Summary
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.
Background HIV-1 infection increases plasma levels of inflammatory markers. Combination antiretroviral therapy (cART) does not restore inflammatory markers to normal levels. Since intensification of ...cART with raltegravir reduced CD8 T-cell activation in the Discor-Ral and IntegRal studies, we have evaluated the effect of raltegravir intensification on several soluble inflammation markers in these studies. Methods Longitudinal plasma samples (0-48 weeks) from the IntegRal (n = 67, 22 control and 45 intensified individuals) and the Discor-Ral studies (44 individuals with CD4 T-cell counts<350 cells/ mu l, 14 control and 30 intensified) were assayed for 25 markers. Mann-Whitney, Wilcoxon, Spearman test and linear mixed models were used for analysis. Results At baseline, different inflammatory markers were strongly associated with HCV co-infection, lower CD4 counts and with cART regimens (being higher in PI-treated individuals), but poorly correlated with detection of markers of residual viral replication. Although raltegravir intensification reduced inflammation in individuals with lower CD4 T-cell counts, no effect of intensification was observed on plasma markers of inflammation in a global analysis. An association was found, however, between reductions in immune activation and plasma levels of the coagulation marker D-dimer, which exclusively decreased in intensified patients on protease inhibitor (PI)-based cART regimens (P = 0.040). Conclusions The inflammatory profile in treated HIV-infected individuals showed a complex association with HCV co-infection, the levels of CD4 T cells and the cART regimen. Raltegravir intensification specifically reduced D-dimer levels in PI-treated patients, highlighting the link between cART composition and residual viral replication; however, raltegravir had little effect on other inflammatory markers.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND:The failure to increase CD4 T-cell counts in some ART-suppressed subjects (immunodiscordance) has been related to perturbed CD4 T-cell homeostasis and impacts clinical evolution.
...METHODS:We evaluated different definitions of immunodiscordance based on CD4 T-cell counts (cutoff) or CD4 T-cell increases from nadir value (ΔCD4) using supervised random forest classification of 74 immunological and clinical variables from 196 ART-suppressed individuals. Unsupervised clustering was performed using relevant variables identified in the supervised approach from 191 individuals.
RESULTS:Cutoff definition of 400 CD4 cells/μL performed better than any other definition in segregating immunoconcordant and immunodiscordant individuals (85% accuracy), using markers of activation, nadir and death of CD4 T-cells. Unsupervised clustering of relevant variables using this definition revealed large heterogeneity between immunodiscordant individuals and segregated subjects into three distinct subgroups with distinct production, PD-1 expression, activation and death of T-cells. Surprisingly, a non-negligible number of immunodiscordant subjects (22%) showed high frequency of recent thymic emigrants and low CD4 T-cell activation and death, very similar to immunoconcordant subjects. Notably, HLA-DR, PD-1 and CD45RA expression in CD4 T-cells allowed reproducing subgroup segregation (81.4% accuracy). Despite sharp immunological differences, similar and persistently low CD4 values were maintained in these subjects overtime.
CONCLUSIONS:A cutoff value of 400 CD4 T cells/μl classified better immunodiscordant and immunoconcordant individuals than any ΔCD4 classification. Immunodiscordance may present several, even opposite, immunological patterns that are identified by a simple immunological follow-up. Subgroup classification may help clinicians to delineate diverse approaches that may be needed to boost CD4 T-cell recovery.
We evaluated the effect of different doses of pegylated interferon (PEG-IFN)-alpha2a/ribavirin (RBV) on several T-cell activation markers in HIV-HCV-coinfected patients and their relationship with ...changes in plasma HCV RNA.
Frozen peripheral blood mononuclear cells (PBMCs) from 22 patients receiving two different PEG-IFN-alpha2a schedules were analysed by six-colour flow cytometry. Cell-surface expression of CD38 was quantified. HIV and HCV viral loads, as well as absolute CD4+ and CD8+ T-cell counts, were recorded during the follow up (72 weeks).
