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Human immunodeficiency virus 1 (HIV-1) infection is characterized by a dynamic and persistent state of viral replication that overwhelms the host immune system in the absence of antiretroviral therapy (ART). The impact of prolonged treatment on the antiviral efficacy of HIV-1-specific CD8+T cells has nonetheless remained unknown. Here, we used single-cell technologies to address this issue in a cohort of aging individuals infected early during the pandemic and subsequently treated with continuous ART. Our data showed that long-term ART was associated with a process of clonal succession, which effectively rejuvenated HIV-1-specific CD8+T cell populations in the face of immune senescence. Tracking individual transcriptomes further revealed that initially dominant CD8+T cell clonotypes displayed signatures of exhaustion and terminal differentiation, whereas newly dominant CD8+T cell clonotypes displayed signatures of early differentiation and stemness associated with natural control of viral replication. These findings reveal a degree of immune resilience that could inform adjunctive treatments for HIV-1.

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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.

Supplemental Digital Content is available in the textTo further understand the exceptional HIV-1 control observed in Post-Treatment Controllers (PTCs) from the Virological and Immunological Sustained CONtrol after Treatment Interruption study we investigated their HIV-specific T-cell responses. Polyfunctionality of HIV-specific CD4 and CD8 T cells and the ratios of HIV-specific CD4 T cells per infected cells were similar in post-treatment controllers, continuously early-treated patients and long-term non-progressors Overall early treatment appears to preserve robust HIV-specific CD4+T cells, which might contribute to the posttreatment control of HIV.

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Human leukocyte antigen (HLA) class I-driven long-term protection against HIV-1 is mainly associated with HLA-B27 and HLA-B57. This effect is observed early after infection. Clarification needs to be established concerning the moment of action for the other HLA-B or HLA-C alleles.

Background The long-term immunological benefit of protease inhibitor (PI)-sparing antiretroviral therapy (ART) using non-nucleoside reverse transcriptase inhibitors (NNRTIs) remains poorly investigated.Methods A total of 120 ART-naive, HIV-1-infected participants were included in the immunology substudy of INITIO, an international randomized trial comparing two NRTIs (didanosine + stavudine) combined with either: one NNRTI (efavirenz; EFV), one non-boosted PI (nelfinavir; NFV), or one NNRTI + one PI (EFV/NFV). CD4+T-cell counts, HIV-1 plasma RNA load (VL), T-cell pheno-type, T-cell proliferation and IFN-? production against opportunistic/recall and HIV-1 antigens/peptides were compared at baseline and at week (W) 96 and W156.Results Participants (37 EFV, 44 NFV, 39 EFV/NFV) had similar baseline VL; median CD4+T-cell counts/mm3were: 144 (64–303) EFV, 212 (42–313) NFV and 257 (86–331) EFV/NFV. At W156, the proportion of patients with VL =50 copies/ml was not different between the arms (P=0.3). From baseline to W156 there was a significant increase in CD4+T-cell counts (P<0.001) and in naive CD4+T cells (P<0.001), with no difference between arms and percentages of total and activated CD8+T cells decreased significantly (P<0.001) in all arms. The decrease in activated memory CD4+T-cells was significantly greater in the EFV arm at W96 (P=0.03) and W156 (P=0.01), but did not persist after adjusting for baseline CD4+T-cell counts. During follow-up, responses to opportunistic pathogens increased in all patients while specific T-cell responses to HIV-1-p24 and gp160 recombinant proteins or to Gag and Nef peptides were not restored.Conclusion Regimens using/sparing PIs provide similar levels of long-term immune reconstitution even in patients with low CD4+T-cell counts.

CCR6, a homeostatic chemokine receptor, is shown here to characterize subsets of both central and effector memory T cells that secrete high levels of IL-2 and TNF-α in response to polyclonal and antigen-specific stimulation. CCR6+T lymphocytes disappeared dramatically from the peripheral blood of HIV-infected patients as HIV disease progressed. The capacity of CD4+CCR6+to secrete multiple cytokines remained intact among HIV-infected long-term nonprogressors but was partially lost from subjects with standard disease progression. CCR6+T lymphocytes, regardless of their CCR7 expression, accumulated in the spleen of HIV-infected patients, where they died by apoptosis. Assessment of CCR6 expression allowed us to describe novel memory T-cell subpopulations capable of high cytokine production and provided evidence of a pathologic CCR6-dependent pathway of memory T-cell homing that may participate in the loss of memory response against infections.

CCR6, a homeostatic chemokine receptor, is shown here to characterize subsets of both central and effector memory T cells that secrete high levels of IL-2 and TNF-α in response to polyclonal and antigen-specific stimulation. CCR6+ T lymphocytes disappeared dramatically from the peripheral blood of HIV-infected patients as HIV disease progressed. The capacity of CD4+CCR6+ to secrete multiple cytokines remained intact among HIV-infected long-term nonprogressors but was partially lost from subjects with standard disease progression. CCR6+ T lymphocytes, regardless of their CCR7 expression, accumulated in the spleen of HIV-infected patients, where they died by apoptosis. Assessment of CCR6 expression allowed us to describe novel memory T-cell subpopulations capable of high cytokine production and provided evidence of a pathologic CCR6-dependent pathway of memory T-cell homing that may participate in the loss of memory response against infections.

