maraviroc increases CCR5 surface expression on activated T cells, even at low doses (0.1 μM). Slight differences were detected in the frequency and mean fluorescence intensity of activation markers at high concentrations of maraviroc. Expression of CD25, CD38 and HLA-DR tended to decrease in both CD4+ and CD8+ T lymphocytes, whereas expression of CD69 tended to increase. Maraviroc clearly inhibits T cell migration induced by chemokines in a dose-dependent manner. Moreover, at 100 μM, maraviroc tends to inhibit T cell proliferation. CONCLUSIONS: These data showed that in vitro exposure to maraviroc decreases some activation expression markers on T lymphocytes and also migration towards chemoattractants. These results support the additional immunological effects of CCR5 blockade and suggest that maraviroc might have potential capacity to inhibit HIV-associated chronic inflammation and activation, both by directly affecting T cell activation and by reducing entrapment of lymphocytes in lymph nodes.
Journal of Antimicrobial Chemotherapy 11/2012; · 5.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Presenting episodes of intermittent viremia (EIV) under cART is frequent, but there exists some controversy about their consequences. They have been described to induce changes in immune responses potentially associated to a better control of HIV infection. Conversely, it has been suggested that EIV increase the risk of virological failure. Methods: A retrospective analysis of a prospective, randomized double blinded placebo-controlled study was performed. Twenty-six successfully treated HIV-infected adults were randomized to receive an immunization schedule or placebo, and after one year of follow-up cART was discontinued. Influence of EIV on T-cell subsets, HIV-1 specific T-cell immune responses, viral load rebound and the risk of developing genotypic mutations were evaluated, taking into account the immunization received. Results: Patients with EIV above 200 copies/mL under cART had a lower proportion of CD4+, CD4+CD45RA+RO- T-cells, a higher proportion of CD8+ and CD4+CD38+HLADR+ T-cells and higher HIV specific CD8+ T-cell responses compared to persistently undetectable patients. After cART interruption, patients with EIV presented a significantly higher viral rebound (p = 0.007), associated with higher increases in HIV specific lymphoproliferative responses and T-cell populations with activation markers. When patients with EIV between 20-200 copies/mL were included, most of the differences disappeared. Conclusion: Patients who present EIV above 200 copies/ml showed a lower CD4+ T-cell count and higher activation markers under cART. After treatment interruption, they showed higher specific immune responses against HIV that did not prevent a higher virologic rebound. EIV between 20 and 200 copies/ml did not have this deleterious effect.
AIDS research and human retroviruses 11/2012; · 2.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Resistance to medication, adverse effects in the medium-to-long-term and cost all place important limitations on lifelong adherence to combined antiretroviral therapy (cART). In this context, new therapeutic alternatives to 'cART for life' in HIV-infected patients merit investigation. Some data suggest that strong T cell-mediated immunity to HIV can indeed limit virus replication and protect against CD4 depletion and disease progression. The combination of cART with immune therapy to restore and/or boost immune-specific responses to HIV has been proposed, the ultimate aim being to achieve a 'functional cure'. In this scenario, new, induced, HIV-specific immune responses would be able to control viral replication to undetectable levels, mimicking the situation of the minority of patients who control viral replication without treatment and do not progress to AIDS. Classical approaches such as whole inactivated virus or recombinant protein initially proved useful as therapeutic vaccines. Overall, however, the ability of these early vaccines to increase HIV-specific responses was very limited and study results were discouraging, as no consistent immunogenicity was demonstrated and there was no clear impact on viral load. Recent years have seen the development of new approaches based on more innovative vectors such as DNA, recombinant virus or dendritic cells. Most clinical trials of these new vectors have demonstrated their ability to induce HIV-specific immune responses, although they show very limited efficacy in terms of controlling viral replication. However, some preliminary results suggest that dendritic cell-based vaccines are the most promising candidates. To improve the effectiveness of these vaccines, a better understanding of the mechanisms of protection, virological control and immune deterioration is required; without this knowledge, an efficacious therapeutic vaccine will remain elusive.
Human vaccines & immunotherapeutics. 05/2012; 8(5):569-81.
