Comprehensive analysis of early T cell responses to acute Zika Virus infection during the first epidemic in Bahia, Brazil.

BACKGROUND: In most cases, Zika virus (ZIKV) causes a self-limited acute illness in adults, characterized by mild clinical symptoms that resolve within a few days. Immune responses, both innate and adaptive, play a central role in controlling and eliminating virus-infected cells during the early stages of infection. AIM: To test the hypothesis that circulating T cells exhibit phenotypic and functional activation characteristics during the viremic phase of ZIKV infection. METHODS: A comprehensive analysis using mass cytometry was performed on peripheral blood mononuclear cells obtained from patients with acute ZIKV infection (as confirmed by RT-PCR) and compared with that from healthy donors (HD). The frequency of IFN-γ-producing T cells in response to peptide pools covering immunogenic regions of structural and nonstructural ZIKV proteins was quantified using an ELISpot assay. RESULTS: Circulating CD4+ and CD8+ T lymphocytes from ZIKV-infected patients expressed higher levels of IFN-γ and pSTAT-5, as well as cell surface markers associated with proliferation (Ki-67), activation ((HLA-DR, CD38) or exhaustion (PD1 and CTLA-4), compared to those from HD. Activation of CD4+ and CD8+ memory T cell subsets, including Transitional Memory T Cells (TTM), Effector Memory T cells (TEM), and Effector Memory T cells Re-expressing CD45RA (TEMRA), was prominent among CD4+ T cell subset of ZIKV-infected patients and was associated with increased levels of IFN-γ, pSTAT-5, Ki-67, CTLA-4, and PD1, as compared to HD. Additionally, approximately 30% of ZIKV-infected patients exhibited a T cell response primarily directed against the ZIKV NS5 protein. CONCLUSION: Circulating T lymphocytes spontaneously produce IFN-γ and express elevated levels of pSTAT-5 during the early phase of ZIKV infection whereas recognition of ZIKV antigen results in the generation of virus-specific IFN-γ-producing T cells.

Identification of natural killer markers associated with fatal outcome in COVID-19 patients.

Introduction: Increasing evidence has shown that coronavirus disease 19 (COVID-19) severity is driven by a dysregulated immunological response. Previous studies have demonstrated that natural killer (NK) cell dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of NK cell markers as a driver of death in the most critically ill patients. Methods: We enrolled 50 non-vaccinated hospitalized patients infected with the initial virus or the alpha variant of SARS-CoV-2 with moderate or severe illness, to evaluate phenotypic and functional features of NK cells. Results: Here, we show that, consistent with previous studies, evolution NK cells from COVID-19 patients are more activated, with the decreased activation of natural cytotoxicity receptors and impaired cytotoxicity and IFN-γ production, in association with disease regardless of the SARS-CoV-2 strain. Fatality was observed in 6 of 17 patients with severe disease; NK cells from all of these patients displayed a peculiar phenotype of an activated memory-like phenotype associated with massive TNF-α production. Discussion: These data suggest that fatal COVID-19 infection is driven by an uncoordinated inflammatory response in part mediated by a specific subset of activated NK cells.

Impact of Anti PD-1 Immunotherapy on HIV Reservoir and Anti-Viral Immune Responses in People Living with HIV and Cancer.

