RESUMO
UNLABELLED: HIV establishes reservoirs of infected cells that persist despite effective antiretroviral therapy (ART). In most patients, the virus begins to replicate soon after treatment interruption. However, a low frequency of infected cells at the time of treatment interruption has been associated with delayed viral rebound. Likewise, individuals who control the infection spontaneously, so-called HIV-1 controllers (HICs), carry particularly low levels of infected cells. It is unclear, however, whether and how this small number of infected cells contributes to durable viral control. Here we compared 38 HICs with 12 patients on effective combined antiretroviral therapy (cART) and found that the low frequency of infected cells in the former subjects was associated both with less efficient viral reactivation in resting CD4(+) T cells and with less efficient virion production ex vivo We also found that a potent HIV-specific CD8(+) T cell response was present only in those HICs whose CD4(+) T cells produced virus ex vivo Long-term spontaneous control of HIV infection in HICs thus appears to be sustained on the basis of the inefficient reactivation of viruses from a limited number of infected cells and the capacity of HICs to activate a potent HIV-specific CD8(+) T cell response to counteract efficient viral reactivation events. IMPORTANCE: There is a strong scientific interest in developing strategies to eradicate the HIV-1 reservoir. Very rare HIV-1-infected patients are able to spontaneously control viremia for long periods of time (HIV-1 controllers [HICs]) and are put forward as a model of HIV-1 remission. Here, we show that the low viral reservoirs found in HICs are a critical part of the mechanisms underlying viral control and result in a lower probability of HIV-1 reactivation events, resulting in limited HIV-1 release and spread. We found that those HICs in whom viral reactivation and spread from CD4(+) T cells in vitro were the most difficult were those with diminished CD8(+) T cell responses. These results suggest that, in some settings, low HIV-1 reservoirs decisively contribute to at least the temporary control of infection without antiretroviral therapy. We believe that this work provides information of relevance in the context of the search for HIV-1 remission.
Assuntos
Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/virologia , HIV-1/fisiologia , Ativação Viral , Adulto , Idoso , Fármacos Anti-HIV/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1/crescimento & desenvolvimento , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Latência Viral , Replicação ViralRESUMO
Some HIV controllers (HICs) experience CD4+T cell count loss and/or lose their ability to control HIV. In this study, we investigated the rate of immunologic and/or virologic progression (ImmP/VirP) and its determinants in the ANRS CO21/CODEX cohort. Immunologic progression was defined as a lasting fall in CD4+T cell count below 350/mm(3) or more than 200/mm(3) with a baseline count below 600/mm(3). Virologic progression was defined as a HIV viral load (VL) above 2000 copies/mL on two consecutive determinations. Clinical characteristics, immune activation, ultrasensitive HIV VL and total HIV DNA were analyzed. Disease progression was observed in 15 of the 217 patients followed up between 2009 and 2013 (ImmP, n = 10; VirP, n = 5). Progressors had higher ultrasensitive HIV RNA levels at inclusion (i.e. 1-2 years before progression) than non-progressors. ImmP had also lower CD4+T cell nadir and CD4+T cell count at inclusion, and VirP had higher HIV DNA levels in blood. T cell activation and IP10 levels at inclusion were significantly higher in ImmP than in non-progressors. In summary, the lasting loss of CD4+T cells, residual HIV replication and basal levels of immune activation appear to be major determinants of progression in HICs. These factors should be considered for adjusting their follow-up.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , Sobreviventes de Longo Prazo ao HIV , Ativação Linfocitária/imunologia , Carga Viral/imunologia , Adulto , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Progressão da Doença , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
The soluble CD14 (sCD14) level was found associated with mortality during the chronic phase of human immunodeficiency virus (HIV) infection. Here we assessed its prognostic value in 138 patients with primary HIV infection. Higher sCD14 levels were associated with death, from myocardial infarction, but this was based on 3 deaths only. Among 68 untreated patients, those with higher sCD14 levels had more rapid spontaneous CD4 cell decline during the first 18 months following primary infection. This association persisted after adjustment for age, the CD4 cell count, and HIV viral load at diagnosis.
