• AIDS
• CAR‐T cells
• HIV
• adoptive cell transfer
• cell‐ based therapies
• stem cells

• Humans
• HIV Infections/therapy
• HIV Infections/immunology
• HIV Infections/virology
• Immunotherapy, Adoptive/methods
• HIV-1/immunology
• Cell- and Tissue-Based Therapy/methods
• B-Lymphocytes/immunology

• C-type lectin
• Mincle
• adjuvant
• formulation
• ligand
• vaccine

• VUW20/928 Health Research Council of New Zealand

• Peptides
• adjuvants
• cancer
• epitopes
• immune response
• infectious diseases
• vaccines

• CD8+ T cell
• dendritic cell
• hBLT mouse
• lymphoid tissue
• vaccine

• Broadly neutralizing antibodies
• HIV cure
• Immunotherapies
• Latency
• T-cells
• Target-cell immune resistance

Dendritic cells (DCs) play a critical role in mediating innate and adaptive immune responses. Since their discovery in the late 1970's, DCs have been recognized as the most potent antigen-presenting cells (APCs). DCs have a superior capacity for acquiring, processing, and presenting antigens to T cells and they express costimulatory or coinhibitory molecules that determine immune activation or anergy. For these reasons, cell-based therapeutic approaches using DCs have been explored in cancer and infectious diseases but with limited success. In humans, DCs are divided into heterogeneous subsets with distinct characteristics. Two major subsets are CD11c⁺ myeloid (m)DCs and CD11c⁻ plasmacytoid (p)DCs. pDCs are different from mDCs and play an essential role in the innate immune system via the production of type I interferons (IFN). However, pDCs are also able to take-up antigens and effectively cross present them. Given the rarity of pDCs in blood and technical difficulties in obtaining them from human blood samples, the understanding of human pDC biology and their potential in immunotherapeutic approaches (e.g. cell-based vaccines) is limited. However, due to the recent advancements in cell culturing systems that allow for the generation of functional pDCs from CD34⁺ hematopoietic stem and progenitor cells (HSPC), studying pDCs has become easier. In this mini-review, we hypothesize about the use of pDCs as a cell-based therapy to treat HIV by enhancing anti-HIV-immune responses of the adaptive immune system and enhancing the anti-viral responses of the innate immune system. Additionally, we discuss obstacles to overcome before this approach becomes clinically applicable.

• CD8+ T cells
• DC vaccine
• HIV
• HIV latency
• NK cells
• dendritic cells
• pDC
• plasmacytoid DC

Dendritic cells (DC) are key phagocytic cells that play crucial roles in both the innate and adaptive immune responses against the human immunodeficiency virus type 1 (HIV-1). By processing and presenting pathogen-derived antigens, dendritic cells initiate a directed response against infected cells. They activate the adaptive immune system upon recognition of pathogen-associated molecular patterns (PAMPs) on infected cells. During the course of HIV-1 infection, a successful adaptive (cytotoxic CD8⁺ T-cell) response is necessary for preventing the progression and spread of infection in a variety of cells. Dendritic cells have thus been recognized as a valuable tool in the development of immunotherapeutic approaches and vaccines effective against HIV-1. The advancements in dendritic cell vaccines in cancers have paved the way for applications of this form of immunotherapy to HIV-1 infection. Clinical trials with patients infected with HIV-1 who are well-suppressed by antiretroviral therapy (ART) were recently performed to assess the efficacy of DC vaccines, with the goal of mounting an HIV-1 antigen-specific T-cell response, ideally to clear infection and eliminate the need for long-term ART. This review summarizes and compares methods and efficacies of a number of DC vaccine trials utilizing autologous dendritic cells loaded with HIV-1 antigens. The potential for advancement and novel strategies of improving efficacy of this type of immunotherapy is also discussed.

HIV infection can be effectively treated by lifelong administration of combination antiretroviral therapy, but an effective vaccine will likely be required to end the HIV epidemic. Although the majority of current vaccine strategies focus on the induction of neutralizing antibodies, there is substantial evidence that cellular immunity mediated by CD8⁺ T cells can sustain long-term disease-free and transmission-free HIV control and may be harnessed to induce both therapeutic and preventive antiviral effects. In this Review, we discuss the increasing evidence derived from individuals who spontaneously control infection without antiretroviral therapy as well as preclinical immunization studies that provide a clear rationale for renewed efforts to develop a CD8⁺ T cell-based HIV vaccine in conjunction with B cell vaccine efforts. Further, we outline the remaining challenges in translating these findings into viable HIV prevention, treatment and cure strategies.