The role of immune checkpoints (ICPs) in both anti-HIV T cell exhaustion and HIV reservoir persistence, has suggested that an HIV cure therapeutic strategy could involve ICP blockade. We studied the impact of anti-PD-1 therapy on HIV reservoirs and anti-viral immune responses in people living with HIV and treated for cancer. At several timepoints, we monitored CD4 cell counts, plasma HIV-RNA, cell associated (CA) HIV-DNA, EBV, CMV, HBV, HCV, and HHV-8 viral loads, activation markers, ICP expression and virus-specific T cells. Thirty-two patients were included, with median follow-up of 5 months. The CA HIV-DNA tended to decrease before cycle 2 (p = 0.049). Six patients exhibited a ≥0.5 log10 HIV-DNA decrease at least once. Among those, HIV-DNA became undetectable for 10 months in one patient. Overall, no significant increase in HIV-specific immunity was observed. In contrast, we detected an early increase in CTLA-4 + CD4+ T cells in all patients (p = 0.004) and a greater increase in CTLA-4+ and TIM-3 + CD8+ T cells in patients without HIV-DNA reduction compared to the others (p ≤ 0.03). Our results suggest that ICP replacement compensatory mechanisms might limit the impact of anti-PD-1 monotherapy on HIV reservoirs, and pave the way for combination ICP blockade in HIV cure strategies.

Initiating Antiretroviral Treatment Early in Infancy Has Long-term Benefits on the Human Immunodeficiency Virus Reservoir in Late Childhood and Adolescence.

BACKGROUND: Early combined antiretroviral therapy (cART) limits the total HIV-DNA load in children. However, data on its impact in older children and adolescents remain scarce. This study compares HIV reservoirs in children (5-12 years) and adolescents (13-17 years) who started cART <6 months (early [E-] group) or >2 years (late [L-] group). METHODS: The ANRS-EP59-CLEAC study prospectively enrolled 76 patients perinatally infected with HIV-1 who reached HIV-RNA <400 copies/mL <24 months after cART initiation, regardless of subsequent viral suppression (E-group: 27 children, 9 adolescents; L-group: 19 children, 21 adolescents). Total and integrated HIV-DNA were quantified in blood and in CD4+ T-cell subsets. A substudy assessed HIV reservoir inducibility after ex vivo peripheral blood mononuclear cell (PBMC) stimulation. RESULTS: Total HIV-DNA levels were lower in early- versus late-treated patients (children: 2.14 vs 2.87 log copies/million PBMCs; adolescents: 2.25 vs 2.74 log; P < .0001 for both). Low reservoir was independently associated with treatment precocity, protective HLA, and low cumulative viremia since cART initiation. The 60 participants with undetectable integrated HIV-DNA started cART earlier than other patients (4 vs 54 months; P = .03). In those with sustained virological control, transitional and effector memory CD4+ T cells were less infected in the E-group than in the L-group (P = .03 and .02, respectively). Viral inducibility of reservoir cells after normalization to HIV-DNA levels was similar between groups. CONCLUSIONS: Early cART results in a smaller blood HIV reservoir until adolescence, but all tested participants had an inducible reservoir. This deserves cautious consideration for HIV remission strategies.

NK Cell Responses in Zika Virus Infection Are Biased towards Cytokine-Mediated Effector Functions.

Zika virus (ZIKV) is a mosquito-borne flavivirus that has emerged as a global concern because of its impact on human health. ZIKV infection during pregnancy can cause microcephaly and other severe brain defects in the developing fetus and there have been reports of the occurrence of Guillain-Barré syndrome in areas affected by ZIKV. NK cells are activated during acute viral infections and their activity contributes to a first line of defense because of their ability to rapidly recognize and kill virus-infected cells. To provide insight into NK cell function during ZIKV infection, we have profiled, using mass cytometry, the NK cell receptor-ligand repertoire in a cohort of acute ZIKV-infected female patients. Freshly isolated NK cells from these patients contained distinct, activated, and terminally differentiated, subsets expressing higher levels of CD57, NKG2C, and KIR3DL1 as compared with those from healthy donors. Moreover, KIR3DL1+ NK cells from these patients produced high levels of IFN-γ and TNF-α, in the absence of direct cytotoxicity, in response to in vitro stimulation with autologous, ZIKV-infected, monocyte-derived dendritic cells. In ZIKV-infected patients, overproduction of IFN-γ correlated with STAT-5 activation (r = 0.6643; p = 0.0085) and was mediated following the recognition of MHC class 1-related chain A and chain B molecules expressed by ZIKV-infected monocyte-derived dendritic cells, in synergy with IL-12 production by the latter cells. Together, these findings suggest that NK cells contribute to the generation of an efficacious adaptive anti-ZIKV immune response that could potentially affect the outcome of the disease and/or the development of persistent symptoms.