Assuntos
Progressão da Doença , Infecções por HIV/mortalidade , HIV-1 , Receptores de Lipopolissacarídeos/sangue , Adulto , Idoso , Antirretrovirais/uso terapêutico , Biomarcadores/sangue , Contagem de Linfócito CD4 , Estudos de Coortes , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Masculino , Carga ViralRESUMO
BACKGROUND: Early combination antiretroviral therapy (cART) initiation at the time of primary HIV-1 infection could restrict the establishment of HIV reservoirs. We aimed to assess the effect of a cART regimen intensified with raltegravir and maraviroc, compared with standard triple-drug cART, on HIV-DNA load. METHODS: In this randomised, open-label, phase 3 trial, we recruited patients from hospitals across France. Inclusion criteria were primary HIV-1 infection (an incomplete HIV-1 western blot and detectable plasma HIV-RNA), with either symptoms or a CD4+ cell count below 500 cells per µL. Patients were randomly assigned (1:1) to an intensive, five-drug cART regimen (raltegravir 400 mg and maraviroc 150 mg twice daily, and a fixed-dose combination of tenofovir disoproxil fumarate 300 g plus emtricitabine 200 g, darunavir 800 g, and ritonavir 100 g once daily) or a standard triple-drug cART regimen (tenofovir disoproxil fumarate 300 g plus emtricitabine 200 g, darunavir 800 g, and ritonavir 100 g once daily) using a predefined randomised list generated by randomly selected variable block sizes. The primary endpoint was the median number of HIV-DNA copies per 10(6) peripheral blood mononuclear cells (PBMC) at month 24, analysed in the modified intention-to-treat population, defined as all patients who started their assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01033760. FINDINGS: Between April 26, 2010, and July 13, 2011, 110 patients were enrolled, of whom 92 were randomly assigned and 90 started treatment (45 in each treatment group). Six (13%) patients in the intensive cART group and two (4%) in the standard cART group discontinued before month 24. At month 24, HIV-DNA loads were similar between groups (2·35 [IQR 2·05-2·50] log10 per 10(6) PBMC in the intensive cART group vs 2·25 [1·71-2·55] in the standard cART group; p=0·21). Eight grade 3-4 clinical adverse events were reported in seven patients in the intensive cART group and seven grade 3-4 clinical adverse events were reported in seven patients in the standard cART group. Three serious clinical adverse events occurred: two (pancreatitis and lipodystrophy) in the standard cART group, which were regarded as treatment related, and one event (suicide attempt) in the intensive cART group that was unrelated to treatment. INTERPRETATION: After 24 months, cART intensified with raltegravir and maraviroc did not have a greater effect on HIV blood reservoirs than did standard cART. These results should help to design future trials of treatments aiming to decrease the HIV reservoir in patients with primary HIV-1 infection. FUNDING: Inserm-ANRS, Gilead Sciences, Janssen Pharmaceuticals, Merck, and ViiV Laboratories.