PEG-IFN-alpha2a/RBV treatment decreased the absolute numbers of CD8+ and CD4+ T-cells. The decrease in CD8+ T-cells was more pronounced, resulting in increased percentages of CD4+ T-cells. Percentages of naive/memory CD4+ T-cell subsets remained unchanged, although the percentage of CD38+CD45RO+ cells significantly increased. By contrast, the CD8+ T-cell compartment significantly reduced the percentage of CD45RO+ cells and HLA-DR+ cells, whereas the percentage of CD38 expressing cells was increased because of a significant increase in cell-surface CD38 expression. Changes in CD8+ T-cells were similar for both PEG-IFN-alpha2a/RBV doses, but high doses induced more severe perturbations in CD4+ T-cells. All changes returned to baseline levels after treatment cessation and, except for the loss of naive CD4+ T-cells, were not associated with virological response.
Transient lymphopaenia induced by PEG-IFN-alpha2a/RBV differentially affects T-cell subsets. Activated HLA-DR+ and CD45RO+ cells were selectively reduced in peripheral blood, whereas CD38 expression was up-regulated mainly in memory cells. Increasing PEG-IFN-alpha2a/RBV doses mainly affect CD4+ T-cells but failed to modify clinical outcome.
BACKGROUNDSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfections have been reported; however, most cases are milder than the primary infection. We report the first case of a ...life-threatening critical presentation of a SARS-CoV-2 reinfection.METHODSA 62-year-old man from Palamós (Spain) suffered a first mild coronavirus disease 2019 (COVID-19) episode in March 2020, confirmed by 2 independent SARS-CoV-2 nasopharyngeal polymerase chain reaction (PCR) assays and a normal radiograph. He recovered completely and tested negative on 2 consecutive PCRs. In August 2020, the patient developed a second SARS-CoV-2 infection with life-threatening bilateral pneumonia and Acute respiratory distress syndrome criteria, requiring COVID-19-specific treatment (remdesivir + dexamethasone) plus high-flow oxygen therapy. Nasopharyngeal swabs from the second episode were obtained for virus quantification by real-time PCR, for virus outgrowth and sequencing. In addition, plasma and peripheral blood mononuclear cells during the hospitalization period were used to determine SARS-CoV-2-specific humoral and T-cell responses.RESULTSGenomic analysis of SARS-CoV-2 showed that the virus had probably originated shortly before symptom onset. When the reinfection occurred, the subject showed a weak immune response, with marginal humoral and specific T-cell responses against SARS-CoV-2. All antibody isotypes tested as well as SARS-CoV-2 neutralizing antibodies increased sharply after day 8 postsymptoms. A slight increase of T-cell responses was observed at day 19 after symptom onset.CONCLUSIONSThe reinfection was firmly documented and occurred in the absence of robust preexisting humoral and cellular immunity. SARS-CoV-2 immunity in some subjects is unprotective and/or short-lived; therefore, SARS-CoV-2 vaccine schedules inducing long-term immunity will be required to bring the pandemic under control.