A Comparison of Cell Activation, Exhaustion, and Expression of HIV Coreceptors and Restriction Factors in HIV-1- and HIV-2-Infected Nonprogressors.

Human immunodeficiency viruses induce rare attenuated diseases due either to HIV-1 in the exceptional long-term nonprogressors (LTNPs) or to HIV-2 in West Africa. To better understand characteristics of these two disease types we performed a multiplex comparative analysis of cell activation, exhaustion, and expression of coreceptors and restriction factors in CD4 T cells susceptible to harbor those viruses. We analyzed by flow cytometry the expression of HLA-DR, PD1, CCR5, CXCR6, SAMHD1, Blimp-1, and TRIM5α on CD4 T cell subsets from 10 HIV-1+ LTNPs and 14 HIV-2+ (12 nonprogressors and 2 progressors) of the ANRS CO-15 and CO-5 cohorts, respectively, and 12 HIV- healthy donors (HD). The V3 loop of the HIV-1 envelope from 6 HIV-1+ LTNPs was sequenced to determine the CXCR6-binding capacity. Proportions of HLA-DR+ and PD1+ cells were higher in memory CD4 T subsets from HIV-1 LTNPs compared with HIV-2 and HD. Similar findings were observed for CCR5+ cells although limited to central-memory CD4 T cell (TCM) and follicular helper T cell subsets, whereas all major subsets from HIV-1 LTNPs contained less CXCR6+ cells compared with HIV-2. All six V3 loop sequences from HIV-1 LTNPs contained a proline at position 326. Proportions of SAMHD1+ cells were higher in all resting CD4 T subsets from HIV-1 LTNPs compared with the other groups, whereas Blimp-1+ and Trim5α+ cells did not differ. The CD4 T cell subsets from HIV-1 LTNPs differ from those of HIV-2-infected subjects by higher levels of activation, exhaustion, and SAMHD1 expression that can reflect the distinct patterns of host/virus relationships.

Conventional Dendritic Cells and Slan+ Monocytes During HIV-2 Infection.

HIV-2 infection is characterized by low viremia and slow disease progression as compared to HIV-1 infection. Circulating CD14++CD16+ monocytes were found to accumulate and CD11c+ conventional dendritic cells (cDC) to be depleted in a Portuguese cohort of people living with HIV-2 (PLWHIV-2), compared to blood bank healthy donors (HD). We studied more precisely classical monocytes; CD16+ inflammatory (intermediate, non-classical and slan+ monocytes, known to accumulate during viremic HIV-1 infection); cDC1, important for cross-presentation, and cDC2, both depleted during HIV-1 infection. We analyzed by flow cytometry these PBMC subsets from Paris area residents: 29 asymptomatic, untreated PLWHIV-2 from the IMMUNOVIR-2 study, part of the ANRS-CO5 HIV-2 cohort: 19 long-term non-progressors (LTNP; infection ≥8 years, undetectable viral load, stable CD4 counts≥500/µL; 17 of West-African origin -WA), and 10 non-LTNP (P; progressive infection; 9 WA); and 30 age-and sex-matched controls: 16 blood bank HD with unknown geographical origin, and 10 HD of WA origin (GeoHD). We measured plasma bacterial translocation markers by ELISA. Non-classical monocyte counts were higher in GeoHD than in HD (54 vs. 32 cells/µL, p = 0.0002). Slan+ monocyte counts were twice as high in GeoHD than in HD (WA: 28 vs. 13 cells/µL, p = 0.0002). Thus cell counts were compared only between participants of WA origin. They were similar in LTNP, P and GeoHD, indicating that there were no HIV-2 related differences. cDC counts did not show major differences between the groups. Interestingly, inflammatory monocyte counts correlated with plasma sCD14 and LBP only in PLWHIV-2, especially LTNP, and not in GeoHD. In conclusion, in LTNP PLWHIV-2, inflammatory monocyte counts correlated with LBP or sCD14 plasma levels, indicating a potential innate immune response to subclinical bacterial translocation. As GeoHD had higher inflammatory monocyte counts than HD, our data also show that specific controls are important to refine innate immunity studies.

