CD8+ T cells fail to limit SIV reactivation following ART withdrawal until after viral amplification

To define the contribution of CD8⁺ T cell responses to control of SIV reactivation during and following antiretroviral therapy (ART), we determined the effect of long-term CD8⁺ T cell depletion using a rhesusized anti-CD8β monoclonal antibody on barcoded SIVmac239 dynamics on stable ART and after ART cessation in rhesus macaques (RMs). Among the RMs with full CD8⁺ T cell depletion in both blood and tissue, there were no significant differences in the frequency of viral blips in plasma, the number of SIV RNA⁺ cells and the average number of RNA copies/infected cell in tissue, and levels of cell-associated SIV RNA and DNA in blood and tissue relative to control-treated RMs during ART. Upon ART cessation, both CD8⁺ T cell–depleted and control RMs rebounded in fewer than 12 days, with no difference in the time to viral rebound or in either the number or growth rate of rebounding SIVmac239M barcode clonotypes. However, effectively CD8⁺ T cell–depleted RMs showed a stable, approximately 2-log increase in post-ART plasma viremia relative to controls. These results indicate that while potent antiviral CD8⁺ T cell responses can develop during ART-suppressed SIV infection, these responses effectively intercept post-ART SIV rebound only after systemic viral replication, too late to limit reactivation frequency or the early spread of reactivating SIV reservoirs.     

The HIV-1 proviral landscape reveals that Nef contributes to HIV-1 persistence in effector memory CD4+ T cells

Despite long-term antiretroviral therapy (ART), HIV-1 persists within a reservoir of CD4⁺ T cells that contribute to viral rebound if treatment is interrupted. Identifying the cellular populations that contribute to the HIV-1 reservoir and understanding the mechanisms of viral persistence are necessary to achieve an effective cure. In this regard, through Full-Length Individual Proviral Sequencing, we observed that the HIV-1 proviral landscape was different and changed with time on ART across naive and memory CD4⁺ T cell subsets isolated from 24 participants. We found that the proportion of genetically intact HIV-1 proviruses was higher and persisted over time in effector memory CD4⁺ T cells when compared with naive, central, and transitional memory CD4⁺ T cells. Interestingly, we found that escape mutations remained stable over time within effector memory T cells during therapy. Finally, we provided evidence that Nef plays a role in the persistence of genetically intact HIV-1. These findings posit effector memory T cells as a key component of the HIV-1 reservoir and suggest Nef as an attractive therapeutic target.     

Antigen-driven clonal selection shapes the persistence of HIV-1–infected CD4+ T cells in vivo

Clonal expansion of infected CD4⁺ T cells is a major mechanism of HIV-1 persistence and a barrier to achieving a cure. Potential causes are homeostatic proliferation, effects of HIV-1 integration, and interaction with antigens. Here, we show that it is possible to link antigen responsiveness, the full proviral sequence, the integration site, and the T cell receptor β-chain (TCRβ) sequence to examine the role of recurrent antigenic exposure in maintaining the HIV-1 reservoir. We isolated CMV- and Gag-responding CD4⁺ T cells from 10 treated individuals. Proviral populations in CMV-responding cells were dominated by large clones, including clones harboring replication-competent proviruses. TCRβ repertoires showed high clonality driven by converging adaptive responses. Although some proviruses were in genes linked to HIV-1 persistence (BACH2, STAT5B, MKL1), the proliferation of infected cells under antigenic stimulation occurred regardless of the site of integration. Paired TCRβ and integration site analysis showed that infection could occur early or late in the course of a clone’s response to antigen and could generate infected cell populations too large to be explained solely by homeostatic proliferation. Together, these findings implicate antigen-driven clonal selection as a major factor in HIV-1 persistence, a finding that will be a difficult challenge to eradication efforts.     

