Targeting HIV persistence in the tissue

HIV; TissueVIH; TejidoVIH; TeixitPurpose of review The complex nature and distribution of the HIV reservoir in tissue of people with HIV remains one of the major obstacles to achieve the elimination of HIV persistence. Challenges include the tissue-specific states of latency and viral persistence, which translates into high levels of reservoir heterogeneity. Moreover, the best strategies to reach and eliminate these reservoirs may differ based on the intrinsic characteristics of the cellular and anatomical reservoir to reach. Recent findings While major focus has been undertaken for lymphoid tissues and follicular T helper cells, evidence of viral persistence in HIV and non-HIV antigen-specific CD4+ T cells and macrophages resident in multiple tissues providing long-term protection presents new challenges in the quest for an HIV cure. Considering the microenvironments where these cellular reservoirs persist opens new venues for the delivery of drugs and immunotherapies to target these niches. New tools, such as single-cell RNA sequencing, CRISPR screenings, mRNA technology or tissue organoids are quickly developing and providing detailed information about the complex nature of the tissue reservoirs. Summary Targeting persistence in tissue reservoirs represents a complex but essential step towards achieving HIV cure. Combinatorial strategies, particularly during the early phases of infection to impact initial reservoirs, capable of reaching and reactivating multiple long-lived reservoirs in the body may lead the path.This work was primarily supported by grants from the Spanish Health Institute Carlos III (PI20/00160), co-funded by ERDF/ESF, “A way to make Europe”/“Investing in your future”, the Fundació La Marató TV3 (202112–30 FMTV3) and the Gilead fellowships GLD21/00049

Regulatory KIR+ RA+ T cells accumulate with age and are highly activated during viral respiratory disease

Severe respiratory viral infectious diseases such as influenza and COVID-19 especially affect the older population. This is partly ascribed to diminished CD8+ T-cell responses a result of aging. The phenotypical diversity of the CD8+ T-cell population has made it difficult to identify the impact of aging on CD8+ T-cell subsets associated with diminished CD8+ T-cell responses. Here we identify a novel human CD8+ T-cell subset characterized by expression of Killer-cell Immunoglobulin-like Receptors (KIR+ ) and CD45RA (RA+ ). These KIR+ RA+ T cells accumulated with age in the blood of healthy individuals (20-82 years of age, n = 50), expressed high levels of aging-related markers of T-cell regulation, and were functionally capable of suppressing proliferation of other CD8+ T cells. Moreover, KIR+ RA+ T cells were a major T-cell subset becoming activated in older adults suffering from an acute respiratory viral infection (n = 36), including coronavirus and influenza virus infection. In addition, older adults with influenza A infection showed that higher activation status of their KIR+ RA+ T cells associated with longer duration of respiratory symptoms. Together, our data indicate that KIR+ RA+ T cells are a unique human T-cell subset with regulatory properties that may explain susceptibility to viral respiratory disease at old age

The adaptive immune system in early life: The shift makes it count.

Respiratory infectious diseases encountered early in life may result in life-threatening disease in neonates, which is primarily explained by the relatively naive neonatal immune system. Whereas vaccines are not readily available for all infectious diseases, vaccinations have greatly reduced childhood mortality. However, repeated vaccinations are required to reach protective immunity in infants and not all vaccinations are effective at young age. Moreover, protective adaptive immunity elicited by vaccination wanes more rapidly at young age compared to adulthood. The infant adaptive immune system has previously been considered immature but this paradigm has changed during the past years. Recent evidence shows that the early life adaptive immune system is equipped with a strong innate-like effector function to eliminate acute pathogenic threats. These strong innate-like effector capacities are in turn kept in check by a tolerogenic counterpart of the adaptive system that may have evolved to maintain balance and to reduce collateral damage. In this review, we provide insight into these aspects of the early life’s adaptive immune system by addressing recent literature. Moreover, we speculate that this shift from innate-like and tolerogenic adaptive immune features towards formation of immune memory may underlie different efficacy of infant vaccination in these different phases of immune development. Therefore, presence of innate-like and tolerogenic features of the adaptive immune system may be used as a biomarker to improve vaccination strategies against respiratory and other infections in early life

Response kinetics reveal novel features of ageing in murine T cells.

