Role of HIV-specific CD8+ T cells in pediatric HIV cure strategies after widespread early viral escape

Leitman, Ellen M.; Thobakgale, Christina; Adland, Emily; Ansari, Azim; Raghwani, Jayna; Prendergast, Andrew J.; Tudor‐Williams, Gareth; Kiepiela, Photini; Hemelaar, Joris; Brener, Jacqui; M-H., Tsai; Mori, Masahiko; Riddell, Lynn; Luzzi, Graz; Jooste, Pieter; Ndung’u, Thumbi; Walker, Bruce D.; Pybus, Oliver G.; Kellam, Paul; Naranbhai, Vivek; Matthews, Philippa C.; Gall, Astrid; Pjr., Goulder

doi:10.1084/jem.20162123

Cited by 30 publications

(41 citation statements)

References 120 publications

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“…These collective findings raise questions of whether cross-reacting antigens might, in addition to small amounts of virus production in vivo, contribute to maintaining some of these memory responses—and, if such responses contributed to remission in this child. Importantly, lack of detection does not preclude having CD8+ T cell responses 48 , or other protective responses such as ADCC/phagocytosis in the presence of maternal/child antibody, that may have been active early in life and possibly essential to the outcome of HIV-1 remission. The rapid decline in VL over a month prior to ART initiation may be of considerable importance in understanding the reasons behind virological control in the child.…”

Section: Discussionmentioning

confidence: 99%

A child with perinatal HIV infection and long-term sustained virological control following antiretroviral treatment cessation

et al. 2019

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Understanding HIV remission in rare individuals who initiated antiretroviral therapy (ART) soon after infection and then discontinued, may inform HIV cure interventions. Here we describe features of virus and host of a perinatally HIV-1 infected child with long-term sustained virological control. The child received early limited ART in the Children with HIV Early antiRetroviral therapy (CHER) trial. At age 9.5 years, diagnostic tests for HIV are negative and the child has characteristics similar to uninfected children that include a high CD4:CD8 ratio, low T cell activation and low CCR5 expression. Virus persistence (HIV-1 DNA and plasma RNA) is confirmed with sensitive methods, but replication-competent virus is not detected. The child has weak HIV-specific antibody and T cell responses. Furthermore, we determine his HLA and KIR genotypes. This case aids in understanding post-treatment control and may help design of future intervention strategies.

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Section: Discussionmentioning

confidence: 99%

A child with perinatal HIV infection and long-term sustained virological control following antiretroviral treatment cessation

et al. 2019

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“…Studies have shown that virus-specific CD8+ cytotoxic T lymphocyte (CTL) responses are crucial for controlling HIV/SIV infection and replication ( 1 – 3 ). However, viral infection, especially chronic HIV-1/SIV infection, often cause the exhaustion and dysfunction of CD8+ T cells due to continuous antigenic stimulation ( 35 – 37 ).…”

Section: Discussionmentioning

confidence: 99%

“…The pandemic of acquired immune deficiency syndrome (AIDS), which is caused by human immunodeficiency virus type 1 (HIV-1), continues to be a serious challenge for global public health. Virus-specific CD8+ cytotoxic T lymphocyte (CTL) responses are crucial for controlling the infection of HIV-1 and simian immunodeficiency virus (SIV) ( 1 – 3 ), and therefore, candidates that are capable of inducing robust CTL responses are being widely developed for an effective HIV-1 vaccine. After termination of the highly anticipated STEP trial of Merck's adenovirus-vector HIV vaccine ( 4 , 5 ), which was a major setback to the field of T cell-based HIV vaccine research, increasing findings in the era of post-STEP demonstrated that the next generation of T cell-based HIV vaccine candidates should enhance the quantity and quality of CTL responses to confer superior protective efficacy ( 6 – 8 ).…”

Section: Introductionmentioning

confidence: 99%

Immune Protection of SIV Challenge by PD-1 Blockade During Vaccination in Rhesus Monkeys

Pan

Feng

et al. 2018

Front. Immunol.