Assuntos
Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Adulto , Feminino , França , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Humanos , Leucócitos Mononucleares/virologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Carga ViralRESUMO
During HIV infection, increased CD57 expression among CD8(+) T cells has been associated with immune senescence and defective immune responses. Interestingly, CD57-expressing CD8(+) T cells exhibit a dual profile, being simultaneously highly cytotoxic (terminally differentiated effectors) and poorly proliferative (replicative senescent). Recent publications point toward a positive role of CD57-expressing CD8(+) T cell subsets, presumably due to their high cytolytic activity. We further investigated the phenotype of CD57-expressing CD8(+) T cells in healthy donors and during HIV infection combining CD57 expression to Eomesodermin (EOMES), a T box transcription factor which determines, coordinately with T-bet, effector and memory CD8(+) T cell differentiation. We defined in healthy donors two functionally distinct CD57-expressing CD8(+) T cell subsets exhibiting different levels of EOMES expression: EOMES(hi) CD57(+) and EOMES(int) CD57(+) CD8(+) T cells. EOMES(hi) CD57(+) cells exhibited low cytotoxic activity but preserved proliferative capacity and interleukin 7 (IL-7) receptor expression, whereas EOMES(int) CD57(+) cells exhibited obvious cytotoxic functions and a more terminally differentiated phenotype. We next performed a similar analysis in different contexts of HIV infection: primary infected patients, long-term viremic patients, aviremic patients treated with antiretroviral therapy, and HIV controllers; we demonstrated a higher percentage of CD57-expressing cells in all HIV-infected patients regardless of virological status. When heterogeneity in EOMES expression among CD57 cells was taken into account, we detected significantly higher proportions of EOMES(hi) CD57(+) cells among HIV-specific and nonspecific CD8(+) T cells from HIV controllers than in aviremic antiretroviral-treated patients and viremic patients. Importantly, such a peculiar non-terminally differentiated EOMES(hi) CD57(+) phenotypic profile was associated with viral control. Importance: This study demonstrates that functional heterogeneity exists among CD57-expressing CD8 T cells, which include both terminally differentiated, highly cytotoxic EOMES(int) CD57(+) CD8(+) T cells and less differentiated EOMES(hi) CD57(+) CD8 T cells, which do not exhibit immediate cytotoxic functions but present high proliferative capacity. Interestingly, HIV controllers present a high proportion of EOMES(hi) CD57 cells among CD57-expressing HIV-specific CD8 T cells compared to both long-term viremic and aviremic antiretroviral therapy (ART)-treated patients, suggesting a beneficial role for this cell subset in viral control.
Assuntos
Antígenos CD57/imunologia , Linfócitos T CD8-Positivos/virologia , Infecções por HIV/virologia , Proteínas com Domínio T/metabolismo , Adulto , Infecções por HIV/imunologia , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: HIV controllers (HIC) are rare HIV-1-infected patients who exhibit spontaneous viral control. HIC have high frequency of CD38-/HLA-DR+ HIV-specific CD8+ T cells. Here we examined the role of this subset in HIC status. MATERIALS AND METHODS: We compared CD38-/HLA-DR+ CD8+ T cells with the classical CD38+/HLA-DR+ activated phenotype in terms of 1) their activation status, reflected by CD69, CD25, CD71, CD40 and Ki67 expression, 2) functional parameters: Bcl-2 expression, proliferative capacity, and IFN-γ and IL-2 production, and 3) cytotoxic activity. We also investigated how this particular profile is generated. RESULTS: Compared to CD38+/HLA-DR+ cells, CD38-/HLA-DR+ cells exhibited lower expression of several activation markers, better survival capacity (Bcl-2 MFI, 367 [134-462] vs 638 [307-747], Pâ=â0.001), higher frequency of polyfunctional cells (15% [7%-33%] vs 21% [16%-43%], Pâ=â0.0003), greater proliferative capacity (0-fold [0-2] vs 3-fold [2]-[11], Pâ=â0.007), and higher cytotoxicity in vitro (7% [3%-11%] vs 13% [6%-22%], Pâ=â0.02). The CD38-/HLA-DR+ profile was preferentially generated in response to low viral antigen concentrations. CONCLUSIONS: These data highlight the role of CD38-/HLA-DR+ HIV-specific CD8+ T cell cytotoxicity in HIC status and provide insights into the mechanism by which they are generated. Induction of this protective CD8+ subset may be important for vaccine strategies.