Recently, antibody-mediated control of HIV infection has received considerable attention. Here, the authors discuss the importance of CD8⁺ T cells in HIV infection and suggest that efforts to develop vaccines that target these cells in conjunction with B cells should be renewed.

• HIV/AIDS
• dendritic cells
• immunotherapy

• CTL
• HLA
• Uganda
• adaptation
• epitope
• evolution
• human immunodeficiency virus
• immune escape
• subtype

• AIDS Vaccines
• Genotype
• Genotyping Techniques/methods
• HIV Infections/blood
• HIV Infections/immunology
• HIV Infections/virology
• HIV-1/classification
• HIV-1/genetics
• HIV-1/immunology
• HIV-1/pathogenicity
• HLA Antigens/blood
• HLA Antigens/genetics
• Human Immunodeficiency Virus Proteins/blood
• Human Immunodeficiency Virus Proteins/genetics
• Humans
• Immune Evasion
• Immunity, Cellular
• Phylogeny
• Polymorphism, Genetic
• Uganda
• gag Gene Products, Human Immunodeficiency Virus/blood
• gag Gene Products, Human Immunodeficiency Virus/genetics
• nef Gene Products, Human Immunodeficiency Virus/blood
• nef Gene Products, Human Immunodeficiency Virus/genetics
• pol Gene Products, Human Immunodeficiency Virus/blood
• pol Gene Products, Human Immunodeficiency Virus/genetics

• HHSN261200800001C NCI NIH HHS
• HHSN261200800001E NCI NIH HHS
• P30 AI027763 NIAID NIH HHS
• HHS | National Institutes of Health (NIH)
• Michael Smith Foundation for Health Research (MSFHR)
• Canada Research Chairs (Chaires de recherche du Canada)
• Gouvernement du Canada | Canadian Institutes of Health Research (CIHR)

Harnessing dendritic cells (DC) to treat HIV infection is considered a key strategy to improve anti-HIV treatment and promote the discovery of functional or sterilizing cures. Although this strategy represents a promising approach, the results of currently published trials suggest that opportunities to optimize its performance still exist. In addition to the genetic and clinical characteristics of patients, the efficacy of DC-based immunotherapy depends on the quality of the vaccine product, which is composed of precursor-derived DC and an antigen for pulsing. Here, we focus on some factors that can interfere with vaccine production and should thus be considered to improve DC-based immunotherapy for HIV infection.

• HIV
• clinical trial
• dendritic cells
• immunotherapy
• therapeutic vaccine

• HIV-1
• Therapeutic vaccine
• functional cure
• immunotherapy
• reservoir

The scientific community still faces the challenge of developing strategies to cure HIV-1. One of these pursued strategies is the development of immunotherapeutic vaccines based on dendritic cells (DCs), pulsed with the virus, that aim to boost HIV-1 specific immune response. We aimed to review DCs-based therapeutic vaccines reports and critically assess evidence to gain insights for the improvement of these strategies. We performed a systematic review, followed by meta-analysis and meta-regression, of clinical trial reports. Twelve studies were selected for meta-analysis. The experimental vaccines had low efficiency, with an overall success rate around 38% (95% confidence interval = 26.7%–51.3%). Protocols differed according to antigen choice, DC culture method, and doses, although multivariate analysis did not show an influence of any of them on overall success rate. The DC-based vaccines elicited at least some immunogenicity, that was sometimes associated with plasmatic viral load transient control. The protocols included both naïve and antiretroviral therapy (ART)-experienced individuals, and used different criteria for assessing vaccine efficacy. Although the vaccines did not work as expected, they are proof of concept that immune responses can be boosted against HIV-1. Protocol standardization and use of auxiliary approaches, such as latent HIV-1 reservoir activation and patient genomics are paramount for fine-tuning future HIV-1 cure strategies.