[Show abstract][Hide abstract] ABSTRACT: Changes in natural killer (NK) cells according to their phenotype and expression of certain regulatory receptors were analyzed in a double-blind, controlled study of antiretroviral therapy (ART)-untreated HIV-seropositive patients, who had been vaccinated with monocyte-derived dendritic cells pulsed with inactivated HIV-1 autologous virus. This work extends other recently published studies of the same group of HIV-1(+) vaccinated patients, which demonstrated that the viral load significantly decreases and correlates inversely with an increase in HIV-specific T-cell responses in vaccinated patients, but not in controls who received placebo. Our results indicate that this vaccine raises the level of the NK CD56(neg) cell subpopulation, while levels of the NK CD56(dim) and NK CD56(bright) cells expressing the inhibitory receptor CD85j/ILT-2 fell in vaccinated patients. Taken together, these results suggest that this vaccine might enhance innate immunity by amplifying the inflammatory and cytolytic capacity.
[Show abstract][Hide abstract] ABSTRACT: Background: Patients with a discordant response to cART, defined as persistent CD4 + T-cell counts <200 cells/mm(3) and lack CD4 increase despite virologic suppression on HAART, have an increased risk of morbidity and mortality. Several studies have suggested a potential benefit of intensification with maraviroc (MVC) on CD4+T-cell recovery. Methods: A 24-week prospective, open-label, randomized, controlled study. Subjects on cART, plasma HIV RNA <37 copies/mL for at least 12 months, and CD4 < 200 cells/L, with CD4-gain in the previous 12 months <50 cells/µL, were randomized to add MVC (A) or continuing same cART (B). Randomisation was stratified by the presence of liver cirrhosis (CH) (n = 10) and non-CH (n = 28). We measured by flow cytometry changes in the following parameters of CD4 + and CD8 + T-cell subsets: activation (CD38, HLA-DR), senescence (CD28, CD57, CD45RA and RO), coreceptors (CCR5 and CXCR4) and apoptosis (Annexin-V). Results: Thirty-eight subjects were included at the final analysis. Median values were: age 51 years (IQR, 44-57), time with VL < 37 copies/mL before entry 43 months (IQR 24-62 months), baseline CD4 + T-cell count 144 cells/µL (IQR 106-181). Four subjects were lost of follow-up (3 in A, 1 in B). One subject from group B experienced confirmed virologic failure at week 24. Adverse events were similar in both arms. Median increase in CD4 + T-cell count from baseline to weeks 2,4 and 24 in both groups were +15.5 vs -1 (p = 0.025); +16.5 vs -2.5 (p = 0.158); +46.5 vs + 6.50 (p = 0.190). Similar trend towards a higher CD4 increase were seen in both CH and non-CH individuals. At W24, 8 subjects from arm A vs 1 subject from arm B achieved a CD4 + T-cell count above 200 cells/µL (p < 0.05). Markers of immune activation (CD38 and HLA-DR) decreased during MVC intensification, especially in CD8+ T cells (p < 0.01) whereas apoptosis did not. Additionally CCR5 expression tended to increase (p = 0.051) in CD8 T cells from arm A subjects. No significant differences were found in the immunological assay between cirrhotic and non cirrhotic individuals. Conclusions: MVC intensification was safe and was associated with a significant a trend towards increasing CD4 + T-cell counts both in cirrhotic as well as non-cirrhotic patients with discordant response. The addition of MVC was associated with a decrease in markers of immune activation in both groups.
Journal of the International AIDS Society 01/2012; 15(6):18384. · 3.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: The generation of new immunogens able to elicit strong specific immune responses remains a major challenge in the attempts to obtain a prophylactic or therapeutic vaccine against HIV/AIDS. We designed and constructed a defective recombinant virus based on the HIV-1 genome generating infective but non-replicative virions able to elicit broad and strong cellular immune responses in HIV-1 seropositive individuals. RESULTS: Viral particles were generated through transient transfection in producer cells (293-T) of a full length HIV-1 DNA carrying a deletion of 892 base pairs (bp) in the pol gene encompassing the sequence that codes for the reverse transcriptase (NL4-3/ΔRT clone). The viral particles generated were able to enter target cells, but due to the absence of reverse transcriptase no replication was detected. The immunogenic capacity of these particles was assessed by ELISPOT to determine γ-interferon production in a cohort of 69 chronic asymptomatic HIV-1 seropositive individuals. Surprisingly, defective particles produced from NL4-3/ΔRT triggered stronger cellular responses than wild-type HIV-1 viruses inactivated with Aldrithiol-2 (AT-2) and in a larger proportion of individuals (55% versus 23% seropositive individuals tested). Electron microscopy showed that NL4-3/ΔRT virions display immature morphology. Interestingly, wild-type viruses treated with Amprenavir (APV) to induce defective core maturation also induced stronger responses than the same viral particles generated in the absence of protease inhibitors. CONCLUSIONS: We propose that immature HIV-1 virions generated from NL4-3/ΔRT viral clones may represent new prototypes of immunogens with a safer profile and stronger capacity to induce cellular immune responses than wild-type inactivated viral particles.