Rapamycin limits CD4+ T cell proliferation in simian immunodeficiency virus–infected rhesus macaques on antiretroviral therapy

Proliferation of latently infected CD4⁺ T cells with replication-competent proviruses is an important mechanism contributing to HIV persistence during antiretroviral therapy (ART). One approach to targeting this latent cell expansion is to inhibit mTOR, a regulatory kinase involved with cell growth, metabolism, and proliferation. Here, we determined the effects of chronic mTOR inhibition with rapamycin with or without T cell activation in SIV-infected rhesus macaques (RMs) on ART. Rapamycin perturbed the expression of multiple genes and signaling pathways important for cellular proliferation and substantially decreased the frequency of proliferating CD4⁺ memory T cells (TM cells) in blood and tissues. However, levels of cell-associated SIV DNA and SIV RNA were not markedly different between rapamycin-treated RMs and controls during ART. T cell activation with an anti-CD3LALA antibody induced increases in SIV RNA in plasma of RMs on rapamycin, consistent with SIV production. However, upon ART cessation, both rapamycin and CD3LALA–treated and control-treated RMs rebounded in less than 12 days, with no difference in the time to viral rebound or post-ART viral load set points. These results indicate that, while rapamycin can decrease the proliferation of CD4⁺ TM cells, chronic mTOR inhibition alone or in combination with T cell activation was not sufficient to disrupt the stability of the SIV reservoir.     

Gut-derived bacterial toxins impair memory CD4+ T cell mitochondrial function in HIV-1 infection

People living with HIV (PLWH) who are immune nonresponders (INRs) are at greater risk of comorbidity and mortality than are immune responders (IRs) who restore their CD4⁺ T cell count after antiretroviral therapy (ART). INRs have low CD4⁺ T cell counts (<350 c/μL), heightened systemic inflammation, and increased CD4⁺ T cell cycling (Ki67⁺). Here, we report the findings that memory CD4⁺ T cells and plasma samples of INRs from several cohorts are enriched in gut-derived bacterial solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) that both negatively correlated with CD4⁺ T cell counts. In vitro PCS or IS blocked CD4⁺ T cell proliferation, induced apoptosis, and diminished the expression of mitochondrial proteins. Electron microscopy imaging revealed perturbations of mitochondrial networks similar to those found in INRs following incubation of healthy memory CD4⁺ T cells with PCS. Using bacterial 16S rDNA, INR stool samples were found enriched in proteolytic bacterial genera that metabolize tyrosine and phenylalanine to produce PCS. We propose that toxic solutes from the gut bacterial flora may impair CD4⁺ T cell recovery during ART and may contribute to CD4⁺ T cell lymphopenia characteristic of INRs.     

NLRP3 inflammasome induces CD4+ T cell loss in chronically HIV-1–infected patients

Chronic HIV-1 infection is generally characterized by progressive CD4⁺ T cell depletion due to direct and bystander death that is closely associated with persistent HIV-1 replication and an inflammatory environment in vivo. The mechanisms underlying the loss of CD4⁺ T cells in patients with chronic HIV-1 infection are incompletely understood. In this study, we simultaneously monitored caspase-1 and caspase-3 activation in circulating CD4⁺ T cells, which revealed that pyroptotic and apoptotic CD4⁺ T cells are distinct cell populations with different phenotypic characteristics. Levels of pyroptosis and apoptosis in CD4⁺ T cells were significantly elevated during chronic HIV-1 infection, and decreased following effective antiretroviral therapy. Notably, the occurrence of pyroptosis was further confirmed by elevated gasdermin D activation in lymph nodes of HIV-1–infected individuals. Mechanistically, caspase-1 activation closely correlated with the inflammatory marker expression and was shown to occur through NLRP3 inflammasome activation driven by virus-dependent and/or -independent ROS production, while caspase-3 activation in CD4⁺ T cells was more closely related to T cell activation status. Hence, our findings show that NLRP3-dependent pyroptosis plays an essential role in CD4⁺ T cell loss in HIV-1–infected patients and implicate pyroptosis signaling as a target for anti–HIV-1 treatment.     