The impact of ageing on the immune system results in defects in T cell responsiveness. The search for ageing hallmarks has been challenging due to the complex nature of immune responses in which the kinetics of T cell responsiveness have largely been neglected. We aimed to unravel hallmarks of ageing in the kinetics of the murine T cell response. To this end, we assessed ageing-related T-cell response kinetics by studying the effect of the duration and strength of in vitro stimulation on activation, proliferation, and cytokine secretion by T cells of young and aged mice. Collectively, our data show that stimulatory strength and time kinetics of cytokine secretion, activation markers, and proliferation of Th, Tc, and Treg cells are crucial in understanding the impact of ageing on T cells. Despite low proliferative capacity, T cell subsets of aged mice do respond to stimulation by upregulation of activation markers and secretion of cytokines. These findings therefore indicate that replicative senescence of aged T cells is not a measure of unresponsiveness per se, but rather stress that ageing influences the kinetics of proliferation, upregulation of activation markers and cytokine secretion each to a different extent

Co-Expression of TIGIT and Helios Marks Immunosenescent CD8 T Cells During Aging.

Aging leads to alterations in the immune system that result in ineffective responsiveness against pathogens. Features of this process, collectively known as immunosenescence, accumulate in CD8+ T cells with age and have been ascribed to differentiation of these cells during the course of life. Here we aimed to identify novel markers in CD8+ T cells associated with immunosenescence. Furthermore, we assessed how these markers relate to the aging-related accumulation of highly differentiated CD27-CD28- cells. We found that co-expression of the transcription factor Helios and the aging-related marker TIGIT identifies CD8+ T cells that fail to proliferate and show impaired induction of activation markers CD69 and CD25 in response to stimulation in vitro. Despite this, in blood of older adults we found TIGIT+Helios+ T cells to become highly activated during an influenza-A virus infection, but these higher frequencies of activated TIGIT+Helios+ T cells associate with longer duration of coughing. Moreover, in healthy individuals, we found that TIGIT+Helios+ CD8+ T cells accumulate with age in the highly differentiated CD27-CD28- population. Interestingly, TIGIT+Helios+ CD8+ T cells also accumulate with age among the less differentiated CD27+CD28- T cells before their transit into the highly differentiated CD27-CD28- stage. This finding suggests that T cells with immunosenescent features become prominent at old age also within the earlier differentiation states of these cells. Our findings show that co-expression of TIGIT and Helios refines the definition of immunosenescent CD8+ T cells and challenge the current dogma of late differentiation stage as proxy for T-cell immunosenescence

Diversity of aging of the immune system classified in the cotton rat (Sigmodon hispidus) model of human infectious diseases.

Susceptibility and declined resistance to human pathogens like respiratory syncytial virus (RSV) at old age is well represented in the cotton rat (Sigmodon hispidus). Despite providing a preferred model of human infectious diseases, little is known about aging of its adaptive immune system. We aimed to define aging-related changes of the immune system of this species. Concomitantly, we asked whether the rate of immunological alterations may be stratified by physiological aberrations encountered during aging. With increasing age, cotton rats showed reduced frequencies of T cells, impaired induction of antibodies to RSV, higher incidence of aberrations of organs and signs of lipemia. Moreover, old animals expressed high biological heterogeneity, but the age-related reduction of T cell frequency was only observed in those specimens that displayed aberrant organs. Thus, cotton rats show age-related alterations of lymphocytes that can be classified by links with health status

Limited induction of polyfunctional lung-resident memory T cells against SARS-CoV-2 by mRNA vaccination compared to infection

Resident memory T cells at the respiratory tract may play critical roles in the response to respiratory infections including SARS-CoV-2. Here the authors characterise the lung resident T cell response generated in response to mRNA vaccination of SARS-CoV-2 Spike or in convalescent patients after natural infection. They show reduced frequency and functionality of tissue resident T cells in vaccinated versus convalescent patients which may impact disease control and vaccination strategies

Reduced -specific CD4 T-Cell Responses at Older Age.