PLoS ONE 01/2012; 7(11):e48848. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the safety and immunogenicity of a modified vaccinia virus Ankara vector expressing HIV-1 antigens from clade B (MVA-B), a phase-I, doubled-blind placebo-controlled trial was performed.
30 HIV-uninfected volunteers at low risk of HIV-1 infection were randomly allocated to receive 3 intramuscular injections (1×10(8)pfu/dose) of MVA-B (n=24) or placebo (n=6) at weeks 0, 4 and 16. All volunteers were followed 48 weeks. Primary end-points were adverse events and immunogenicity.
A total of 169 adverse events were reported, 164 of grade 1-2, and 5 of grade 3 (none related to vaccination). Overall 75% of the volunteers showed positive ELISPOT responses at any time point. The magnitude (median) of the total responses induced was 288SFC/10(6)PBMC at week 18. Antibody responses against Env were observed in 95% and 72% of vaccinees at week 18 and 48, respectively. HIV-1 neutralizing antibodies were detected in 33% of volunteers.
MVA-B was safe, well tolerated and elicited strong and durable T-cell and antibody responses in 75% and 95% of volunteers, respectively. These data support further exploration of MVA-B as an HIV-1 vaccine candidate. Clinical Trials.gov identifier: NCT00679497.
[Show abstract][Hide abstract] ABSTRACT: Attenuated poxvirus vectors expressing human immunodeficiency virus type 1 (HIV-1) antigens are considered promising HIV/AIDS vaccine candidates. Here, we describe the nature of T cell immune responses induced in healthy volunteers participating in a phase I clinical trial in Spain after intramuscular administration of three doses of the recombinant MVA-B-expressing monomeric gp120 and the fused Gag-Pol-Nef (GPN) polyprotein of clade B. The majority (92.3%) of the volunteers immunized had a positive specific T cell response at any time postvaccination as detected by gamma interferon (IFN-γ) intracellular cytokine staining (ICS) assay. The CD4(+) T cell responses were predominantly Env directed, whereas the CD8(+) T cell responses were similarly distributed against Env, Gag, and GPN. The proportion of responders after two doses of MVA-B was similar to that obtained after the third dose of MVA-B vaccination, and the responses were sustained (84.6% at week 48). Vaccine-induced CD8(+) T cells to HIV-1 antigens after 1 year were polyfunctional and distributed mainly within the effector memory (TEM) and terminally differentiated effector memory (TEMRA) T cell populations. Antivector T cell responses were mostly induced by CD8(+) T cells, highly polyfunctional, and of TEMRA phenotype. These findings demonstrate that the poxvirus MVA-B vaccine candidate given alone is highly immunogenic, inducing broad, polyfunctional, and long-lasting CD4 and CD8 T cell responses to HIV-1 antigens, with preference for TEM. Thus, on the basis of the immune profile of MVA-B in humans, this immunogen can be considered a promising HIV/AIDS vaccine candidate.