中国HIV早期感染者CD+4CD+25Foxp3+调节性T淋巴细胞变化研究

目的 研究1年以内感染HIV的感染者(早期感染者,EHI)体内CD+4 CD+25 Foxp3+调节性T淋巴细胞水平及其与疾病进展相关性.方法 随机选取51例HIV感染者,依据感染时间及CD+4 T淋巴细胞水平分为3组:EHI组30例、HIV组15例、AIDS组6例,20名健康人作为对照组,各组对象的年龄、性别具有可比性.用EDTA抗凝管采集全血,应用FACSAria流式细胞仪及Foxp3染色试剂盒,检测外周血单个核细胞CD+4CD+25Foxp3+调节性T淋巴细胞表达水平,分析EHI者及全部HIV感染者CD+4 CD+25Foxp3+调节性T淋巴细胞表达水平与CD+4T淋巴细胞数量、病毒调定点、病毒载量及淋巴细胞活化水平间的相关性.结果 健康对照组、EHI组、HIV组及AIDS组CD+4C+25Foxp3+T淋巴细胞百分率逐级上升,其中EHI组CD+4CD+25Foxp3+T淋巴细胞百分率[3.79(2.11～5.43)%]低于AIDS组[8.09(4.90～8.90)%],差异有统计学意义(Z=-2.29,P=0.022);EHI组CD+4 CD+25Foxp3+T淋巴细胞百分率与病毒调定点正相关(r=0.479,P=0.038),与CD4T淋巴细胞计数呈负相关(r=-0.455,P=0.011),与CD+3 HLA+T淋巴细胞呈正相关(r=0.533,P=0.002).结论 中国EHI者CD+4 CD+25Foxp3+调节性T淋巴细胞百分率高与高病毒调定点及低CD+4 T淋巴细胞数量相关,提示CD+4 CD+25Fox3+调节性T淋巴细胞是加速HIV感染早期疾病进展的因素之一.     

HIV／AIDS患者CD4＋T淋巴细胞数的变化与外周血淋巴细胞总数的变量的关系研究

目的研究人免疫缺陷病毒（HIV）感染者和艾滋病（AIDS）患者CIM＋T淋巴细胞数的变化（△CD4＋T）和外周血淋巴细胞总数的变量（△TLC）的相关性,探讨用△TLC预测CD4＋T在监测HIV疾病进展和高效抗逆转录病毒治疗（HAART）疗效中发挥的作用。方法分析91例HIV／AIDS患者CD4＋T和TLC及△CD4＋T和△TLC的相关性,通过ROC面积、敏感度、特异度、阳性预测值和阴性预测值分析,寻找能有效预测CD4＋T淋巴细胞数〈200个／μl,〈350个／μl,时TLC的范围;△CD4＋T淋巴细胞数为50个／μl、100个／μl、200个／μl、300个／μl时△TLC的范围。结果91例HIV／AIDS患者CD4＋T和TLC相关系数r为0．716,P〈0．01;△TLC和△CD4＋T具有更强的相关性,相关系数r为0．809,P〈0．01。用1300个／μl和1700个／μl TLC预测CD4＋T200个／μl和350个／μl具有显著的预测价值。用△TLC 170个／μl、330个／μl、630个／μl、910个／μl分别预测△CD4＋T50个／μl、100个／μl、200个／μl、300个／μl,各项预测指标基本上在90％以上,显著高于相同时间下TLC预测CD4＋T的效果。结论人免疫缺陷病毒（HIV）感染者和艾滋病（AIDS）患者CD4＋T淋巴细胞数的变化（△CD4＋T）和外周血淋巴细胞总数的变量（△TLC）具有直线相关性。在条件匮乏的艾滋病高发区,可以应用△TLC预测△CD4＋T．比TLC更加直观、准确的反映HIV感染者疾病进展和评价AIDS患者HAART的疗效。     

Cell derived liposomes expressing CCR5 as a new targeted drug-delivery system for HIV infected cells