Correlation between blood telomere length and CD4+ CD8+ T-cell subsets changes 96 weeks after initiation of antiretroviral therapy in HIV-1-positive individuals.

In 31 participants who started first-line antiretroviral therapy in the NEAT 001/ANRS 143 clinical trial, we found after 96 weeks a statistically significant increase in blood telomere length (TL) of 0.04 (T/S Ratio) (p = 0.03). This increase was positively correlated with both the change in the percentage of CD4+ T-cells and with the decrease of CD38+ molecules on Central Memory CD8+ and negatively correlated with the change in the percentage of CD4+ Effector Memory cells. Increase in TL could be an expression of immune reconstitution and the associated decrease in immune activation. We acknowledge for the low statistical power due to the small sample size and the potential for false positive results due to multiple testing. Hence, further studies are needed to confirm these observations.

Persistent deficiency of mucosal-associated invariant T cells during dermatomyositis.

OBJECTIVES: Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are important for antibacterial immunity and may have regulatory roles. MAIT cells are decreased during SLE. However, their frequencies and phenotype have not been investigated in DM. We studied MAIT cell frequencies and phenotype in DM patients with active and inactive disease (after treatment). METHODS: Peripheral blood flow cytometry analysis of MAIT cells was compared between DM (n = 22), SLE (n = 10), psoriasis (n = 7) and atopic dermatitis (n = 5) patients, and healthy controls (n = 19). RESULTS: A dramatic decrease of circulating MAIT cell frequency was observed in active DM and SLE patients compared with healthy controls and other inflammatory skin diseases [active DM: median = 0.25% (interquartile range 0.19-0.6%), P < 0.0001; active SLE: median = 0.61 (0.55-0.77), P < 0.0001 vs healthy controls: 2.32% (1.18-4.45%)]. MAIT cells from active DM patients had an abnormal phenotype including increased expression of CD25 and cytotoxic T-lymphocyte-associated protein 4 that correlated with their low frequency in the blood. CONCLUSION: In DM, peripheral blood MAIT cells are dramatically reduced and have an activated/exhausted phenotype that may be linked to increased activation-induced cell death.

Limited HIV-2 reservoirs in central-memory CD4 T-cells associated to CXCR6 co-receptor expression in attenuated HIV-2 infection.

The low pathogenicity and replicative potential of HIV-2 are still poorly understood. We investigated whether HIV-2 reservoirs might follow the peculiar distribution reported in models of attenuated HIV-1/SIV infections, i.e. limited infection of central-memory CD4 T lymphocytes (TCM). Antiretroviral-naive HIV-2 infected individuals from the ANRS-CO5 (12 non-progressors, 2 progressors) were prospectively included. Peripheral blood mononuclear cells (PBMCs) were sorted into monocytes and resting CD4 T-cell subsets (naive [TN], central- [TCM], transitional- [TTM] and effector-memory [TEM]). Reactivation of HIV-2 was tested in 30-day cultures of CD8-depleted PBMCs. HIV-2 DNA was quantified by real-time PCR. Cell surface markers, co-receptors and restriction factors were analyzed by flow-cytometry and multiplex transcriptomic study. HIV-2 DNA was undetectable in monocytes from all individuals and was quantifiable in TTM from 4 individuals (median: 2.25 log10 copies/106 cells [IQR: 1.99-2.94]) but in TCM from only 1 individual (1.75 log10 copies/106 cells). HIV-2 DNA levels in PBMCs (median: 1.94 log10 copies/106 PBMC [IQR = 1.53-2.13]) positively correlated with those in TTM (r = 0.66, p = 0.01) but not TCM. HIV-2 reactivation was observed in the cells from only 3 individuals. The CCR5 co-receptor was distributed similarly in cell populations from individuals and donors. TCM had a lower expression of CXCR6 transcripts (p = 0.002) than TTM confirmed by FACS analysis, and a higher expression of TRIM5 transcripts (p = 0.004). Thus the low HIV-2 reservoirs differ from HIV-1 reservoirs by the lack of monocytic infection and a limited infection of TCM associated to a lower expression of a potential alternative HIV-2 co-receptor, CXCR6 and a higher expression of a restriction factor, TRIM5. These findings shed new light on the low pathogenicity of HIV-2 infection suggesting mechanisms close to those reported in other models of attenuated HIV/SIV infection models.

