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BACKGROUND: Clinical trials of the mRNA coronavirus disease 2019 (COVID-19) vaccines excluded individuals with primary antibody deficiencies. OBJECTIVE: To evaluate whether antibody and T-cell responses to mRNA COVID-19 vaccination in patients with common variable immunodeficiency (CVID) and specific antibody deficiency (SAD) were comparable to those in healthy controls. METHODS: We measured antibody responses against the spike glycoprotein and the receptor-binding domain (RBD) in addition to severe acute respiratory syndrome coronavirus 2 specific T-cell responses using peripheral blood mononuclear cells 2 to 8 weeks after the subjects completed the primary 2-dose vaccine series. RESULTS: The study comprised 12 patients with CVID, 7 patients with SAD, and 10 controls. Individuals with CVID had lower immunoglobulin (Ig) G and Ig A levels against spike glycoprotein than did both individuals with SAD (P = .27 and P = .01, respectively) and controls (P = .01 and P = .004, respectively). The CVID group developed lower IgG titers against the RBD epitope than did the control group (P = .01). Participants with CVID had lower neutralizing titers than did the control group (P = .002). All participants with SAD developed neutralizing titers. All 3 groups (SAD, CVID, and control) developed antigen-specific CD4+ and CD8+ T-cell responses after vaccination. CONCLUSION: Our results suggest that patients with CVID may have impaired antibody responses to COVID-19 vaccination but intact T-cell responses, whereas patients with SAD would be expected to have both intact antibody and T-cell responses to vaccination.
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COVID-19 , Imunodeficiência de Variável Comum , Doenças da Imunodeficiência Primária , Humanos , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Leucócitos Mononucleares , Vacinação , Imunoglobulina G , GlicoproteínasRESUMO
Platelets, which are small anuclear cell fragments, play important roles in thrombosis and hemostasis, but also actively release factors that can both suppress and induce viral infections. Platelet-released factors include sCD40L, microvesicles (MVs), and alpha granules that have the capacity to exert either pro-inflammatory or anti-inflammatory effects depending on the virus. These factors are prime targets for use in extracellular vesicle (EV)-based therapy due to their ability to reduce viral infections and exert anti-inflammatory effects. While there are some studies regarding platelet microvesicle-based (PMV-based) therapy, there is still much to learn about PMVs before such therapy can be used. This review provides the background necessary to understand the roles of platelet-released factors, how these factors might be useful in PMV-based therapy, and a critical discussion of current knowledge of platelets and their role in viral diseases.
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Fatores de Coagulação Sanguínea/metabolismo , Plaquetas/metabolismo , Vesículas Extracelulares/metabolismo , Viroses/metabolismo , Animais , Micropartículas Derivadas de Células/metabolismo , Humanos , Ativação Plaquetária/fisiologiaRESUMO
Current efforts toward human immunodeficiency virus (HIV) eradication include approaches to augment immune recognition and elimination of persistently infected cells following latency reversal. Natural killer (NK) cells, the main effectors of the innate immune system, recognize and clear targets using different mechanisms than CD8+ T cells, offering an alternative or complementary approach for HIV clearance strategies. We assessed the impact of interleukin 15 (IL-15) treatment on NK cell function and the potential for stimulated NK cells to clear the HIV reservoir. We measured NK cell receptor expression, antibody-dependent cell-mediated cytotoxicity (ADCC), cytotoxicity, interferon gamma (IFN-γ) production, and antiviral activity in autologous HIV replication systems. All NK cell functions were uniformly improved by IL-15, and, more importantly, IL-15-treated NK cells were able to clear latently HIV-infected cells after exposure to vorinostat, a clinically relevant latency-reversing agent. We also demonstrate that NK cells from HIV-infected individuals aviremic on antiretroviral therapy can be efficiently stimulated with IL-15. Our work opens a promising line of investigation leading to future immunotherapies to clear persistent HIV infection using NK cells.IMPORTANCE In the search for an HIV cure, strategies to enhance immune function to allow recognition and clearance of HIV-infected cells following latency reversal are being evaluated. Natural killer (NK) cells possess characteristics that can be exploited for immunotherapy against persistent HIV infection. We demonstrate that NK cells from HIV-positive donors can be strongly stimulated with IL-15, improving their antiviral and cytotoxic potential and, more importantly, clearing HIV-infected cells after latency reversal with a clinically relevant drug. Our results encourage further investigation to design NK cell-based immunotherapies to achieve HIV eradication.