Residual immunity to the smallpox virus raises key questions about the persistence of long-term immune memory in the absence of antigen, since vaccination ended in 1980. IFN-γ–producing effector–memory and proliferative memory T cells were compared in 79 vaccinees 13–25 yr after their last immunization and in unvaccinated individuals. Only 20% of the vaccinees displayed both immediate IFN-γ–producing effector–memory responses and proliferative memory responses at 6 d; 52.5% showed only proliferative responses; and 27.5% had no detectable vaccinia-specific responses at all. Both responses were mediated by CD4 and CD8 T cells. The vaccinia-specific IFN-γ–producing cells were composed mainly of CD4Pos CD45RANeg CD11aHi CD27Pos and CCR7Neg T cells. Their frequency was low but could be expanded in vitro within 7 d. Time since first immunization affected their persistence: they vanished 45 yr after priming, but proliferative responses remained detectable. The number of recalls did not affect the persistence of residual effector–memory T cells. Programmed revaccination boosted both IFN-γ and proliferative responses within 2 mo of recall, even in vaccinees with previously undetectable residual effector–memory cells. Such long-term maintenance of vaccinia-specific immune memory in the absence of smallpox virus modifies our understanding of the mechanism of persistence of long-term memory to poxviruses and challenges vaccination strategies.

Although the mouse spleen dendritic cell (DC) is perhaps the most intensively studied DC type, little has been published concerning its human equivalent. In this report, rare event flow cytometry and in situ immunofluorescence were used to study the surface phenotype and distribution of HLA-DR+CD3−14−16−19− human spleen DC. Spleens from organ donors with different clinical histories were used. Most (81% ± 9%; n = 14) spleen DCs expressed high levels of the integrin CD11c. CD11c+ DCs were distributed in 3 distinct regions—the peri-arteriolar T-cell zones, the B-cell zones, and the marginal zone, where they formed a ring of cells surrounding the white pulp, just inside a ring of CD14+ red pulp macrophages, apparently more regularly organized than the previously described marginating DC population in the mouse spleen. The T-cell zones contained CD86+ DCs, among which a subpopulation expressed CD83. These mature/activated CD86+DCs represented a minority (12% ± 8%) of total spleen DCs in most organ donors: most spleen DCs are immature. In 3 of 18 (17%) donors, however, most (54%-81%) of spleen DCs were CD86+, suggesting that in vivo DC activation had occurred. In one donor, a radical shift in DC distribution from the marginal zone to the T-cell zones was also observed. This activation of spleen DCs in vivo was reminiscent of the effects of experimental microbial product injection in mice, and it seemed to correlate with bacterial infection or multiple trauma.

Although the mouse spleen dendritic cell (DC) is perhaps the most intensively studied DC type, little has been published concerning its human equivalent. In this report, rare event flow cytometry and in situ immunofluorescence were used to study the surface phenotype and distribution of HLA-DR+CD3−14−16−19−human spleen DC. Spleens from organ donors with different clinical histories were used. Most (81% ± 9%; n = 14) spleen DCs expressed high levels of the integrin CD11c. CD11c+DCs were distributed in 3 distinct regions—the peri-arteriolar T-cell zones, the B-cell zones, and the marginal zone, where they formed a ring of cells surrounding the white pulp, just inside a ring of CD14+red pulp macrophages, apparently more regularly organized than the previously described marginating DC population in the mouse spleen. The T-cell zones contained CD86+DCs, among which a subpopulation expressed CD83. These mature/activated CD86+DCs represented a minority (12% ± 8%) of total spleen DCs in most organ donors: most spleen DCs are immature. In 3 of 18 (17%) donors, however, most (54%-81%) of spleen DCs were CD86+, suggesting that in vivo DC activation had occurred. In one donor, a radical shift in DC distribution from the marginal zone to the T-cell zones was also observed. This activation of spleen DCs in vivo was reminiscent of the effects of experimental microbial product injection in mice, and it seemed to correlate with bacterial infection or multiple trauma.

Human immunodeficiency virus (HIV) infection is characterized by the massive infiltration of secondary lymphoid organs with activated CD8+T lymphocytes. While converging data indicated that these cells were HIV-specific cytotoxic T lymphocytes (CTLs) responsible for HIV spread limitation, direct evidence was lacking. Here, the presence of HIV-specific effector CTLs was demonstrated directly ex vivo in 15 of 24 microdissected splenic white pulps from an untreated patient and in 1 of 24 tonsil germinal centers from a second patient with incomplete viral suppression following bitherapy. These patients had plasma HIV RNA loads of 5900 and 820 copies per milliliter. The frequencies of HIV-1 DNA+cells in their lymphoid organs were more than 1 in 50 and 1 in 175, respectively. Spliced viral messenger RNA (a marker for ongoing viral replication) was present in most immunocompetent structures tested. Conversely, CTL activity was not found in spleens from 2 patients under highly active antiretroviral therapy, with undetectable plasma viral load. These patients had much lower spleen DNA+cell frequencies (1 in 2700 and 1 in 3800) and no white pulps containing spliced RNA. CTL effector activity as well as spliced viral messenger RNA were both concentrated in the white pulps and germinal centers. This colocalization indicates that viral replication in immunocompetent structures of secondary lymphoid organs triggers anti-HIV effector CTLs to these particular locations, providing clues to target therapeutic intervention.