Anti-retroviral-therapies against HIV/AIDS focus on inhibiting viral growth and may slow AIDS progression, but not cure the disease. Here we describe an approach to treat HIV as a cellular pathology by targeting cell derived liposomes against HIV-infected cells. Cell-derived-liposomes were prepared from the cytoplasmatic membranes of cells expressing CCR5, the human receptor for gp120, that is found on the surface of virions and HIV-infected cells. The specific targeting and cytotoxicity of the cell-derived liposomes towards gp120-expressing cells were studied. Cell-derived liposomes exhibited unilamellar morphology and were found to be of 100-200 nm in diameter. Moreover, CCR5 that was expressed on the surface of the cell-derived liposomes was biologically active and correctly oriented. Cell-derived liposomes incubated with HIV-infected model cells exhibited significant and specific targeting to those gp120-expressing cells. To demonstrate the system efficacy, EDTA was selected as liposomal encapsulate and was shown to cause high cytotoxic effect when introduced into the cell cytoplasm. Finally, cell-derived liposomes containing EDTA led to a 60% reduction in the viability of gp120-expressing cells compared to no effect on control cells that do not express gp120. These results demonstrate the specific targeting and cytotoxic effect of CCR5-conjugated cell-derived liposomes towards gp120-expressing HIV model cells, suggesting for a potential new therapeutic approach.     

趋化因子受体CCR4、CCR5在系统性红斑狼疮患者外周血CD4＋T淋巴细胞上的表达及其意义

目的探讨系统性红斑狼疮（SLE）患者趋化因子受体CCR4和CCR5在外周血淋巴细胞表面的表达及其意义。方法流式细胞仪计数法对113例SLE患者和50例健康体检者外周血淋巴细胞表面CCR4和CCR5的表达情况进行检测,分析及评价SLE患者外周血淋巴细胞中CCR4＋和CCR5＋T淋巴细胞的百分数。结果非狼疮性肾炎（nLN）SLE组外周血CCR4＋CD4＋T%明显高于健康对照组（P〈0.01）;狼疮性肾炎SLE组外周血CCR4＋CD4＋T%明显高于健康对照组（P〈0.001）;LNSLE组外周血CCR4＋CD4＋T%明显高于nLNSLE组（P〈0.01）;nLNSLE组外周血CCR5＋CD4＋T%高于健康对照组（P〈0.05）;LNSLE组外周血CCR5＋CD4＋T%明显高于健康对照组（P〈0.001）;LNSLE组外周血CCR5＋CD4＋T%明显高于nLNSLE组（P〈0.01）。SLE活动组血清CCR4＋CD4＋T%与CCR5＋CD4＋T%较非活动组和对照组明显升高（P〈0.01）;活动性狼疮性肾炎（LN）与活动性无肾损伤组及对照组比较,其差异具有显著统计学意义（P〈0.01）。nLNSLE组外周血CCR4＋CD4＋T%与CCR5＋CD4＋T%有相关性（r=0.619,P〈0.05）;LNSLE组外周血CCR4＋CD4＋T%与CCR5＋CD4＋T%有明显相关性（r=0.68,P〈0.01）;血清CCR4＋CD4＋T%水平随着SLE疾病活动水平明显升高,与总的系统性红斑狼疮疾病活动性指数（SLEDAI）评分密切相关（r=0.6382,P〈0.001）;与SLEDAI肾评分亦密切相关（r=0.6980,P〈0.001）;而CCR5＋CD4＋T%与疾病活动度不相关（r=0.16,P〉0.05）。结论以上结果表明CCR4和CCR5在T细胞趋化至病变部位的过程中可能发挥重要作用,CCR4＋CD4＋T%与CCR5＋CD4＋T%可能在肾损伤中起着十分重要的作用,血清CCR4＋CD4＋T%、CCR5＋CD4＋T%与SLE疾病活动密切相关,可作为SLE疾病活动,尤其是监测狼疮性肾损伤的重要指标。     

Blockade of T cell costimulation reveals interrelated actions of CD4+ and CD8+ T cells in control of SIV replication