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HIV-1/imunologia , Imunoterapia/métodos , Interleucina-15/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/efeitos dos fármacos , Latência Viral/imunologia , Adulto , Antirretrovirais/farmacologia , Citotoxicidade Celular Dependente de Anticorpos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Células Cultivadas , Infecções por HIV/imunologia , Infecções por HIV/terapia , Infecções por HIV/virologia , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Interferon gama/imunologia , Receptores de Células Matadoras Naturais/biossíntese , Receptores de Células Matadoras Naturais/imunologia , VorinostatRESUMO
Eradication of HIV infection will require the identification of all cellular reservoirs that harbor latent infection. Despite low or lack of CD4 receptor expression on Vδ2 T cells, infection of these cells has previously been reported. We found that upregulation of the CD4 receptor may render primary Vδ2 cells target for HIV infection in vitro and we propose that HIV-induced immune activation may allow infection of γδ T cells in vivo. We assessed the presence of latent HIV infection by measurements of DNA and outgrowth assays within Vδ2 cells in 18 aviremic patients on long-standing antiretroviral therapy. In 14 patients we recovered latent but replication-competent HIV from highly purified Vδ2 cells demonstrating that peripheral Vδ2 T cells are a previously unrecognized reservoir in which latent HIV infection is unexpectedly frequent.
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Linfócitos T CD4-Positivos/virologia , Infecções por HIV/virologia , HIV-1/fisiologia , Subpopulações de Linfócitos T/virologia , Latência Viral/fisiologia , Separação Celular , Citometria de Fluxo , Humanos , Receptores de Antígenos de Linfócitos T gama-deltaRESUMO
UNLABELLED: Central memory (TCM) CD4(+) T cells are the principal reservoir of latent HIV-1 infection that persists despite durable, successful antiretroviral therapy (ART). In a study that measured HIV DNA in 17 patients and replication-competent HIV in 4 patients, pools of resting and activated transitional memory (T(TM)) CD4(+) T cells were found to be a reservoir for HIV infection. As defective viruses account for the majority of integrated HIV DNA and do not reflect the actual frequency of latent, replication-competent proviral infection, we assessed the specific contribution of resting T(TM) cells to latent HIV infection. We measured the frequency of replication-competent HIV in purified resting memory cell subpopulations by a limiting-dilution, quantitative viral outgrowth assay (QVOA). HIV was routinely detected within the resting central memory compartment but was infrequently detected within the resting T(TM) compartment. These observations suggest that prolonged ART may limit persistent latent infection in the T(TM) compartment. Our results confirm the importance of latent infection within the TCM compartment and again focus attention on these cells as the most important latent viral reservoir. While proliferation may drive expansion of detectable viral genomes in cells, the frequency of replication-competent HIV must be carefully assessed. Latent infection appears to wane within the transitional memory compartment in patients who have sustained successful viral suppression via ART or were treated very early in infection. IMPORTANCE: Antiretroviral therapy (ART) has led to a significant decrease in morbidity and mortality among HIV-infected patients. However, HIV integrates into the genome of CD4(+) T cells, generating pools of long-lived cells that are reservoirs of latent HIV. Two main subsets of CD4(+) T cells, central memory and transitional memory cells, were reported to be major reservoirs of HIV infection. However, this study primarily measured the HIV DNA content, which also includes defective proviruses that would not be able to replicate and initiate new rounds of infection. By analyzing the replication-competent virus in both cell subsets, we showed that transitional memory cells may not be a durable reservoir in patients on successful ART.