Assuntos
ADP-Ribosil Ciclase 1/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Antígenos HLA-DR/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto , Antígenos CD/imunologia , Estudos de Casos e Controles , Células Cultivadas , Feminino , Citometria de Fluxo , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Humanos , Imunofenotipagem , Ativação Linfocitária , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Although HIV controllers (HICs) achieve long-term control of viremia in the absence of antiretroviral therapy (ART), they display marked immune activation. The levels of inflammatory biomarkers in HICs and the biomarkers' relationships with immunologic and virologic status have yet to be fully characterized. DESIGN: A cohort study. METHODS: Plasma levels of seven biomarkers [tumor necrosis factor (TNF)α, interleukin (IL)6, IL10, interferon gamma-induced protein 10 (IP10), monocyte chemoattractant protein-1 (MCP1), soluble CD14 (sCD14), soluble CD163 (sCD163)] were compared in 70 HICs, 33 HIV-1-infected, treatment-naive noncontrollers (viremic patients), 30 ART-treated patients and 40 healthy donors. In HICs, we investigated the interplay between biomarkers, cell activation and the CD4⺠T-cell count. RESULTS: HICs had higher levels of IP10, TNFα and sCD14 than healthy donors did (P < 0.01 for each). Also, TNFα and sCD14 levels of the HICs were similar to those measured in viremic and ART-treated patients. However, the levels of IL6 and IL10 were significantly lower in HICs than in viremic or ART-treated patients. In HICs, only IP10 levels differed significantly from those in both healthy donors and viremic patients, and were positively correlated with the expression of CD8⺠and CD4⺠T-cell activation markers. The IP10 levels of HICs were still elevated 12 and 24 months after the initial assay. Lastly, IP10 levels at enrollment were negatively correlated with the CD4⺠T-cell count at enrollment and 12 months later. CONCLUSION: HICs display a number of inflammatory features associated with persistent T-cell immune activation.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Quimiocina CXCL10/sangue , Citocinas/sangue , Infecções por HIV/imunologia , Infecções por HIV/patologia , Sobreviventes de Longo Prazo ao HIV , Ativação Linfocitária , Adulto , Biomarcadores/sangue , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
CD8(+) T cell responses are thought to play an important role during HIV infection, particularly in HIV controllers (HIC) in whom viral replication is spontaneously controlled without any treatment. We have demonstrated that CD8(+) T cells from these subjects are able to suppress viral replication in vitro. In parallel, HIV-specific CD8(+) responses were shown to be strong and of high quality, with proliferative abilities and cytotoxic capacities, in HIC. The HLA-B*57 allele, which is associated with a better clinical outcome in HIV infection, is overrepresented in HIC. However, we showed that these patients constitute a heterogeneous group that includes subjects who present weak suppression of viral replication in vitro and HIV-specific responses. We performed an extensive study of 101 HIC (49 HLA-B*57(+) and 52 HLA-B*57(-)) to determine the impact of HLA-B*57 on the HIV-specific CD8(+) response. The HLA-B*57-restricted response displayed better qualitative features, such as higher functional avidity, higher proliferation capacity, and a higher level of cytokine production, than responses not restricted by HLA-B*57. However, the highest frequencies of HIV-specific CD8(+) T cells were observed only in a subset of HLA-B*57(+) subjects. They were tightly associated with the ability to suppress viral replication in vitro. In contrast, the subset of HLA-B*57(+) subjects with a weak ability to suppress viral replication had significantly lower ultrasensitive viral loads than all the other groups of controllers. In conclusion, both HLA-B*57 and the amount of ultrasensitive viral load seem to play a role in HIV-specific CD8(+) T cell responses in HIC.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV/genética , Antígenos HLA-B/sangue , RNA Viral/sangue , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , HIV/fisiologia , Infecções por HIV/virologia , Humanos , Masculino , Replicação ViralRESUMO
The role of Antibody-dependent cellular cytotoxicity (ADCC) responses in HIV-1 controllers is still unclear due to the heterogeneity of these patients. We analyzed 67 HIV-1 controllers and found significantly higher levels of ADCC antibodies in controllers versus viremic subjects (p = 0.017). Moreover, multivariate analysis revealed significantly higher ADCC titers in HLA B57- controllers compared to HLA-B57+ ones (p = 0.0086). These data suggest a role for ADCC in immune control of HIV, especially in HLA B57 negative controllers.