In vivo blockade of CD28 and CD40 T cell costimulation pathways during acute simian immunodeficiency virus (SIV) infection of rhesus macaques was performed to assess the relative contributions of CD4+ T cells, CD8+ T cells, and Ab responses in modulating SIV replication and disease progression. Transient administration of CTLA4-Ig and anti-CD40L mAb to SIV-infected rhesus macaques resulted in dramatic inhibition of the generation of both SIV-specific cellular and humoral immune responses. Acute levels of proliferating CD8+ T cells were associated with early control of SIV viremia but did not predict ensuing set point viremia or survival. The level of in vivo CD4+ T cell proliferation during acute SIV infection correlated with concomitant peak levels of SIV plasma viremia, whereas measures of in vivo CD4+ T cell proliferation that extended into chronic infection correlated with lower SIV viral load and increased survival. These results suggest that proliferating CD4+ T cells function both as sources of virus production and as antiviral effectors and that increased levels of CD4+ T cell proliferation during SIV infections reflect antigen-driven antiviral responses rather than a compensatory homeostatic response. These results highlight the interrelated actions of CD4+ and CD8+ T cell responses in vivo that modulate SIV replication and pathogenesis.     

CD81和趋化因子CC受体5与丙型肝炎合并人类免疫缺陷病毒感染的相关性研究

目的 检测外周血CD4＋及CD8＋T淋巴细胞表面CD81、CCR5的表达,探讨与丙型肝炎病毒（HCV）单纯感染、人类免疫缺陷病毒（HIV）单纯感染和HCV/HIV合并感染的关系.方法 采用流式细胞术,检测HCV感染组（n=21）、HIV感染组（n=14）、HCV/HIV感染组（n=28）及正常对照组（n=30）人外周血CD4＋及CD8＋T淋巴细胞表面CD81和CCR5的表达.结果 与正常对照组相比,外周血CD4＋T淋巴细胞表面CD81,在HCV感染组表达变化不明显,而在HIV感染组和HCV/HIV合并感染组中低表达;CD8＋T淋巴细胞表面CD81,在HCV感染组、HIV感染组和HCV/HIV合并感染组中都呈高表达.外周血CD4＋T和CD8＋T淋巴细胞表面CCR5,在HIV感染组高表达,而在HCV感染组和HCV/HIV合并感染组中低表达.结论 HCV/HIV合并感染中,影响外周血CD4＋及CD8＋T淋巴细胞表面CCR5表达的主要因素是HCV感染;而合并感染对CD4＋及CD8＋T淋巴细胞表面CD81的表达,其影响作用是不相同的.     

Revealing the role of CD4+ T cells in viral immunity

Protective immunity to chronic and acute viral infection relies on both the innate and adaptive immune response. Although neutralizing antibody production by B cells and cytotoxic activity of CD8(+) T cells are well-accepted components of the adaptive immune response to viruses, identification of the specific role of CD4(+) T cells in protection has been more challenging to establish. Delineating the contribution of CD4(+) T cells has been complicated by their functional heterogeneity, breadth in antigen specificity, transient appearance in circulation, and sequestration in tissue sites of infection. In this minireview, we discuss recent progress in identifying the multiple roles of CD4(+) T cells in orchestrating and mediating the immune responses against viral pathogens. We highlight several recent reports, including one published in this issue, that have employed comprehensive and sophisticated approaches to provide new evidence for CD4(+) T cells as direct effectors in antiviral immunity.     

Proteome-wide analysis of HIV-specific naive and memory CD4+ T cells in unexposed blood donors