Human immunodeficiency virus (HIV) infection is characterized by the massive infiltration of secondary lymphoid organs with activated CD8+ T lymphocytes. While converging data indicated that these cells were HIV-specific cytotoxic T lymphocytes (CTLs) responsible for HIV spread limitation, direct evidence was lacking. Here, the presence of HIV-specific effector CTLs was demonstrated directly ex vivo in 15 of 24 microdissected splenic white pulps from an untreated patient and in 1 of 24 tonsil germinal centers from a second patient with incomplete viral suppression following bitherapy. These patients had plasma HIV RNA loads of 5900 and 820 copies per milliliter. The frequencies of HIV-1 DNA+ cells in their lymphoid organs were more than 1 in 50 and 1 in 175, respectively. Spliced viral messenger RNA (a marker for ongoing viral replication) was present in most immunocompetent structures tested. Conversely, CTL activity was not found in spleens from 2 patients under highly active antiretroviral therapy, with undetectable plasma viral load. These patients had much lower spleen DNA+ cell frequencies (1 in 2700 and 1 in 3800) and no white pulps containing spliced RNA. CTL effector activity as well as spliced viral messenger RNA were both concentrated in the white pulps and germinal centers. This colocalization indicates that viral replication in immunocompetent structures of secondary lymphoid organs triggers anti-HIV effector CTLs to these particular locations, providing clues to target therapeutic intervention.

ABSTRACTImmune control of human immunodeficiency virus (HIV) is not restored by highly active antiretroviral therapies (HAART) during chronic infection. We examined the capacity of repeated structured therapeutic interruptions (STI) to restore HIV-specific CD4 and CD8 T-cell responses that controlled virus production. Eleven STI (median duration, 7 days; ranges, 4 to 24 days) were performed in three chronically HIV-infected patients with CD4 counts above 400/mm3and less than 200 HIV RNA copies/ml after 18 to 21 months of HAART; treatment resumed after 1 week or when virus became detectable. HIV-specific T-cell responses were analyzed by proliferation, gamma interferon (IFN-?) production, and enzyme-linked immunospot assays. Seven virus rebounds were observed (median, 4,712 HIV-1 RNA copies/ml) with a median of 7 days during which CD4 and CD8 counts did not significantly change. After treatment resumed, the viral load returned below 200 copies/ml within 3 weeks. Significant CD4 T-cell proliferation and IFN-? production against HIV p24 appeared simultaneously with or even before the virus rebounds in all patients. These CD4 responses lasted for less than 3 weeks and disappeared before therapeutic control of the virus had occurred. Increases in the numbers of HIV-specific CD8 T cells were delayed compared to changes in HIV-specific CD4 T-cell responses. No delay or increase in virus doubling time was observed after repeated STI. Iterative reexposure to HIV during short STI in chronically infected patients only transiently mobilized HIV-specific CD4 T1-helper cells, which might be rapidly altered by virus replication. Such kinetics might explain the failure at delaying subsequent virus rebounds and raises concerns about strategies based on STI to restore durable HIV-specific T-cell responses in chronic HIV infection.

ABSTRACTThe impact of drug resistance mutations induced by nucleoside reverse transcriptase (RT) inhibitors (NRTI) on cytotoxic T-lymphocyte (CTL) recognition of human immunodeficiency virus type 1 strain LAI (HIV-1LAI) RT was addressed in 35 treated or untreated patients. Two HIV-1LAIRT regions encompassing mutation M41L, L74V, M184V, and T215Y/F were recognized in 75 and 83% mutated and in 33 and 42% unmutated samples, respectively. A total of 41 new CTL epitopes overlapping these mutations were predicted. Mutations enhanced HLA-binding scores of 17 epitopes, decreased scores of 5, and had no effect in 19. Four predicted epitopes containing mutations 41, 74, and 184 were tested and recognized by CD8 cells from mutated or unmutated samples, with frequencies up to 270 gamma interferon spot-forming cells per 106peripheral blood mononuclear cells. Therefore, RT mutations induced by NRTI can increase the immunogenicity of RT for CTL and might allow a better immune control of resistant viruses in vivo, suggesting that specific immune therapy might help prevent these mutations.

No relevant conflicts of interest to declare.

Introduction: A simple test to identify recovery of CMV-specific T cell immunity in the post hematopoietic stem cell transplant (HSCT) period could assist clinicians in managing CMV related complications. The current assays of cell mediated immunity require specialised personnel and equipment, take a long time to perform and are often not available in a routine diagnostic laboratory. We therefore assessed CMV-specific CD8+ T cell immunity using a rapid high throughput Quantiferon-CMV assay to characterise the kinetics of CMV-specific immunity following HSCT.