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Though immune correlates for protection are still under investigation, potent cytotoxic T lymphocyte responses are desirable for an ideal HIV-1 vaccine. PD-1 blockade enhances SIV-specific CD8+ T cells. However, little information has been reported about how it affects the immunogenicity and protection of prophylactic SIV vaccines in nonhuman primates. Here, we show that PD-1 blockade during vaccination substantially improved protective efficacy in SIV challenged macaques. The PD-1 pathway was blocked using a monoclonal antibody specific to human PD-1. Administration of this antibody effectively augmented and sustained vaccine-induced SIV-specific T cell responses for more than 42 weeks after first immunization in rhesus monkeys, as compared with SIV vaccination only. Importantly, after intrarectally repeated low-dosage challenge with highly pathogenic SIVmac239, monkeys with PD-1 blockade during vaccination achieved full protection against incremental viral doses of up to 50,000 TICD50. These findings highlight the importance of PD-1 blockade during vaccination for the development of HIV vaccines.

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“…Furthermore, a recent study demonstrated that HIV-infected children, as opposed to HIV-infected adults, were able to generate HIV variant-specific CD8 + T cell responses limiting the selection of escape-epitope variants early in infection [ 191 ]. A superior immune response against natural influenza virus infections has also been observed in children aged 4–14, but is not well understood [ 192 ], identifying a key window for vaccination of the T cell compartment to do better than nature.…”

Section: Universal Vaccine May Still Need To Thwart Viral Escapementioning

confidence: 99%

Harnessing the Power of T Cells: The Promising Hope for a Universal Influenza Vaccine

et al. 2018

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Next-generation vaccines that utilize T cells could potentially overcome the limitations of current influenza vaccines that rely on antibodies to provide narrow subtype-specific protection and are prone to antigenic mismatch with circulating strains. Evidence from animal models shows that T cells can provide heterosubtypic protection and are crucial for immune control of influenza virus infections. This has provided hope for the design of a universal vaccine able to prime against diverse influenza virus strains and subtypes. However, multiple hurdles exist for the realisation of a universal T cell vaccine. Overall primary concerns are: extrapolating human clinical studies, seeding durable effective T cell resident memory (Trm), population human leucocyte antigen (HLA) coverage, and the potential for T cell-mediated immune escape. Further comprehensive human clinical data is needed during natural infection to validate the protective role T cells play during infection in the absence of antibodies. Furthermore, fundamental questions still exist regarding the site, longevity and duration, quantity, and phenotype of T cells needed for optimal protection. Standardised experimental methods, and eventually simplified commercial assays, to assess peripheral influenza-specific T cell responses are needed for larger-scale clinical studies of T cells as a correlate of protection against influenza infection. The design and implementation of a T cell-inducing vaccine will require a consensus on the level of protection acceptable in the community, which may not provide sterilizing immunity but could protect the individual from severe disease, reduce the length of infection, and potentially reduce transmission in the community. Therefore, increasing the standard of care potentially offered by T cell vaccines should be considered in the context of pandemic preparedness and zoonotic infections, and in combination with improved antibody vaccine targeting methods. Current pandemic vaccine preparedness measures and ongoing clinical trials under-utilise T cell-inducing vaccines, reflecting the myriad questions that remain about how, when, where, and which T cells are needed to fight influenza virus infection. This review aims to bring together basic fundamentals of T cell biology with human clinical data, which need to be considered for the implementation of a universal vaccine against influenza that harnesses the power of T cells.

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Role of HIV-specific CD8+ T cells in pediatric HIV cure strategies after widespread early viral escape

Abstract: A major obstacle to an HIV cure in adult infection is a viral reservoir largely composed of CTL escape mutants. Leitman et al. demonstrate that in children, but not adults, escape variant–specific CTLs are generated that can successfully “corner” the virus.

Cited by 30 publications

References 120 publications

A child with perinatal HIV infection and long-term sustained virological control following antiretroviral treatment cessation

A child with perinatal HIV infection and long-term sustained virological control following antiretroviral treatment cessation

Immune Protection of SIV Challenge by PD-1 Blockade During Vaccination in Rhesus Monkeys

Harnessing the Power of T Cells: The Promising Hope for a Universal Influenza Vaccine

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