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Linfócitos T CD4-Positivos/virologia , HIV-1/isolamento & purificação , HIV-1/fisiologia , Carga Viral , Replicação Viral , Adulto , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Protease-activated receptors (PARs) are a subfamily of four G-protein-coupled receptors mediating multiple functions. PARs expression was studied in subpopulations of human lymphocytes. Our results indicate that natural killer cells expressed mRNA for PAR1, PAR2 and PAR3, CD4+ T cells expressed PAR1 and PAR2, while γδ and CD8+ T cells only expressed PAR1. PAR4 was absent at mRNA level and B cells did not express any PAR. Analyses of the cell surface PARs expression by flow cytometry were consistent with the mRNA data and also between different donors. PAR1 is the most abundant member of the PAR family present in lymphocytes.
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Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Células Matadoras Naturais/metabolismo , Receptor PAR-1/genética , Receptor PAR-2/genética , Receptores de Trombina/genética , Linfócitos B/citologia , Antígenos CD4/genética , Antígenos CD4/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Células Matadoras Naturais/citologia , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Receptor PAR-1/imunologia , Receptor PAR-2/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Trombina/imunologiaRESUMO
Human Vγ9δ2 (Vδ2) T cells represent a unique effector T cell population in humans and primates detecting nonpeptid phosphoantigens, playing an important role in antimicrobial and antitumor immunity. Currently, it is believed that various leukocyte subsets can promote phosphoantigen-driven Vδ2 cell expansion, but the essential cell type required remains elusive. We have used high purity cell sorting to analyze the cellular requirements for (E)-4-hydroxy-3-methyl-but-2-enyl-pyrophosphate (HMBPP)-driven Vδ2 cell expansion. To our knowledge, we show for the first time that primary human MHC-class II(+) cells are indispensable for HMBPP- and isopentenylpyrophosphate-driven Vδ2 cell expansion. In contrast, MHC-class II(-) cells are unable to promote Vδ2 cell expansion. Moreover, purified primary human TCRαß(+) T cells, CD4(+), or CD8(+) T cells also failed to promote HMBPP-mediated Vδ2 expansion. Depletion of CD4(+)CD25(+) T cells demonstrated that inability of TCRαß(+) cells to expand Vδ2 cells was not related to the presence of regulatory T cells. Separation of MHC-class II(+) cells into dendritic cells, monocytes, and B cells revealed that dendritic cells were the most potent Vδ2 expanders. Pulsing experiments demonstrated that HMBPP transforms MHC-class II(+) but not negative cells into Vδ2 expanders. MHC-class II-blocking experiments with mAbs and secondary MHC-class II induction on CD4(+) T cells after CD3/CD28 costimulation indicated that MHC-class II is necessary, but not sufficient to promote Vδ2 expansion. Our results provide novel insight into the primary cell-specific requirements for human Vδ2 expansion.
Assuntos
Difosfatos/farmacologia , Hemiterpenos/farmacologia , Antígenos de Histocompatibilidade Classe II/imunologia , Fatores Imunológicos/farmacologia , Compostos Organofosforados/farmacologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Anticorpos/imunologia , Anticorpos/farmacologia , Antígenos CD/genética , Antígenos CD/imunologia , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Proliferação de Células/efeitos dos fármacos , Separação Celular , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Ativação Linfocitária/efeitos dos fármacos , Depleção Linfocítica , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Cultura Primária de Células , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacosRESUMO
Human T-cell leukemia virus type 1 (HTLV-1) can cause HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). Current treatment options for HAM/TSP are limited. We present a woman with rapidly-progressive HAM/TSP with significant, sustained clinical improvement following initiation of mycophenolate mofetil (MMA). Peripheral blood mononuclear cells from the patient, her asymptomatic carrier husband and eight healthy controls were isolated. Frequencies of T-cell populations upon exposure to low and high MMA concentrations and differences in proliferation were analyzed using flow cytometry and a CSFE-proliferation assay. Characterization of T-cell function and proliferation showed higher levels of GranzymeB in HTLV-1+ donors. The improvement and stability of symptoms in this patient with HAM/TSP following MMA initiation requires further study as a potential treatment for HAM/TSP.