The preexisting HIV-1–specific T cell repertoire must influence both the immunodominance of T cells after infection and immunogenicity of vaccines. We directly compared two methods for measuring the preexisting CD4⁺ T cell repertoire in healthy HIV-1–negative volunteers, the HLA-peptide tetramer enrichment and T cell library technique, and show high concordance (r = 0.989). Using the library technique, we examined whether naive, central memory, and/or effector memory CD4⁺ T cells specific for overlapping peptides spanning the entire HIV-1 proteome were detectable in 10 HLA diverse, HIV-1–unexposed, seronegative donors. HIV-1–specific cells were detected in all donors at a mean of 55 cells/million naive cells and 38.9 and 34.1 cells/million in central and effector memory subsets. Remarkably, peptide mapping showed most epitopes recognized by naive (88%) and memory (56%) CD4⁺ T cells had been previously reported in natural HIV-1 infection. Furthermore, 83% of epitopes identified in preexisting memory subsets shared epitope length matches (8–12 amino acids) with human microbiome proteins, suggestive of a possible cross-reactive mechanism. These results underline the power of a proteome-wide analysis of peptide recognition by human T cells for the identification of dominant antigens and provide a baseline for optimizing HIV-1–specific helper cell responses by vaccination.Only one candidate HIV vaccine, a canarypox vectored gp120 with a protein boost, has shown any efficacy (Rerks-Ngarm et al., 2009). The limited protection correlated with induction of nonneutralizing antibodies to the VI/V2 region of the virus Envelope protein (Env; Rerks-Ngarm et al., 2009; Haynes et al., 2012). This modest success has stimulated efforts to design vaccines that generate more efficient neutralizing antibodies, together with potent CD4⁺ T cell responses capable of providing help to B cells and cytotoxic T cells (Burton et al., 2012). Understanding how the magnitude and specificity of these helper T cells can be optimized will be critical to the design of an effective vaccine.Primary immune responses are probably influenced strongly by the preexisting repertoire of B and T cells. However, characterization and quantification of these repertoires is difficult due to the extremely low number of circulating naive precursor cells (Jenkins et al., 2001; Su et al., 2013). Previous studies of naive CD4⁺ T cell repertoires in humans and mice have relied on magnetic beads to enrich MHC tetramer binding cells (Moon et al., 2007; Kwok et al., 2012; Su et al., 2013). However, although this approach gives precise information on responses to particular MHC-peptide epitopes, it does not measure the total repertoire and misses previously unknown epitopes. An alternative T cell library technique requires no prior knowledge of donor HLA type or epitope specificity (Geiger et al., 2009). The method presorts circulating T cells into naive and memory subsets which are seeded at limiting dilution before polyclonal expansion in the presence of PHA, allogeneic feeder cells, and IL-2. Individual cultures are then screened for proliferative responses to a protein or series of peptides representing the pathogen of interest (Geiger et al., 2009). Combined with epitope mapping and the Poisson distribution, the T cell library technique can provide quantitative data on the specificity of the entire preexisting naive and memory repertoire.The existence of HIV-1–specific memory cells in seronegative donors was originally suggested by studies of highly exposed HIV-1 seronegative (HESN) donors. It has been shown that 25–61% of HESNs have demonstrable HIV-1–specific memory cells, probably primed by exposure to the virus. Surprisingly, HIV-1–specific CD4⁺ T cells were also detected in 24–44% of unexposed donors (Ritchie et al., 2011), although it was not clear whether the latter came from cross-reactive memory T cells or naive T cells primed in vitro. More recently, the existence of low frequency (1–10/million) memory CD4⁺ T cells, specific for a known HIV-1 Gag epitope, was demonstrated by HLA DR4 tetramers in 50% of HIV-1 unexposed HLA DR4⁺ adults (Su et al., 2013), but it was not clear how generalizable the HIV-1 result was beyond the single epitope–HLA DR4 combination.The present study first validates the library technique by direct comparison with the tetramer enrichment method for measuring precursor T cell frequencies. We then use the T cell library technique to provide the first proteome-wide analysis of the frequencies and specificities of preexposure HIV-1–specific naive and memory CD4⁺ T cells in a HLA diverse population of HIV-1 unexposed donors.     