• clinical trial
• dendritic cell
• human immunodeficiency virus
• meta-regression
• vaccine

• AIDS Vaccines/therapeutic use
• Clinical Trials as Topic
• Dendritic Cells/immunology
• HIV Infections/drug therapy
• HIV Infections/immunology
• HIV Infections/prevention & control
• Humans
• Immunotherapy/methods

HIV-1 virus-like particles (VLPs) are promising vaccine candidates against HIV-1 infection. They are capable of preserving the native conformation of HIV-1 antigens and priming CD4+ and CD8+ T cell responses efficiently via cross presentation by both major histocompatibility complex (MHC) class I and II molecules. Progress has been achieved in the preclinical research of HIV-1 VLPs as prophylactic vaccines that induce broadly neutralizing antibodies and potent T cell responses. Moreover, the progress in HIV-1 dendritic cells (DC)-based immunotherapy provides us with a new vision for HIV-1 vaccine development. In this review, we describe updates from the past 5 years on the development of HIV-1 VLPs as a vaccine candidate and on the combined use of HIV particles with HIV-1 DC-based immunotherapy as efficient prophylactic and therapeutic vaccination strategies.

• HIV-1
• adjuvants
• dendritic cells
• dendritic cells-based immunotherapy
• vaccine
• virus-like paticles (VLPs)

• antigen discovery
• genome-based
• malaria
• protective immunity
• rational vaccine design
• vaccine

• Adjuvant
• CD8 T cells
• Cytotoxic T lymphocytes
• Functional cure
• HIV-1
• Human trial
• Peptide
• Therapeutic vaccine

• Adult
• CD8-Positive T-Lymphocytes/immunology
• Cohort Studies
• Computational Biology
• Enzyme-Linked Immunospot Assay
• Epitopes/immunology
• Female
• HIV Infections/immunology
• HIV-1/immunology
• Histocompatibility Antigens Class I/immunology
• Humans
• Interferon-gamma/metabolism
• Male
• Middle Aged

• Howard Hughes Medical Institute
• HHSN261200800001C NCI NIH HHS
• Intramural NIH HHS
• P30 AI060354 NIAID NIH HHS
• HHSN261200800001E NCI NIH HHS

Viral protein U (Vpu) is an accessory protein associated with two main functions important in human immunodeficiency virus type 1 (HIV-1) replication and dissemination; these are down-regulation of CD4 receptor through mediating its proteasomal degradation and enhancement of virion release by antagonizing tetherin/BST2. It is also well established that Vpu is one of the most highly variable proteins in the HIV-1 proteome. However it is still unclear what drives Vpu sequence variability, whether Vpu acquires polymorphisms as a means of immune escape, functional advantage, or otherwise. It is assumed that the host-pathogen interaction is a cause of polymorphic phenotype of Vpu and that the resulting functional heterogeneity of Vpu may have critical significance in vivo. In order to comprehensively understand Vpu variability, it is important to integrate at the population level the genetic association approaches to identify specific amino acid residues and the immune escape kinetics which may impose Vpu functional constraints in vivo. This review will focus on HIV-1 accessory protein Vpu in the context of its sequence variability at population level and also bring forward evidence on the role of the host immune responses in driving Vpu sequence variability; we will also highlight the recent findings that illustrate Vpu functional implication in HIV-1 pathogenesis.

• Human immunodeficiency virus type 1
• Vpu
• Sequence variability
• Immune responses
• Human leukocyte antigen class I

• Flt3L
• HBV immunotherapy
• HCV
• HIV
• dendritic cells
• endocytic receptors

• APL
• CTA
• DNA vaccine
• Prostate cancer
• SSX

Hemophilia patients infected with human immunodeficiency virus (HIV) 30 years ago show increased proportions of activated CD8⁺DR⁺ blood lymphocytes. We hypothesized that this might indicate a cellular immune response directed against HIV and might be the reason for long-term clinical stability of these patients. CD8⁺ peripheral blood lymphocytes (PBL) reactive with six HIV and two cytomegalovirus (CMV) pentamers were determined in heparinized whole blood. Additional lymphocyte subsets as well as plasma cytokines and HIV-1 load were studied. Long-term HIV-infected hemophilia patients with (n=15) or without (n=33) currently detectable HIV-1 load in the plasma showed higher proportions of CD8⁺ lymphocytes reactive with HIV (p<0.001) and CMV pentamers (p=0.010) than healthy individuals. The cellular anti-HIV response tended to be stronger and more polyclonal in patients during periods of viral replication than in patients with retroviral quiescence (p=0.077). Anti-HIV CD8⁺ lymphocyte responses were strongest in patients with high counts of activated CD8⁺DR⁺ T (r=0.353; p=0.014) and low CD19⁺ B lymphocyte counts (r=−0.472; p=0.001). Patients with or without HIV-1 viral load showed normal Th1 and Th2 plasma cytokine levels and high plasma interleukin-6 (versus healthy controls, p=0.001) and tumor necrosis factor-α (p=0.020). Hemophilia patients who have been living with HIV for more than 30 years showed a polyclonal CD8⁺ T-cell response against HIV and CMV. This cellular antiviral immune response was strongest during periods of HIV-1 replication and remained detectable during periods of HIV-1 quiescence. We hypothesize that the consistent cellular anti-HIV-1 response in combination with highly active antiretroviral therapy ensures stability and survival of these chronically HIV-1–infected hemophilia patients.