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Vírus Linfotrópico T Tipo 1 Humano , Paraparesia Espástica Tropical , Humanos , Feminino , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Ácido Micofenólico/uso terapêutico , Leucócitos Mononucleares , Paraparesia Espástica Tropical/tratamento farmacológico , Paraparesia Espástica Tropical/diagnósticoRESUMO
Nonreceptor tyrosine phosphatases (NTPs) play an important role regulating protein phosphorylation and have been proposed as attractive therapeutic targets for cancer and metabolic diseases. We have previously identified that 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) enhanced STAT activation upon cytokine stimulation leading to increased reactivation of latent HIV and effector functions of NK and CD8 T cells. Here, we demonstrated that HODHBt interacts with and inhibits the NTPs PTPN1 and PTPN2 through a mixed inhibition mechanism. We also confirmed that PTPN1 and PTPN2 specifically control the phosphorylation of different STATs. The small molecule ABBV-CLS-484 (AC-484) is an active site inhibitor of PTPN1 and PTPN2 currently in clinical trials for advanced solid tumors. We compared AC-484 and HODHBt and found similar effects on STAT5 and immune activation albeit with different mechanisms of action leading to varying effects on latency reversal. Our studies provide the first specific evidence that enhancing STAT phosphorylation via inhibition of PTPN1 and PTPN2 is an effective tool against HIV.
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Curative strategies for human immunodeficiency virus (HIV-1) infection are hindered by incomplete characterization of the latent reservoir and limited enhancement of anti-HIV immune responses. In this study, we identified a novel dual role for peripheral and tissue-resident Vδ1 T cells within the gastrointestinal mucosa of virally suppressed people with HIV. Phenotypic analyses identified an increased frequency of highly differentiated, cytotoxic effector Vδ1 T cells that exerted potent inhibition of HIV-1 replication in vitro coinciding with direct increases in cytolytic function. Conversely, we detected an enrichment of HIV-1 DNA in tissue-resident CD4+Vδ1 T cells in situ. Despite low CD4 expression, we found circulating Vδ1 T cells also contained HIV-1 DNA which was replication-competent. We show that TCR-mediated activation of peripheral Vδ1 T cells induced de novo upregulation of CD4 providing a plausible mechanism for increased permissibility to infection. These findings highlight juxtaposing roles for Vδ1 T cells in HIV-1 persistence including significant contribution to tissue reservoirs.
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Under non-pathological conditions, human γδ T cells represent a small fraction of CD3+ T cells in peripheral blood (1-10%). They constitute a unique subset of T lymphocytes that recognize stress ligands or non-peptide antigens through MHC-independent presentation. Major human γδ T cell subsets, Vδ1 and Vδ2, expand in response to microbial infection or malignancy, but possess distinct tissue localization, antigen recognition, and effector responses. We hypothesized that differences at the gene, phenotypic, and functional level would provide evidence that γδ T cell subpopulations belong to distinct lineages. Comparisons between each subset and the identification of the molecular determinants that underpin their differences has been hampered by experimental challenges in obtaining sufficient numbers of purified cells. By utilizing a stringent FACS-based isolation method, we compared highly purified human Vδ1 and Vδ2 cells in terms of phenotype, gene expression profile, and functional responses. We found distinct genetic and phenotypic signatures that define functional differences in γδ T cell populations. Differences in TCR components, repertoire, and responses to calcium-dependent pathways suggest that Vδ1 and Vδ2 T cells are different lineages. These findings will facilitate further investigation into the ligand specificity and unique role of Vδ1 and Vδ2 cells in early immune responses.