B7-H6-mediated downregulation of NKp30 in natural killer cells contributes to HIV-2 immune escape.

OBJECTIVE: HIV-1 and HIV-2 differ notably in their epidemiology, with worldwide HIV-1 spread and HIV-2 mainly confined to West Africa. Natural killer (NK) cells are critical antiviral effectors of the immune system; however, limited information is available about these innate effector cells during HIV-2 infection. METHOD: In this study, 24 untreated HIV-2-infected patients were analyzed and compared with 21 long-term nonprogressor and 10 controller HIV-1 patients, and healthy donors. Extensive phenotype and functional NK-cell characteristics, as well as ligands of activating NK receptors involved in NK lysis were determined by flow cytometry. RESULTS: We report in HIV-2 patients a very significant reduced expression of the activating NKp30 receptor (P < 0.0001) on NK cells, much higher than observed in HIV-1 patients. The impaired expression of NKp30 is correlated negatively with HLA-DR (r = -0.5970; P = 0.0002), and positively with both NKG2A (r = 0.5324; P < 0.0001) and Siglec-7 (r = 0.5621; P = 0.0004). HIV-2 patients with NKp30 NK cells displayed overproduction of IFN-γ (P < 0.0001) associated with impaired cytolytic function when tested against target cells expressing surface B7-H6. This cellular ligand of NKp30 is strongly detectable as a surface molecule on CD4 T cells infected by HIV-2. CONCLUSION: Altogether, our data suggested that the defective expression of NKp30 may be induced by the chronic engagement of this receptor by B7-H6 expressed on HIV-2-infected target cells. This represents a novel mechanism by which the chronic ligand exposure by the viral environment may subvert NK-cell-mediated function to establish persistent HIV-2 infection.

Serum Tryptophan-Derived Quinolinate and Indole-3-Acetate Are Associated With Carotid Intima-Media Thickness and its Evolution in HIV-Infected Treated Adults.

BACKGROUND: HIV-infected individuals undergoing effective antiretroviral therapy (ART) present an increased risk of atherosclerotic cardiovascular disease. We identified serum metabolites associated with carotid intima-media thickness (c-IMT) and its evolution. METHODS: One hundred forty-three hydrophilic serum metabolites were measured by ultraperformance liquid chromatography coupled with high-resolution mass spectrometry in 49 HIV+ ART+, 48 HIV+ ART-naïve and 50 HIV-negative, age-matched, never-smoking male triads. Metabolites differentially altered between groups ("features") were defined as having a Benjamini-Hochberg-adjusted P value <.05 from a t test and >0.25 log2 absolute mean fold change in metabolite levels. c-IMT was measured across 12 sites at inclusion in all individuals and at the carotid artery (cca) after a median of 5.1 years in 32 HIV+ ART+ individuals. The difference in c-IMT (cross-sectional analysis) and slope of cca-IMT regression/progression per year (longitudinal analysis) for each log10 (area) increase in metabolite level were estimated with linear regression. RESULTS: Compared with HIV-, metabolite features of HIV+ ART+ were increased N6,N6,N6-trimethyl-L-lysine and decreased ferulate and 5-hydroxy-L-tryptophan, whereas features of HIV+ ART-naïve were increased malate, kynurenine, 2-oxoglutarate, and indole-3-acetate and decreased succinate and 5-hydroxy-L-tryptophan. In HIV+ ART+ individuals, quinolinate and/or indole-3-acetate were positively associated with c-IMT (P < .03), cca-IMT (P < .03), and cca-IMT progression (P < .008). These associations were not observed in HIV+ ART-naïve or HIV-negative individuals. In HIV+ ART+ individuals, the metabolites xanthosine and uridine, from nucleotide metabolism, and g-butyrobetaine, from lysine/dietary choline degradation, were also positively or negatively associated with c-IMT and/or cca-IMT (all P < .01), but not its evolution. CONCLUSIONS: In these highly selected HIV-positive ART-controlled males, 2 novel metabolites derived from tryptophan catabolism, indole-3-acetate and quinolinate, were associated with c-IMT and its progression.