Assuntos
Citotoxicidade Celular Dependente de Anticorpos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Sobreviventes de Longo Prazo ao HIV , HIV-1/imunologia , Antígenos HLA-B/imunologia , Adulto , Anticorpos Antivirais/imunologia , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , RNA Viral/imunologia , Viremia/imunologia , Viremia/virologiaRESUMO
OBJECTIVES: HIV-controllers spontaneously maintain HIV viremia at an undetectable level. We aimed to describe the delay to control from seroconversion, the duration of control, and risk factors for losing control. METHODS: HIV-controllers were identified from a pooled dataset of 24 seroconverter cohorts from Europe, Australia, and Canada (CASCADE). HIV-controllers had at least five consecutive viral loads less than 400/500 copies/ml, while antiretroviral therapy naive, for at least 5 years after seroconversion. End of control was defined as two consecutive viral loads above 2000 copies/ml. Duration of control was described using Kaplan-Meier estimates; factors associated with duration of control were identified using a Cox model. CD4⺠cell count evolution during control was described using a mixed model. RESULTS: Of 9896 eligible seroconverters, we identified 140 (1.4%) HIV-controllers, the largest database of HIV-controllers followed from seroconversion. For 64 with viral load measured within 24 months from seroconversion, median delay to control was 16.7 (interquartile range: 7.8-37.9) months. Probability of maintaining control 20 years after seroconversion was 0.74 [95% confidence interval (CI): 0.64-0.85]. Occurrence of blips followed by return to undetectability did not increase the risk of loss of control [hazard ratio: 0.81 (95% CI: 0.10-6.70)]. However, CD4⺠cell loss during control was significantly accelerated in individuals with blips. CONCLUSION: In most individuals, control occurred rapidly after seroconversion; however, more than 3 years were required to achieve control in 25% of HIV-controllers. Control may be sustained even when CD4⺠cell levels are below 500 cells/µl, opening important new perspectives to understand the physiopathology underlying control.
Assuntos
Infecções por HIV/virologia , Soropositividade para HIV/virologia , HIV-1 , Viremia/virologia , Adulto , Austrália , Contagem de Linfócito CD4 , Canadá , Europa (Continente) , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Modelos de Riscos Proporcionais , RNA Viral/sangue , Fatores de Risco , Fatores de Tempo , Carga ViralRESUMO
The expression of certain HLA class I alleles, including HLA-B*27 and HLA-B*57, is associated with better control of human immunodeficiency virus type 1 (HIV-1) infection, but the mechanisms responsible are not fully understood. We sought evidence that pressure from the human restriction factor TRIM5α (hTRIM5α) could contribute to viral control. The hTRIM5α sensitivity of viruses from both HLA-B*57-positive (HLA-B*57(+)) and HLA-B*27(+) patients who spontaneously controlled viral replication, but not viruses from viremic patients expressing these alleles, was significantly greater than that of viruses from patients not expressing these protective HLA-B alleles. Overall, a significant negative correlation between hTRIM5α sensitivity and viral load was observed. In HLA-B*57(+) patients, the T242N mutation in the HLA-B*57-restricted TW10 CD8(+) T lymphocyte (CTL) epitope was strongly associated with hTRIM5α sensitivity. In HLA-B*27(+) controllers, hTRIM5α sensitivity was associated with a significant reduction in emergence of key CTL mutations. In several patients, viral evolution to avoid hTRIM5α sensitivity was observed but could be associated with reduced viral replicative capacity. Thus, in individuals expressing protective HLA-B alleles, the combined pressures exerted by CTL, hTRIM5α, and capsid structural constraints can prevent viral escape both by impeding the selection of necessary resistance/compensatory mutations and forcing the selection of escape mutations that increase hTRIM5α sensitivity or impair viral replicative capacity.