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Linfócitos Intraepiteliais , Neoplasias , Humanos , Subpopulações de Linfócitos T , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos Intraepiteliais/metabolismo , Fenótipo , Neoplasias/metabolismoRESUMO
Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include "shock and kill" strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in ex vivo assays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.
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Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , Infecções por HIV/tratamento farmacológico , Ativação Viral , Latência Viral , Alendronato/uso terapêutico , Alendronato/farmacologiaRESUMO
Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include "shock and kill" strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in ex vivo assays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.
RESUMO
The use of antiretroviral therapy (ART) for Human Immunodeficiency Virus (HIV) treatment has been highly successful in controlling plasma viremia to undetectable levels. However, a complete cure for HIV is hindered by the presence of replication-competent HIV, integrated in the host genome, that can persist long term in a resting state called viral latency. Resting memory CD4+ T cells are considered the biggest reservoir of persistent HIV infection and are often studied exclusively as the main target for an HIV cure. However, other cell types, such as circulating monocytes and tissue-resident macrophages, can harbor integrated, replication-competent HIV. To develop a cure for HIV, focus is needed not only on the T cell compartment, but also on these myeloid reservoirs of persistent HIV infection. In this review, we summarize their importance when designing HIV cure strategies and challenges associated to their identification and specific targeting by the "shock and kill" approach.
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Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is a complex disease which immune response can be more or less potent. In severe cases, patients might experience a cytokine storm that compromises their vital functions and impedes clearance of the infection. Gamma delta (γδ) T lymphocytes have a critical role initiating innate immunity and shaping adaptive immune responses, and they are recognized for their contribution to tumor surveillance, fighting infectious diseases, and autoimmunity. γδ T cells exist as both circulating T lymphocytes and as resident cells in different mucosal tissues, including the lungs and their critical role in other respiratory viral infections has been demonstrated. In the context of SARS-CoV-2 infection, γδ T cell responses are understudied. This review summarizes the findings on the antiviral role of γδ T cells in COVID-19, providing insight into how they may contribute to the control of infection in the mild/moderate clinical outcome.
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COVID-19 , Imunidade Inata , Subpopulações de Linfócitos T , Antivirais , COVID-19/imunologia , Citocinas , Humanos , Receptores de Antígenos de Linfócitos T gama-delta , SARS-CoV-2 , Subpopulações de Linfócitos T/imunologiaRESUMO
Gamma/delta (γδ) T cells are innate-like immune effectors that are a critical component linking innate and adaptive immune responses. They are recognized for their contribution to tumor surveillance and fight against infectious diseases. γδ T cells are excellent candidates for cellular immunotherapy due to their unique properties to recognize and destroy tumors or infected cells. They do not depend on the recognition of a single antigen but rather a broad-spectrum of diverse ligands through expression of various cytotoxic receptors. In this manuscript, we review major characteristics of the most abundant circulating γδ subpopulation, Vδ2 T cells, their immunotherapeutic potential, recent advances in expansion protocols, their preclinical and clinical applications for several infectious diseases and malignancies, and how additional modulation could enhance their therapeutic potential.
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Neoplasias , Receptores de Antígenos de Linfócitos T gama-delta , Humanos , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Ativação Linfocitária , Linfócitos T , Antígenos , Neoplasias/terapia , ImunoterapiaRESUMO
The major barrier to HIV cure is a population of long-lived cells that harbor latent but replication-competent virus, are not eliminated by antiretroviral therapy (ART), and remain indistinguishable from uninfected cells. However, ART does not cure HIV infection, side effects to treatment still occur, and the steady global rate of new infections makes finding a sustained ART-free HIV remission or cure for HIV-seropositive individuals urgently needed. Approaches aimed to cure HIV are mostly based on the "shock and kill" method that entails the use of a drug compound to reactivate latent virus paired together with strategies to boost or supplement the existing immune system to clear reactivated latently infected cells. Traditionally, these strategies have utilized CD8+ cytotoxic lymphocytes (CTL) but have been met with a number of challenges. Enhancing innate immune cell populations, such as γδ T cells, may provide an alternative route to HIV cure. γδ T cells possess anti-viral and cytotoxic capabilities that have been shown to directly inhibit HIV infection and specifically eliminate reactivated, latently infected cells in vitro. Most notably, their access to immune privileged anatomical sites and MHC-independent antigen recognition may circumvent many of the challenges facing CTL-based strategies. In this review, we discuss the role of γδ T cells in normal immunity and HIV infection as well as their current use in strategies to treat cancer. We present this information as means to speculate about the utilization of γδ T cells for HIV cure strategies and highlight some of the fundamental gaps in knowledge that require investigation.