• CMV
• HIV-specific CD8+ T lymphocytes in blood
• long-term HIV-infected hemophilia patients
• stable disease

• HIV
• T cell responses
• dendritic cells
• functional cure
• therapeutic vaccine

• AIDS Vaccines/immunology
• AIDS Vaccines/therapeutic use
• Dendritic Cells/immunology
• HIV Infections/therapy
• Humans
• Immunotherapy/methods
• Treatment Outcome

HIV Gag-specific CD4+ and CD8+ T-cell responses are important for HIV immune control. Pulsing overlapping Gag peptides on autologous lymphocytes (OPAL) has proven immunogenic and effective in reducing viral loads in multiple pigtail macaque studies, warranting clinical evaluation.

We performed a phase I, single centre, placebo-controlled, double-blinded and dose-escalating study to evaluate the safety and preliminary immunogenicity of a novel therapeutic vaccine approach ‘OPAL-HIV-Gag(c)’. This vaccine is comprised of 120 15mer peptides, overlapping by 11 amino acids, spanning the HIV Gag C clade sequence proteome, pulsed on white blood cells enriched from whole blood using a closed system, followed by intravenous reinfusion. Patients with undetectable HIV viral loads (<50 copies/ml plasma) on HAART received four administrations at week 0, 4, 8 and 12, and were followed up for 12 weeks post-treatment. Twenty-three people were enrolled in four groups: 12 mg (n = 6), 24 mg (n = 7), 48 mg (n = 2) or matching placebo (n = 8) with 18 immunologically evaluable. T-cell immunogenicity was assessed by IFNγ ELIspot and intracellular cytokine staining (ICS).

The OPAL-HIV-Gag(c) peptides were antigenic in vitro in 17/17 subjects. After vaccination with OPAL-HIV-Gag(c), 1/6 subjects at 12 mg and 1/6 subjects at 24 mg dose groups had a 2- and 3-fold increase in ELIspot magnitudes from baseline, respectively, of Gag-specific CD8+ T-cells at week 14, compared to 0/6 subjects in the placebo group. No Gag-specific CD4+ T-cell responses or overall change in Rev, Nef, Tat and CMV specific responses were detected. Marked, transient and self-limiting lymphopenia was observed immediately post-vaccination (4 hours) in OPAL-HIV-Gag(c) but not in placebo recipients, with median fall from 1.72 to 0.67 million lymphocytes/mL for active groups (P<0.001), compared to post-placebo from 1.70 to 1.56 lymphocytes/ml (P = 0.16).

Despite strong immunogenicity observed in several Macaca nemestrina studies using this approach, OPAL-HIV-Gag(c) was not significantly immunogenic in humans and improved methods of generating high-frequency Gag-specific T-cell responses are required.

ClinicalTrials.gov, Registry number: NCT01123915, URL trial registry database: http://www.clinicaltrials.gov/ct2/results?term=OPAL-HIV-1001&Search=Search

• AIDS Vaccines/immunology
• AIDS Vaccines/therapeutic use
• Adolescent
• Adult
• CD4-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/immunology
• Female
• HIV Infections/immunology
• HIV Infections/prevention & control
• Humans
• Interferon-gamma/metabolism
• Male
• Middle Aged
• Young Adult

• HLA restriction
• MHC
• adjuvant
• bioinformatic
• epitope vaccine

• AIDS Vaccines/immunology
• Amino Acid Sequence
• Analysis of Variance
• Animals
• CD8-Positive T-Lymphocytes/immunology
• Enzyme-Linked Immunosorbent Assay
• Enzyme-Linked Immunospot Assay
• Epitopes, T-Lymphocyte/immunology
• HIV Core Protein p24/genetics
• HIV Core Protein p24/immunology
• HIV-1/immunology
• HLA-A2 Antigen/genetics
• Immunity, Cellular/immunology
• Mice
• Mice, Transgenic
• Molecular Sequence Data