Pertussis, a human-specific respiratory infectious disease caused by the Gram-negative bacterium Bordetella pertussis (Bp), remains endemic with epidemic years despite high vaccination coverage. Whereas pertussis vaccines and natural infection with Bp confer immune protection, the duration of protection varies and is not lifelong. Recent evidence indicates a considerable underestimation of the pertussis burden among older adults. Whereas the impact of increasing age on Bp-specific humoral immunity has been demonstrated, little is known on immunosenescence of CD4+ T-cell responses in the context of Bp. Here, we aimed to address whether increasing age impacts responsiveness of the Bp-specific CD4+ T-cells in the memory pool following a clinically symptomatic pertussis infection in whole cell vaccine-primed pediatric and adult cases. Cytokine and proliferative responses and phenotypical profiles of CD4+ T cells specific for Bp antigens at an early and late convalescent timepoint were compared. Responses of various Th cytokines, including IFNγ, were significantly lower in older adults at early and late timepoints post diagnosis. In addition, we found lower frequencies of Bp-specific proliferated CD4+ T cells in older adults, in the absence of differences in replication profile. Phenotyping of Bp-specific CD4+ T cells suggested reduced expression of activation markers rather than increased expression of co-inhibitory markers. Altogether, our findings show that the magnitude and functionality of the Bp-specific memory CD4+ T-cell pool decrease at older age. Declined CD4+ T-cell responsiveness to Bp is suggested to contribute to the burden of pertussis in older adults

Long Lasting Antibodies From Convalescent Pertussis Patients Induce ROS Production and Bacterial Killing by Human Neutrophils.

Pertussis is a respiratory infection caused by the Gram-negative bacterium Bordetella pertussis. Despite high vaccination coverage this disease remains a public health concern worldwide. A better understanding of the protective immune responses to B. pertussis is required for the development of improved vaccines. The aim of this study was to determine the production of reactive oxygen species (ROS) by human neutrophils in response to B. pertussis and to determine the contribution of opsonizing antibodies from convalescent pertussis patients in this response. The serum samples from convalescent patients were taken at <3, 9, 18 and 36 months after diagnosis of pertussis. Also included were sera from healthy age-matched controls. We show that neutrophils produced high levels of ROS in response to opsonized, compared to non-opsonized, B. pertussis and that this effect was independent of the time the convalescent serum samples were taken. This indicates the presence of functional opsonizing antibodies up to 3 years after B. pertussis infection. While opsonization of B. pertussis with serum samples from uninfected controls also induced ROS production, sera from infected individuals induced significantly higher ROS levels. Spearman correlations analysis showed that IgG antibodies targeting fimbriae3 followed by pertactin, and BrkA correlate with ROS production. Additionally, we observed that neutrophils killed opsonized B. pertussis in a ROS-dependent manner. Searching for other antigen-specific antibodies from convalescent pertussis patients involved in ROS production by neutrophils may assist in the identification of novel antigens to improve the current pertussis vaccines

Regulatory KIR RA T cells accumulate with age and are highly activated during viral respiratory disease.

Severe respiratory viral infectious diseases such as influenza and COVID-19 especially affect the older population. This is partly ascribed to diminished CD8+ T-cell responses a result of aging. The phenotypical diversity of the CD8+ T-cell population has made it difficult to identify the impact of aging on CD8+ T-cell subsets associated with diminished CD8+ T-cell responses. Here we identify a novel human CD8+ T-cell subset characterized by expression of Killer-cell Immunoglobulin-like Receptors (KIR+ ) and CD45RA (RA+ ). These KIR+ RA+ T cells accumulated with age in the blood of healthy individuals (20-82 years of age, n = 50), expressed high levels of aging-related markers of T-cell regulation, and were functionally capable of suppressing proliferation of other CD8+ T cells. Moreover, KIR+ RA+ T cells were a major T-cell subset becoming activated in older adults suffering from an acute respiratory viral infection (n = 36), including coronavirus and influenza virus infection. In addition, older adults with influenza A infection showed that higher activation status of their KIR+ RA+ T cells associated with longer duration of respiratory symptoms. Together, our data indicate that KIR+ RA+ T cells are a unique human T-cell subset with regulatory properties that may explain susceptibility to viral respiratory disease at old age