Assuntos
Proteínas de Transporte/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Antígeno HLA-B27/imunologia , Adulto , Fatores de Restrição Antivirais , Feminino , Antígeno HLA-B27/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , Carga ViralRESUMO
The strong CD8+ T-cell-mediated HIV-1-suppressive capacity found in a minority of HIV-infected patients in chronic infection is associated with spontaneous control of viremia. However, it is still unclear whether such capacities were also present earlier in the CD8+ T cells from non controller patients and then lost as a consequence of uncontrolled viral replication. We studied 50 patients with primary HIV-1-infection to determine whether strong CD8+ T-cell-mediated HIV suppression is more often observed at that time. Despite high frequencies of polyfunctional HIV-specific CD8+ T-cells and a strong CD4+ T-helper response, CD8+ T-cells from 48 patients lacked strong HIV-suppressive capacities ex vivo. This indicates that the superior HIV-suppressive capacity of CD8+ T-cells from HIV controllers is not a general characteristic of the HIV-specific CD8+ T cell response in primary HIV infection.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Doença Aguda , Adulto , Linfócitos T CD4-Positivos/citologia , Células Cultivadas , Citocinas/metabolismo , Progressão da Doença , Feminino , HIV-1/fisiologia , Humanos , Interleucina-2/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Carga Viral , Replicação ViralRESUMO
The capacity of the immune system to adapt to rapidly evolving viruses is a primary feature of effective immunity, yet its molecular basis is unclear. Here, we investigated protective HIV-1-specific CD8+ T cell responses directed against the immunodominant p24 Gag-derived epitope KK10 (KRWIILGLNK263-272) presented by human leukocyte antigen (HLA)-B∗2705. We found that cross-reactive CD8+ T cell clonotypes were mobilized to counter the rapid emergence of HIV-1 variants that can directly affect T cell receptor (TCR) recognition. These newly recruited clonotypes expressed TCRs that engaged wild-type and mutant KK10 antigens with similar affinities and almost identical docking modes, thereby accounting for their antiviral efficacy in HLA-B∗2705+ individuals. A protective CD8+ T cell repertoire therefore encompasses the capacity to control TCR-accessible mutations, ultimately driving the development of more complex viral escape variants that disrupt antigen presentation.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Antígeno HLA-B27/imunologia , Sequência de Aminoácidos , Apresentação de Antígeno/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Células Clonais/imunologia , Células Clonais/metabolismo , Células Clonais/virologia , Cristalografia por Raios X , Epitopos de Linfócito T/química , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Proteína do Núcleo p24 do HIV/genética , Proteína do Núcleo p24 do HIV/imunologia , Proteína do Núcleo p24 do HIV/metabolismo , Infecções por HIV/virologia , HIV-1/genética , HIV-1/metabolismo , Antígeno HLA-B27/química , Antígeno HLA-B27/metabolismo , Humanos , Epitopos Imunodominantes/química , Epitopos Imunodominantes/imunologia , Epitopos Imunodominantes/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Ligação Proteica/imunologia , Estrutura Terciária de Proteína , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismoRESUMO
Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naïve T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/prevenção & controle , HIV-1/efeitos dos fármacos , Alelos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Estudos de Coortes , Quimioterapia Combinada , Feminino , Seguimentos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Soropositividade para HIV , HIV-1/fisiologia , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/genética , Carga Viral , Viremia/prevenção & controle , Replicação ViralRESUMO
NKG2D mediates an important costimulatory pathway in CD8 T cells. In HIV infection, the authors found that NKG2D expression on both total CD8 and HIV-specific CD8 T cells was significantly lower in viremic patients than in HIV controllers. Antiretroviral therapy partially restored NKG2D expression on HIV-specific CD8 T cells. The authors observed a negative correlation between the respective expression levels of CD38 and NKG2D on total CD8 and HIV-specific CD8 T cells. The maintenance of NKG2D expression on CD8 T cells in HIV controllers may contribute to better cell function.
Assuntos
Linfócitos T CD8-Positivos/química , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/análise , Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Sobreviventes de Longo Prazo ao HIV , Humanos , Resultado do Tratamento , Viremia/imunologiaRESUMO
T cell activation levels, viral load and CD4(+) T cell counts at early stages of HIV-1 infection are predictive of the rate of progression towards AIDS. We evaluated whether the inflammatory profile during primary HIV-1 infection is predictive of the virological and immunological set-points and of disease progression. We quantified 28 plasma proteins during acute and post-acute HIV-1 infection in individuals with known disease progression profiles. Forty-six untreated patients, enrolled during primary HIV-1 infection, were categorized into rapid progressors, progressors and slow progressors according to their spontaneous progression profile over 42 months of follow-up. Already during primary infection, rapid progressors showed a higher number of increased plasma proteins than progressors or slow progressors. The plasma levels of TGF-ß1 and IL-18 in primary HIV-1 infection were both positively associated with T cell activation level at set-point (6 months after acute infection) and together able to predict 74% of the T cell activation variation at set-point. Plasma IP-10 was positively and negatively associated with, respectively, T cell activation and CD4(+) T cell counts at set-point and capable to predict 30% of the CD4(+) T cell count variation at set-point. Moreover, plasma IP-10 levels during primary infection were predictive of rapid progression. In primary infection, IP-10 was an even better predictor of rapid disease progression than viremia or CD4(+) T cell levels at this time point. The superior predictive capacity of IP-10 was confirmed in an independent group of 88 HIV-1 infected individuals. Altogether, this study shows that the inflammatory profile in primary HIV-1 infection is associated with T cell activation levels and CD4(+) T cell counts at set-point. Plasma IP-10 levels were of strong predictive value for rapid disease progression. The data suggest IP-10 being an earlier marker of disease progression than CD4(+) T cell counts or viremia levels.
