RESUMO
The restoration of CD4+ T cells, especially T-helper type 17 (Th17) cells, remains incomplete in the gut mucosa of most human immunodeficiency virus type 1 (HIV-1)-infected individuals despite sustained antiretroviral therapy (ART). Herein, we report an increase in the absolute number of CXCR3+ T cells in the duodenal mucosa during ART. The frequencies of Th1 and CXCR3+ CD8+ T cells were increased and negatively correlated with CCL20 and CCL25 expression in the mucosa. In ex vivo analyses, we showed that interferon γ, the main cytokine produced by Th1 and effector CD8+ T cells, downregulates the expression of CCL20 and CCL25 by small intestine enterocytes, while it increases the expression of CXCL9/10/11, the ligands of CXCR3. Interleukin 18, a pro-Th1 cytokine produced by enterocytes, also contributes to the downregulation of CCL20 expression and increases interferon γ production by Th1 cells. This could perpetuate an amplification loop for CXCR3-driven Th1 and effector CD8+ T cells recruitment to the gut, while impairing Th17 cells homing through the CCR6-CCL20 axis in treated HIV-1-infected individuals.
Assuntos
Infecções por HIV/metabolismo , Interferon gama/metabolismo , Interleucina-18/metabolismo , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Receptores CXCR3/metabolismo , Células Th17/metabolismo , Antirretrovirais/uso terapêutico , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Movimento Celular , Quimiocina CCL20/metabolismo , Quimiocina CXCL10/metabolismo , Quimiocina CXCL11/metabolismo , Quimiocina CXCL9 , Quimiocinas CC/metabolismo , Citocinas/metabolismo , Infecções por HIV/terapia , Humanos , Células Th1/metabolismoRESUMO
The gut CD4(+) T cells, particularly the T helper type 17 (Th17) subset, are not completely restored in most HIV-1-infected individuals despite combined antiretroviral therapy, when initiated at the chronic phase of infection. We show here that the CCR6-CCL20 chemotactic axis is altered, with reduced CCL20 production by small intestine epithelial cells in treated HIV-1-infected individuals. This leads to impaired CCR6(+)CD4(+) T-cell homing, particularly Th17 cells, to the small intestine mucosa. In contrast, the frequency of gut FoxP3(+) T regulatory (Treg) cells, specifically the CCR6(-) subset, was increased. The resulting imbalance in the Th17/CCR6(-) Treg ratio and the associated shift from interleukin (IL)-17 to IL-10 and transforming growth factor-ß (TGF-ß) blunts CCL20 production by enterocytes, perpetuating a negative feedback for the recruitment of CCR6(+)CD4(+) T cells to the small intestine in treated HIV-1-infected individuals.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Quimiocina CCL20/imunologia , Infecções por HIV/imunologia , Receptores CCR6/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto , Terapia Antirretroviral de Alta Atividade , Antígenos CD4/genética , Antígenos CD4/imunologia , Estudos de Casos e Controles , Quimiocina CCL20/genética , Quimiotaxia/efeitos dos fármacos , Quimiotaxia/imunologia , Enterócitos/efeitos dos fármacos , Enterócitos/imunologia , Enterócitos/virologia , Retroalimentação Fisiológica , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/crescimento & desenvolvimento , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/virologia , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/imunologia , Intestino Delgado/virologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Receptores CCR6/deficiência , Receptores CCR6/genética , Transdução de Sinais , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/virologia , Células Th17/efeitos dos fármacos , Células Th17/virologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologiaRESUMO
HIV-1 pol gene sequencing is now used routinely in France to identify mutations associated with resistance to reverse transcriptase (RT) or protease (PR) inhibitors. These sequences may also provide other information, such as the HIV-1 subtype. HIV-1 subtyping was compared using the RT and PR gene sequences to heteroduplex mobility assay (HMA) of the envelope gene. The RT and PR genes of 51 samples that had been subtyped earlier by HMA were sequenced. Sequences were aligned and subtypes were determined by phylogenetic analysis with reference HIV sequences. HMA gave the following subtypes: A (20), B (19), C (1), D (3), F (1), G (3) and CRF01-AE (4). Phylogenetic analysis of the RT gene gave: A (5), B (19), C (2), D (3), F (1), G (6), J (2), CRF01_AE (4), CFR02_AG (7) and undetermined (2). PR gene analysis did not infer subtypes with sufficient confidence. HMA and RT subtyping was not in agreement in nine cases. RT subtyping can identify CFR02_AG and CRF01_AE variants from A subtype RT. It was shown that phylogenetic analysis of the RT gene could provide a useful method for HIV-1 subtyping. The length of the amplicon and the relative performance of each primer pair used in this study favoured RT sequences as a subtyping tool. One potential advantage over env subtyping HMA is the ability to identify some circulating recombinant forms (CRFs).
Assuntos
Proteína gp120 do Envelope de HIV/genética , Infecções por HIV/virologia , Protease de HIV/genética , Transcriptase Reversa do HIV/genética , HIV-1/genética , Fragmentos de Peptídeos/genética , Sequência de Bases , DNA Viral , Genes pol , HIV-1/classificação , Humanos , Dados de Sequência Molecular , Ácidos Nucleicos HeteroduplexesAssuntos
Futilidade Médica , Enfermagem Psiquiátrica , Adulto , Humanos , Masculino , Transtornos Mentais/enfermagemRESUMO
Fifteen kidney transplant recipients with chronic hepatitis C were given 3 million units recombinant alpha2b-interferon for 142+/-35 days. There were significant decreases in hepatitis C virus (HCV) RNA 1 month after the initiation of treatment (p < 0.01), and at the end of treatment (p < 0.05). HCV RNA was undetectable by PCR analysis during treatment in 5 patients. But HCV RNA reappeared in all patients 1 month after the cessation of therapy, and the level of viremia returned to baseline. While all patients had normalized alanine aminotransferase (ALT) activities at the end of therapy, 11 experienced a relapse during the follow-up period (1 year). There was a correlation between the amount of HCV RNA at the end of treatment and the time of relapse. Serum IgM against core protein of HCV were detected in 7/15 patients. Anti-core IgM remained detectable during treatment and afterwards. There was no correlation between IgM status and other virological parameters, or ALT activity.