La infecció pel virus de la immunodeficiència humana (VIH) provoca una deficiència progressiva del sistema immunològic, caracteritzada per una destrucció massiva de les cèl•lules T CD4 i, una ...activació i inflamació immune mantinguda. La Teràpia Antiretroviral de Gran Activitat (o TARGA) indueix una supressió sostinguda de la replicació viral en individus infectats pel VIH, i una reducció de l’activació immune, encara que no es normalitza comparat amb individus no-infectats. Les causes d’aquesta activació immune persistent malgrat la supressió viral són encara desconegudes. Els nostres resultats demostren una dicotomia en les forces que indueixen l’activació immune en els limfòcits T CD4 i CD8 en individus suprimits per la TARGA. La replicació residual del VIH indueix l’activació immune en les cèl•lules T CD8. Per aquest motiu, la intensificació de la TARGA amb raltegravir produeix una reducció específica però reversible de l’activació de les cèl•lules CD8; i per tant, aquestes cèl•lules semblen ser sensors de la replicació viral (en particular l’expressió de CD38). Curiosament, l’expressió de CD38 està sota el control dels interferons de tipus I, el que suggereix que el virus també controla altres respostes inflamatòries, i que aquestes respostes estan íntimament lligades als marcadors d’activació de les cèl•lules T CD8. Contràriament, en individus tractats, la persistència viral té pocs efectes en el compartiment de cèl•lules T CD4, que encara pateix les conseqüències de la depleció pre-TARGA i que determina la recuperació immune. De fet, l’activació de cèl•lules CD4 no es redueix després d’un any de intensificació amb raltegravir. En canvi, la resposta homeostàtica a la depleció de cèl•lules CD4 sembla induir l’activació en aquest compartiment, especialment en pacients tractats que presenten una resposta immunològica deficient malgrat una supressió viral completa (pacients immunodiscordants). Els nostres resultats demostren que els pacients immnodiscordant tenen un menor producció de novo de cèl•lules T CD4, i una major translocació microbiana, activació i mort cel•lular comparat amb pacients amb una bona recuperació immune; malgrat aquestes diferències la immunodiscordància sembla està associada a l’increment de la destrucció cel•lular. L’activació i inflamació persistent en aquests individus procura un ambient que accelera la l’esgotament de les cèl•lules T CD4 i la immunosenescència de la resta del sistema immunològic, contribuint a llarg termini amb les co-morbiditats i l’envelliment prematur. Per aquest motiu, és important determinar les causes de l’activació immune incrementada (i mort cel•lular), per definir les estratègies terapèutiques que poden ser útils per millorar la recuperació immune.
Human immunodeficiency virus (HIV-‐1) infection causes a progressive impairment of the immune system, characterized by a massive CD4 T-‐cell depletion and sustained immune activation and inflammation. Highly active antiretroviral therapy (HAART) induces a sustained effective suppression of viral replication in HIV-‐infected subjects and reduces immune activation, but does not normalize it. The causes of this persistent immunehyperactivation despite viral suppression remain unknown. Our results show a dichotomy between CD4 and CD8 T-‐cell driving forces of immune activation in HIV-‐infected HAART-‐suppressed individuals. The low (but detectable) levels of residual replication drive immune activation in CD8 T-‐cell compartment. Therefore, raltegravir intensification of HAART results in specific and reversible reduction of CD8 T-‐cell activation, which seems to be a sensor of replication events (in particular CD38 expression). Interestingly, CD38 expression is under the control of Type I IFN, suggesting that the virus also controls inflammatory responses and that these responses are intimately linked to CD8 T-‐cell activation markers. Conversely, in treated individuals, viral persitence has low effects on CD4 T-‐cell compartment, which still show the consequences of pre-‐HAART depletion and determine immune recovery. In fact, CD4 T-‐cell activation is not reduced after one year of raltegravir intensification. Instead, the homeostatic response to CD4 T-‐cell depletion might drive activation in this compartment, particularly in HAART-‐treated individuals with satisfactory virological response but poor immune recovery (immunodiscordant subjects). Our results suggest that, even though immunodiscordant individuals showed lower CD4 T-‐cell production and higher microbial translocation, activation and cell death, immunodiscordance seems to be related to increased cell-‐destruction of CD4 T-‐cells. The persistent immune activation and inflammation in these subjects provide a milieu of accelerated immunoexhaustion of CD4 T-‐cells and immunosenescence of the whole immune system, contributing to long-‐term co-‐morbidities and accelerated ageing observed in these subjects. Therefore, determining the causes of this increased hyperactivation and cell-‐death may be important for the development of therapeutic strategies aiming to improve immune recovery.
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