Assuntos
Citocinas/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Contagem de Linfócito CD4 , Quimiocina CXCL10/sangue , Quimiocina CXCL10/imunologia , Estudos de Coortes , Citocinas/sangue , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Infecções por HIV/sangue , Infecções por HIV/virologia , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/imunologia , Interleucina-18/sangue , Interleucina-18/imunologia , Masculino , Pessoa de Meia-Idade , Linfócitos T/metabolismo , Fatores de Tempo , Fator de Crescimento Transformador beta1/sangue , Fator de Crescimento Transformador beta1/imunologia , Carga Viral/imunologia , Adulto JovemRESUMO
BACKGROUND: The occurrence of viral control after interruption of an antiretroviral treatment (ART) initiated during primary HIV-1 infection (PHI) is rare and the frequency and predictive factors of such a control are unknown. METHODS: Within the French ANRS PRIMO Cohort, 164 patients interrupted ART initiated during PHI. We compared patients whose viral load (VL) remained undetectable (<50 copies/ml) or low (50-500 copies/ml) 1 year after ART interruption to those who evidenced a rapid viral rebound. RESULTS: After ART interruption, VL remained undetectable for a median time of 4.5 years in 14 patients ('post-ART controllers') and low in another 14 patients for a median time of 1.5 years. Post-ART controllers also maintained higher CD4(+) T-cell counts compared to other patients. Female gender, a high CD4(+) T-cell count and low VL during PHI, and a high CD4(+) T-cell count and low HIV DNA levels at interruption, were associated with post-ART HIV control. Treatment characteristics did not differ between controllers and non-controllers. Post-ART controllers had lower specific CD8(+) T-cell frequencies and CD8(+) T-cell activation on ART and after ART interruption than non-controllers. CONCLUSIONS: Few patients maintain very low VL after interruption of treatment initiated during PHI. Early patient characteristics were the main factors of viral control, although early initiation of ART and the effect of ART on reservoir might contribute to control.
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Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , HIV-1/patogenicidade , Adulto , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Esquema de Medicação , Ensaio de Imunoadsorção Enzimática , Feminino , Anticorpos Anti-HIV/sangue , Infecções por HIV/virologia , Soropositividade para HIV , HIV-1/imunologia , Humanos , Imunidade Celular , Estimativa de Kaplan-Meier , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/virologia , Ativação Linfocitária , Masculino , RNA Viral/sangue , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Viremia/tratamento farmacológico , Viremia/imunologia , Replicação ViralRESUMO
OBJECTIVES: The ANRS-112 INTERPRIM trial assessed whether fixed-cycles of antiretroviral treatment interruption (ART-STI) combined or not with pegylated interferon alpha-2b (peg-IFN) could lower viral load and achieve a healthier immune system in patients diagnosed during primary HIV-1-infection (PHI). DESIGN AND METHODS: Patients were randomized to receive either continuous ART (cART) during 72 weeks, or cART during 36 weeks followed by three ART-STIs, or the same ART-STIs associated with peg-IFN during the first 14 weeks and each interruption (ART-STI-IFN). Treatment was stopped at week 72. Final evaluation was based on plasma HIV-RNA level 6 months after the last treatment interruption. RESULTS: Eighty-seven percent of patients achieved undetectable HIV-RNA at week 32, with no deleterious impact of sequential treatment interruptions (STIs). Viral rebounds during interruptions were lower in the ART-STI-IFN than in the ART-STI group and during the second and third interruptions compared with the first one. However, HIV-RNA levels, CD4 T-cell counts and CD4 T/CD8 T ratios were similar between groups after the 6-month interruption, with a persistent effect on CD4 T cells and total cell-associated HIV-DNA levels. Predictive factors of virological outcome were HIV-RNA and HIV-DNA levels at PHI and HIV-DNA levels at treatment interruption. HIV-specific responses did not differ between strategies and were not associated with outcome. Forty-eight percent of patients experienced treatment resumption during long-term follow-up without difference between groups. CONCLUSION: When initiated during PHI, STIs associated or not with IFN did not result in a different outcome as compared to cART. All regimens showed a high response rate and a sustained immunological benefit after cessation.