• Adjuvants, Immunologic/administration & dosage
• Adjuvants, Immunologic/therapeutic use
• Adolescent
• Adult
• CD4-Positive T-Lymphocytes/immunology
• CD4-Positive T-Lymphocytes/metabolism
• CD4-Positive T-Lymphocytes/virology
• CD8-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/metabolism
• CD8-Positive T-Lymphocytes/virology
• Epitopes, T-Lymphocyte/administration & dosage
• Epitopes, T-Lymphocyte/immunology
• Epitopes, T-Lymphocyte/therapeutic use
• Female
• HIV Infections/immunology
• HIV Infections/prevention & control
• HIV Infections/therapy
• HLA-A Antigens/administration & dosage
• HLA-A Antigens/genetics
• HLA-B Antigens/administration & dosage
• HLA-B Antigens/genetics
• HLA-C Antigens/administration & dosage
• HLA-C Antigens/genetics
• Humans
• Immunodominant Epitopes/administration & dosage
• Immunodominant Epitopes/immunology
• Immunodominant Epitopes/therapeutic use
• Male
• Middle Aged
• Peptides/administration & dosage
• Peptides/immunology
• Peptides/therapeutic use
• Single-Blind Method
• Young Adult

In recent years, the prevalence of HIV-1 infection has been rapidly increasing among men who have sex with men (MSM). However, it remains unknown how the host immune system responds to the infection in this population. We assessed the quantity of HIV-specific CD8⁺ T-cell responses by using Elispot assay and their functionalities by measuring 5 CD8⁺ T-cell evaluations (IL-2, MIP-1β, CD107a, TNF-α, IFN-γ) with flow cytometry assays among 18 primarily and 37 early chronically HIV-infected MSM. Our results demonstrated that subjects at early chronic phase developed HIV-specific CD8⁺ T-cell responses with higher magnitudes and more diversified functionalities in comparison with those at primary infection. However, populations with IL-2⁺ CD107a⁺ or in combination with other functionality failed to develop in parallel. The multifunctional but not monofunctional HIV-specific CD8⁺ T cells were associated with higher CD4⁺ T -cell counts and lower viral loads. These data revealed that prolonged infection from primary to early chronic infection could selectively increase the functionalities of HIV-specific CD8⁺ T cells in HIV-infected MSM population, the failure to develop IL-2 and cytotoxic functionalities in parallel may explain why the increased HIV-specific CD8⁺ T cells were unable to enhance the containment of HIV-1 replication at the early chronic stage.

• Adult
• CD4-Positive T-Lymphocytes/immunology
• CD4-Positive T-Lymphocytes/pathology
• CD4-Positive T-Lymphocytes/virology
• HIV Infections/blood
• HIV Infections/immunology
• HIV Infections/pathology
• HIV Infections/virology
• HIV-1/immunology
• Humans
• Interferon-gamma/metabolism
• Lymphocyte Count
• Male
• RNA, Viral/blood
• Species Specificity
• T-Lymphocytes, Cytotoxic/immunology
• T-Lymphocytes, Cytotoxic/virology
• Treatment Outcome
• Viral Load/immunology
• Young Adult

Vaccines against many pathogens for which conventional approaches have failed remain an unmet public health priority. Synthetic peptide-based vaccines offer an attractive alternative to whole protein and whole organism vaccines, particularly for complex pathogens that cause chronic infection. Previously, we have reported a promising lipid core peptide (LCP) vaccine delivery system that incorporates the antigen, carrier, and adjuvant in a single molecular entity. LCP vaccines have been used to deliver several peptide subunit-based vaccine candidates and induced high titre functional antibodies and protected against Group A streptococcus in mice. Herein, we have evaluated whether LCP constructs incorporating defined CD4⁺ and/or CD8⁺ T cell epitopes could induce epitope-specific T cell responses and protect against pathogen challenge in a rodent malaria model. We show that LCP vaccines failed to induce an expansion of antigen-specific CD8⁺ T cells following primary immunization or by boosting. We further demonstrated that the LCP vaccines induced a non-specific type 2 polarized cytokine response, rather than an epitope-specific canonical CD8⁺ T cell type 1 response. Cytotoxic responses of unknown specificity were also induced. These non-specific responses were able to protect against parasite challenge. These data demonstrate that vaccination with lipid core peptides fails to induce canonical epitope-specific T cell responses, at least in our rodent model, but can nonetheless confer non-specific protective immunity against Plasmodium parasite challenge.