Zika virus in the eye of the cytokine storm.

Zika virus (ZIKV) is an emerging arbovirus that causes a mosquito-borne disease. Although infection with ZIKV generally leads to mild disease, its recent emergence in the Americas has been associated with an increase in the development of the Guillain-Barré syndrome in adults, as well as with neurological complications, in particular congenital microcephaly, in new-borns. Over the five past years, through the combined efforts of the scientific community, comprehensive remarkable progress aimed at deciphering the clinical, virological, physiopathological, and immunological features of ZIKV infection. This review highlights some of the most recent advances in our understanding of the role of cytokines and chemokines in ZIKV infection, and discusses potential links to pathogenesis.

Immunogenicity and safety of yellow fever vaccine in HIV-1-infected patients.

OBJECTIVES: The objective of this study is to investigate immunogenicity and safety of the yellow fever vaccine (YFV) in HIV-infected (HIV+) patients with high CD4 T-cell counts. DESIGN: In this prospective, comparative study of YFV-naive adults: 40 HIV+ under antiretroviral therapy (ART) with CD4 T-cell count above 350 cells/µl and plasma HIV-RNA less than 50 copies/ml for at least 6 months and 31 HIV-negative (HIV-) received one injection of the YF-17D strain vaccine. METHODS: Serologic response was assessed by using a plaque reduction neutralizing test and YFV-specific T cells by using an INFγ-Elispot assay. RESULTS: YFV was well tolerated in both groups. Most participants had asymptomatic YFV viremia at day (D) 7 after vaccination (77% of HIV- and 82% of HIV+, P = 0.58), with higher plasma level of YFV RNA in HIV+ than in HIV- (median 2.46 log10 copies/ml (range: 1.15-4.16) and 1.91 log10 copies/ml (1.15-3.19), respectively, P = 0.011). A significant but transient decrease in CD4 cell counts was seen at D7 in both groups, more pronounced in HIV- than in HIV+ patients (-261.5 versus -111.5 cells/µl, respectively, P = 0.0003), but no HIV breakthrough was observed in plasma. All participants developed protective neutralizing antibody levels from D28 and up to 1 year after injection. At D91, fewer HIV+ than HIV- participants exhibited YFV T-cell response (20 versus 54%, respectively, P = 0.037). CONCLUSION: At 1 year, YFV was immunogenic and well tolerated in HIV-infected adults under ART with CD4 T-cell counts above 350 cells/µl. However, a lower immunity of YFV T cells in HIV-infected patients was observed as compared with HIV- participants. CLINICAL TRIALS REGISTRATION: NCT01426243.

Neutralizing Antibodies Against a Specific Human Immunodeficiency Virus gp41 Epitope are Associated With Long-term Non-progressor Status.