Journal of Virology 08/2011; 85(21):11468-78. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Infection with HIV-1 frequently results in the loss of specific cellular immune responses and an associated lack of antibodies. Recombinant growth hormone (rGH) administration reconstitutes thymic tissue and boosts the levels of peripheral T cells, so rGH therapy may be an effective adjuvant through promoting the recovery of lost cellular and T-cell-dependent humoral immune responses in immunosuppressed individuals. To test this concept, we administered rGH to a clinically defined group of HIV-1-infected subjects with defective cellular and serological immune responses to at least one of three commonly employed vaccines (hepatitis A, hepatitis B or tetanus toxoid). Of the original 278 HIV-1-infected patients entering the trial, only 20 conformed to these immunological criteria and were randomized into three groups: Group A (n = 8) receiving rGH and challenged with the same vaccine to which they were unresponsive and Groups B (n = 5) and C (n = 7) who received either rGH or vaccination alone, respectively. Of the eight subjects in Group A, five recovered CD4 cellular responses to vaccine antigen and four of these produced the corresponding antibodies. In the controls, three of the five in group B recovered cellular responses with two producing antibodies, whereas three of the seven in Group C recovered CD4 responses, with only two producing antibodies. Significantly, whereas seven of ten patients receiving rGH treatment in Group A (six patients) and B (one patient) recovered T-cell responses to HIVp24, only two of six in Group C responded similarly. In conclusion, reconstitution of the thymus in immunosuppressed adults through rGH hormone treatment restored both specific antibody and CD4 T-cell responses.
[Show abstract][Hide abstract] ABSTRACT: There is increasing interest in the role of immune activation and inflammation in HIV disease, but data on direct effects of HIV replication on immune cell activation are limited.
High sensitivity multiplex bead array assays (MBAAs) were used to measure changes in plasma cytokines and chemokines [interleukin (IL)-1β, IL-2, IL-6, IL-7, IL-8, IL-12p70, IL-17, tumor necrosis factor-α (TNFα), interferon-γ, granulocyte macrophage colony-stimulating factor, IL-4, IL-5, IL-10, IL-13, CXCL10] from randomization (month 0) to month 2 in a random sample of 200 patients from both the drug conservation (DC) and viral suppression (VS) arms of the Strategies for Management of Antiretroviral Therapy (SMART) trial. IL-6 was also measured by ELISA. Data were evaluated using nonparametric correlation and censored parametric analysis of covariance and associations were declared as statistically significant when the Bonferroni-adjusted P-value was less than 0.003.
Compared with the VS arm, significant increases were seen in the DC arm for TNFα (+0.34 log(e) pg/ml, P = 0.0001), IL-10 (+0.33 log(e) pg/ml, P = 0.00001) and CXCL10 (+0.66 log(e) pg/ml, P = 0.00001). IL-6 ELISA poorly correlated with IL-6 MBAA (Spearman's rho = 0.29, P = 0.0001).
Resumption of HIV replication after ceasing antiretroviral therapy is associated predominantly with an increase of monocyte/macrophage-derived cytokines. Measurement of IL-6 levels may be affected by assay method and this should be considered in future studies of biomarkers.
AIDS (London, England) 06/2011; 25(9):1207-17. · 4.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is unknown whether a Toxoplasma gondii-specific T cell response is restored after successful combined antiretroviral therapy (cART) in patients with AIDS and current or previous toxoplasmic encephalitis (TE).
We performed a multicenter cross-sectional study with 17 healthy T. gondii-positive human immunodeficiency virus (HIV)-1-uninfected individuals and 90 patients coinfected with HIV-1 and T. gondii distributed in 5 groups according to their CD4(+) T cell counts and T. gondii infection (with or without current or previous TE). We investigated the lymphocyte proliferative response (LPR) and interferon (IFN)-γ production in response to T. gondii soluble antigen extract (SATg) and as CD4(+) and CD8(+) T cell subsets.
SATg-specific LPR and IFN-γ production were not observed in many of the most immunosuppressed patients (CD4(+) T cell count, <200 cells/μL, with or without current or previous TE). By contrast, these responses occurred in a considerable percentage (LPR, 43%; IFN-γ production, 80%) of patients receiving successful cART (CD4(+) T cell count, >200 cells/μL) who presented with TE and had already stopped secondary TE prophylaxis. Similar results were found in immunocompetent asymptomatic patients who did not receive TE prophylaxis. The predictors of SATg-specific T cell responses and IFN-γ production were a cART-mediated increase in CD4(+) T cell count and LPR to phytohemagglutinin and viral suppression and a decrease in the activated (CD38(+)) CD8(+) T cell count, respectively.
cART restores T. gondii-specific CD4 T cell responses in most patients with AIDS who had previous TE. Our data support the safety of withdrawing TE prophylaxis when the CD4(+) T cell count returns to levels >200 cells/μL.