• Animals
• CD8-Positive T-Lymphocytes/immunology
• Epitopes, T-Lymphocyte/immunology
• Female
• Flow Cytometry
• Malaria/immunology
• Malaria/prevention & control
• Malaria Vaccines/immunology
• Malaria Vaccines/therapeutic use
• Malaria, Falciparum/immunology
• Malaria, Falciparum/prevention & control
• Mice
• Mice, Inbred BALB C
• Vaccination
• Vaccines, Subunit/immunology
• Vaccines, Subunit/therapeutic use

A variety of immune-based therapies has been developed in order to boost or induce protective CD8⁺ T cell responses in order to control HIV replication. Since dendritic cells (DCs) are professional antigen-presenting cells (APCs) with the unique capability to stimulate naïve T cells into effector T cells, their use for the induction of HIV-specific immune responses has been studied intensively. In the present study we investigated whether modulation of the activation state of DCs electroporated with consensus codon-optimized HxB2 gag mRNA enhances their capacity to induce HIV gag-specific T cell responses. To this end, mature DCs were (i) co-electroporated with mRNA encoding interleukin (IL)-12p70 mRNA, or (ii) activated with a cytokine cocktail consisting of R848 and interferon (IFN)-γ. Our results confirm the ability of HxB2 gag-expressing DCs to expand functional HIV-specific CD8⁺ T cells. However, although most of the patients had detectable gag-specific CD8⁺ T cell responses, no significant differences in the level of expansion of functional CD8⁺ T cells could be demonstrated when comparing conventional or immune-modulated DCs expressing IL-12p70. This result which goes against expectation may lead to a re-evaluation of the need for IL-12 expression by DCs in order to improve T-cell responses in HIV-1-infected individuals.

The efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction of responses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccine designs are largely based on viral sequence alignments only, not incorporating experimental data on T cell function and specificity.

Here, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410 overlapping peptides (OLP) spanning the entire HIV-1 proteome. For each OLP, a "protective ratio" (PR) was calculated as the ratio of median viral loads (VL) between OLP non-responders and responders.

For both clades, there was a negative relationship between the PR and the entropy of the OLP sequence. There was also a significant additive effect of multiple responses to beneficial OLP. Responses to beneficial OLP were of significantly higher functional avidity than responses to non-beneficial OLP. They also had superior in-vitro antiviral activities and, importantly, were at least as predictive of individuals' viral loads than their HLA class I genotypes.

The data thus identify immunogen sequence candidates for HIV and provide an approach for T cell immunogen design applicable to other viral infections.

• AIDS Vaccines/immunology
• AIDS Vaccines/therapeutic use
• Antiretroviral Therapy, Highly Active
• Cells, Cultured
• Dendritic Cells/immunology
• Dendritic Cells/metabolism
• Dendritic Cells/virology
• Flow Cytometry
• HIV Infections/prevention & control
• HIV Infections/virology
• HIV-1/immunology
• HIV-1/isolation & purification
• Humans
• Leukocytes, Mononuclear/virology
• Sequence Analysis
• Vaccines, Inactivated/immunology
• Viral Load
• Virus Inactivation

• HHSN261200800001E PHS HHS

CD8 T cells play a vital role in the immunological protection against intracellular pathogens. Ideally, robust effector responses are induced, which eradicate the pathogen, and durable memory CD8 T cells are also established, which help confer protection against subsequent reinfection. The quality and magnitude of these responses is dictated by multiple factors, including their initial interactions with professional antigen-presenting cells, as well as the cytokine milieu and availability of CD4 T cell help. These factors set the transcriptional landscape of the responding T cells, which in turn influences their phenotypic and functional attributes as well as ultimate fate. Under certain conditions, such as during chronic infections, the development of these usually successful responses becomes subverted. Here we discuss advances in our understanding of the cellular and molecular determinants of T cell quality, and the formation of effector, memory, and exhausted CD8 T cells, during acute and chronic infections.