Antibodies (Abs) play a central role in human immunodeficiency virus (HIV) protection due to their multiple functional inhibitory activities. W614A-3S Abs recognize a specific form of a highly conserved motif of the gp41 envelope protein and can elicit viral neutralization to protect CD4+ T cells. Here, we describe in detail the neutralizing profile of W614A-3S Abs in untreated long-term non-progressor (LTNP) HIV-infected patients. W614A-3S Abs were detected in 23.5% (16/68) of untreated LTNP patients compared with <5% (5/104) of HIV-1 progressor patients. The W614A-3S Abs had efficient neutralizing activity that inhibited transmitted founder primary viruses and exhibited Fc-mediated inhibitory functions at low concentrations in primary monocyte-derived macrophages. The neutralizing capacity of W614A-3S Abs was inversely correlated with viral load (r=-0.9013; p<0.0001), viral DNA (r=-0.7696; p=0.0005) and was associated the preservation of high CD4+ T-cell counts and T-cell responses. This study demonstrates that W614A-3S neutralizing Abs may confer a crucial advantage to LTNP patients. These results provide insights for both pathophysiological research and the development of vaccine strategies.

HIV-Specific B Cell Frequency Correlates with Neutralization Breadth in Patients Naturally Controlling HIV-Infection.

HIV-specific broadly neutralizing antibodies (bnAbs) have been isolated from patients with high viremia but also from HIV controllers that repress HIV-1 replication. In these elite controllers (ECs), multiple parameters contribute to viral suppression, including genetic factors and immune responses. Defining the immune correlates associated with the generation of bnAbs may help in designing efficient immunotherapies. In this study, in ECs either positive or negative for the HLA-B*57 protective allele, in treated HIV-infected and HIV-negative individuals, we characterized memory B cell compartments and HIV-specific memory B cells responses using flow cytometry and ELISPOT. ECs preserved their memory B cell compartments and in contrast to treated patients, maintained detectable HIV-specific memory B cell responses. All ECs presented IgG1+ HIV-specific memory B cells but some individuals also preserved IgG2+ or IgG3+ responses. Importantly, we also analyzed the capacity of sera from ECs to neutralize a panel of HIV strains including transmitted/founder virus. 29% and 21% of HLA-B*57+ and HLA-B*57- ECs, respectively, neutralized at least 40% of the viral strains tested. Remarkably, in HLA-B*57+ ECs the frequency of HIV-Env-specific memory B cells correlated positively with the neutralization breadth suggesting that preservation of HIV-specific memory B cells might contribute to the neutralizing responses in these patients.

Identifying Cytomegalovirus Complications Using the Quantiferon-CMV Assay After Allogeneic Hematopoietic Stem Cell Transplantation.

Background: A simple test to identify recovery of CMV-specific T-cell immunity following hematopoietic stem cell transplantation (HSCT) could assist clinicians in managing CMV-related complications. Methods: In an observational, multicenter, prospective study of 94 HSCT recipients we evaluated CMV-specific T-cell immunity at baseline, 3, 6, 9, and 12 months after transplant using the Quantiferon-CMV, an enzyme-linked immunosorbent spot assay (ELISpot), and intracellular cytokine staining. Results: At 3 months after HSCT, participants who developed CMV disease (n = 8) compared with CMV reactivation (n = 26) or spontaneous viral control (n = 25) had significantly lower CD8+ T-cell production of interferon-γ (IFN-γ) in response to CMV antigens measured by Quantiferon-CMV (P = .0008). An indeterminate Quantiferon-CMV result had a positive predictive value of 83% and a negative predictive value of 98% for identifying participants at risk of further CMV reactivation. Participants experiencing CMV reactivation compared with patients without CMV reactivation had a reduced proportion of polyfunctional (IFN-γ+/tumor necrosis factor α-positive) CD4+ and CD8+ T cells and a higher proportion of interleukin 2-secreting cells (P = .01 and P = .002, respectively). Conclusions: Quantifying CMV-specific T-cell immunity after HSCT can identify participants at increased risk of clinically relevant CMV-related outcomes.