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Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/administração & dosagem , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Interferon-alfa/administração & dosagem , Ativação Linfocitária/efeitos dos fármacos , Polietilenoglicóis/administração & dosagem , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/fisiopatologia , Adulto , Fármacos Anti-HIV/farmacologia , Relação CD4-CD8 , DNA Viral/efeitos dos fármacos , Esquema de Medicação , Feminino , Seguimentos , HIV-1/imunologia , Humanos , Interferon alfa-2 , Interferon-alfa/farmacologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/farmacologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Resultado do Tratamento , Carga ViralRESUMO
Regulatory T-cell (Treg) quantification in human immunodeficiency virus (HIV) infection remains ill defined because of the lack of reliable specific markers to identify human Tregs and the diversity of clinical stages of HIV infection. Using a recently described Treg identification strategy based on CD45RA and Foxp3 expression, we performed an extensive quantification of total, naive (CD45RA(+)Foxp3(low)), and effector (CD45RA(-)Foxp3(high)) Tregs in different contexts of HIV infection: primary HIV infection, long-term viremic patients, aviremic patients treated with highly active antiretroviral therapy, and HIV controllers. We showed that although total Treg percentages were mildly affected by HIV infection, Treg absolute numbers were significantly reduced in all groups studied. We demonstrated that although naive Treg numbers were essentially preserved, effector Tregs were consistently affected during HIV infection. Finally, we demonstrated that effector but not total or naive Treg numbers were negatively correlated with the magnitude of HIV-specific CD8 T-cell responses.
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Fatores de Transcrição Forkhead/metabolismo , Infecções por HIV/imunologia , HIV-1/imunologia , Antígenos Comuns de Leucócito/metabolismo , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Terapia Antirretroviral de Alta Atividade , Antígenos CD8/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Citometria de Fluxo , França , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Homeostase , Humanos , Pessoa de Meia-Idade , Linfócitos T Reguladores/metabolismo , Carga ViralRESUMO
BACKGROUND: Interleukin (IL)-2 therapy impacts T-cell homeostasis. Whether IL-2 expanded CD4(+) T cells may persist following viral rebound has not been fully investigated. METHODS: Patients with CD4(+) T cells 500/µl or more and HIV RNA less than 50 copies/ml were randomized to continue antiretroviral therapy (ART) either alone (n = 67) or combined with three IL-2 cycles (n = 81; 6 million units) twice daily for 5 days at weeks 0, 8, and 16 before stopping ART (week 24). Patients were followed up to 168 weeks. RESULTS: At week 24, median CD4(+) T-cell counts were 1198 and 703 cells/µl in the IL-2 and control groups, respectively (Pâ<â0.001). At week 72, 27% (IL-2 group) and 45% (control group; P = 0.03) of patients were in failure (defined as no interruption of ART at week 24, CD4 drop below 350 cells/µl or ART resumption). After week 24, a biphasic decline (before and after week 32) of CD4 was noted -106 and -7 cells/µl per month in controls and -234 and -17 in IL-2 group (all Pâ≤â0.0001). At week 96, IL-2-expanded CD4(+)CD25(+) T cells remained higher than in the control group (26 vs. 16%, P = 0.006). CONCLUSION: In IL-2-treated patients, CD4(+)CD25(+) T cells persisting despite viral replication allow a longer period of ART interruption.