CCR7 is required for the in vivo function of CD4+ CD25+ regulatory T cells

CCR7-mediated migration of naive T cells into the secondary lymphoid organs is a prerequisite for their encounter with mature dendritic cells, the productive presentation of cognate antigen, and consequent T cell proliferation and effector differentiation. Therefore, CCR7 was suggested to play an important role in the initiation of adaptive immune responses. In this study, we show that primary immunity can also develop in the absence of CCR7. Moreover, CCR7-deficient knockout (KO) mice display augmented immune responses. Our data cumulatively suggest that enhanced immunity in CCR7 KO mice is caused by the defective lymph node (LN) positioning of FoxP3(+) CD4(+) CD25(+) regulatory T cells (T reg cells) and the consequent impediment of their function. The FoxP3(+) T reg cells express CCR7 and, after their adoptive transfer, migrate into the LNs of wild-type mice. Here, they proliferate in situ upon antigen stimulation and inhibit the generation of antigen-specific T cells. Conversely, transferred CCR7-deficient T reg cells fail to migrate into the LNs and suppress antigen-induced T cell responses. The transfer of combinations of naive and T reg cells from wild-type and CCR7 KO mice into syngeneic severe combined immunodeficient mice directly demonstrates that CCR7-deficient T reg cells are less effective than their wild-type counterparts in preventing the development of inflammatory bowel disease.     

Relationship of SARS-CoV-2–specific CD4 response to COVID-19 severity and impact of HIV-1 and tuberculosis coinfection

T cells are involved in control of coronavirus disease 2019 (COVID-19), but limited knowledge is available on the relationship between antigen-specific T cell response and disease severity. Here, we used flow cytometry to assess the magnitude, function, and phenotype of SARS coronavirus 2–specific (SARS-CoV-2–specific) CD4⁺ T cells in 95 hospitalized COVID-19 patients, 38 of them being HIV-1 and/or tuberculosis (TB) coinfected, and 38 non–COVID-19 patients. We showed that SARS-CoV-2–specific CD4⁺ T cell attributes, rather than magnitude, were associated with disease severity, with severe disease being characterized by poor polyfunctional potential, reduced proliferation capacity, and enhanced HLA-DR expression. Moreover, HIV-1 and TB coinfection skewed the SARS-CoV-2 T cell response. HIV-1–mediated CD4⁺ T cell depletion associated with suboptimal T cell and humoral immune responses to SARS-CoV-2, and a decrease in the polyfunctional capacity of SARS-CoV-2–specific CD4⁺ T cells was observed in COVID-19 patients with active TB. Our results also revealed that COVID-19 patients displayed reduced frequency of Mycobacterium tuberculosis–specific CD4⁺ T cells, with possible implications for TB disease progression. These results corroborate the important role of SARS-CoV-2–specific T cells in COVID-19 pathogenesis and support the concept of altered T cell functions in patients with severe disease.     

CCR5-dependent homing of naturally occurring CD4+ regulatory T cells to sites of Leishmania major infection favors pathogen persistence

Pathogen persistence after clinical cure is a hallmark of many chronic infections. Previously, we showed that naturally occurring CD4+CD25+ regulatory T (nTreg) cells rapidly accumulate within chronic dermal sites of Leishmania major infection where they suppress anti-pathogen CD4+ T cell responses, favor parasite persistence and dermal pathology, and consequently control concomitant immunity. Here, we postulated that chemokines might direct nTreg cell homing in sites of infection and show that CD4+CD25+ nTreg cells, compared with normal CD4+ T cells, preferentially express the CCR5 chemokine receptor, which enables them to migrate in response to CCR5 ligands in vitro. We show that in contrast to their wild-type (WT) counterparts, CCR5-/- CD4+CD25+ nTreg cells resulted in an increased magnitude of parasite-specific, interferon gamma-producing CD4+ T cells within infection sites, dramatically reduced parasite numbers, and potent resistance to infection, a finding consistent with the clinical outcome of infected CCR5-/- mice. Interestingly, this resistance was related to an inefficient migration of CCR5-/- nTreg cells to infected dermal sites compared with WT nTreg cells. Thus, this study shows that CCR5 directs the homing of CD4+CD25+ nTreg cells to L. major-infected dermal sites where they promote the establishment of infection and long-term survival of the parasite in the immune host.