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Infecções por HIV , HIV-1 , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Infecções por HIV/tratamento farmacológico , Humanos , Latência ViralRESUMO
OBJECTIVES: This study aims to analyze the association of the presence of common polymorphisms [single nucleotide polymorphisms (SNPs)] on Toll-like receptors (TLRs), such as TLR9-1635A/G, TLR2-1892A/C, TLR2-2258G/A, TLR4-899A/G, and TLR4-1196C/T, with the viral rebound after stopping antiretroviral treatment (ART). CCR5-Δ32 deletion and HLA-A/HLA-B alleles were also analyzed. DESIGN: Interruption of ART may be required to investigate the outcome of strategies aimed to achieve drug-free HIV remission or cure. However, interruption of ART is currently not indicated. This was a retrospective longitudinal study that included 57 long-term suppressed HIV-1-infected individuals. METHODS: TLR SNPs were detected by real-time polymerase chain reaction (PCR). CCR5-Δ32 was analyzed by conventional PCR and HLA-A and HLA-B alleles by PCR-SSOP Luminex. RESULTS: HIV-1 RNA rebound at week 4 after treatment interruption positively correlated with pre-ART HIV-1 load (P = 0.025). The TLR9-1635AA genotype was independently associated with a higher HIV-1 rebound compared with those with AG + GG genotype (multivariate stepwise regression analysis, P = 0.004). Women had lower HIV-1 RNA load both at rebound and during the 72 weeks of follow-up compared with men (P < 0.05 at all time-points), whereas CD4 nadir and CD4 count set-point were similar according to sex. The pre-ART viral load was independently associated with the viral set-point (P = 0.001), whereas the presence of the HLA-A01 allele (P = 0.027) and the CD4 nadir (P = 0.001) were associated with the CD4 count set-point. CONCLUSIONS: The association of the TLR9-1635AA genotype with a higher HIV-1 rebound suggests that this SNP may affect the results from strategies requiring interruption of ART aimed to cure HIV-1 infection.
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Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Receptor Toll-Like 9/genética , Contagem de Linfócito CD4 , Feminino , HIV-1 , Humanos , Estudos Longitudinais , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Carga Viral , Latência ViralRESUMO
Crosstalk between innate and adaptive pathways is a critical component to developing an effective, lasting immune response. Among natural effector cells, innate-like γδ T cells promote immunity by facilitating communication between the two compartments and exerting cytotoxic effector functions. Dysregulation of γδ T cell populations is a byproduct of primary Humanimmunodeficiency virus (HIV) infection. This is most pronounced in the depletion and loss of function within cells expressing a Vγ9Vδ2 TCR (Vδ2 cells). Whether or not prolonged viral suppression mediated by antiretroviral therapy (ART) can reverse these effects has yet to be determined. In this study, we present evidence of similar Vδ2 cell functional responses within a cohort of people living with HIV (PLWH) that has been stably suppressed for >1 year and uninfected donors. Through the use of aminobisphosphonate drugs, we were able to generate a comprehensive comparison between ex vivo and expanded Vδ2 cells within each group. Both groups had largely similar compositions of memory and effector phenotypes, post-expansion TCR repertoire diversity, and cytotoxic capabilities. Our findings support the notion that ART promotes the recovery of Vδ2 polyfunctionality and provides insight for strategies aiming to reconstitute the full immune response after infection with HIV.