CD8 T Cell Response Maturation Defined by Anentropic Specificity and Repertoire Depth Correlates with SIVΔnef-induced Protection

Adnan, Sama; Colantonio, Arnaud D.; Yu, Yizhen; Gillis, Jacqueline; Wong, Fred; Becker, Ericka A.; Piatak, Michael; Reeves, R. Keith; Lifson, Jeffrey D.; O’Connor, Shelby L.; Johnson, R. Paul

doi:10.1371/journal.ppat.1004633

Cited by 20 publications

(23 citation statements)

References 50 publications

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“…Genome-wide deep sequencing of replicating virus populations was performed as previously described (13). Briefly, viral RNA was isolated from plasma using the MinElute virus spin kit (Qiagen).…”

Section: Animalsmentioning

confidence: 99%

Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

Gellerup

Balgeman

Nelson

et al. 2016

J Virol

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Anti-HIV CD8 T cells included in therapeutic treatments will need to target epitopes that do not accumulate escape mutations.Identifying the epitopes that do not accumulate variants but retain immunogenicity depends on both host major histocompatibility complex (MHC) genetics and the likelihood for an epitope to tolerate variation. We previously found that immune escape during acute SIV infection is conditional; the accumulation of mutations in T cell epitopes is limited, and the rate of accumulation depends on the number of epitopes being targeted. We have now tested the hypothesis that conditional immune escape extends into chronic SIV infection and that epitopes with a preserved wild-type sequence have the potential to elicit epitope-specific CD8 T cells. We deep sequenced simian immunodeficiency virus (SIV) from Mauritian cynomolgus macaques (MCMs) that were homozygous and heterozygous for the M3 MHC haplotype and had been infected with SIV for about 1 year. When interrogating variation within individual epitopes restricted by M3 MHC alleles, we found three categories of epitopes, which we called categories A, B, and C. Category B epitopes readily accumulated variants in M3-homozygous MCMs, but this was less common in M3-heterozygous MCMs. We then determined that chronic CD8 T cells specific for these epitopes were more likely preserved in the M3-heterozygous MCMs than M3-homozygous MCMs. We provide evidence that epitopes known to escape from chronic CD8 T cell responses in animals that are homozygous for a set of MHC alleles are preserved and retain immunogenicity in a host that is heterozygous for the same MHC alleles. IMPORTANCEAnti-HIV CD8 T cells that are part of therapeutic treatments will need to target epitopes that do not accumulate escape mutations. Defining these epitope sequences is a necessary precursor to designing approaches that enhance the functionality of CD8 T cells with the potential to control virus replication during chronic infection or after reactivation of latent virus. Using MHChomozygous and -heterozygous Mauritian cynomolgus macaques, we have now obtained evidence that epitopes known to escape from chronic CD8 T cell responses in animals that are MHC homozygous are preserved and retain immunogenicity in a host that is heterozygous for the same MHC alleles. Importantly, our findings support the conditional immune escape hypothesis, such that the potential to present a greater number of CD8 T cell epitopes within a single animal can delay immune escape in targeted epitopes. As a result, certain epitope sequences can retain immunogenicity into chronic infection.

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Section: Animalsmentioning

confidence: 99%

Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

Gellerup

Balgeman

Nelson

et al. 2016

J Virol

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“…Recently reported detailed analysis of immune responses and deep sequence characterisation of SIVmac239Δ nef post-vaccination indicated that there is a shift following early, rapid virus escape due to immune pressure to variable regions targeted during the acute phase to a re-focussed immunological response to more conserved epitopes [40]. However, the level of sub-clinical antigenic drive required to deliver such an anentropic state requires clarification, perhaps also in the face of host responses to the vaccine virus, since it was also noted that macaques with undetectable plasma viraemia experienced ongoing sequence evolution of the vaccine virus.…”

Section: Discussionmentioning

confidence: 99%

Role of Occult and Post-acute Phase Replication in Protective Immunity Induced with a Novel Live Attenuated SIV Vaccine

et al. 2016

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In order to evaluate the role of persisting virus replication during occult phase immunisation in the live attenuated SIV vaccine model, a novel SIVmac239Δnef variant (SIVrtTA) genetically engineered to replicate in the presence of doxycycline was evaluated for its ability to protect against wild-type SIVmac239. Indian rhesus macaques were vaccinated either with SIVrtTA or with SIVmac239Δnef. Doxycycline was withdrawn from 4 of 8 SIVrtTA vaccinates before challenge with wild-type virus. Unvaccinated challenge controls exhibited ~107 peak plasma viral RNA copies/ml persisting beyond the acute phase. Six vaccinates, four SIVmac239Δnef and two SIVrtTA vaccinates exhibited complete protection, defined by lack of wild-type viraemia post-challenge and virus-specific PCR analysis of tissues recovered post-mortem, whereas six SIVrtTA vaccinates were protected from high levels of viraemia. Critically, the complete protection in two SIVrtTA vaccinates was associated with enhanced SIVrtTA replication in the immediate post-acute vaccination period but was independent of doxycycline status at the time of challenge. Mutations were identified in the LTR promoter region and rtTA gene that do not affect doxycycline-control but were associated with enhanced post-acute phase replication in protected vaccinates. High frequencies of total circulating CD8+T effector memory cells and a higher total frequency of SIV-specific CD8+ mono and polyfunctional T cells on the day of wild-type challenge were associated with complete protection but these parameters were not predictive of outcome when assessed 130 days after challenge. Moreover, challenge virus-specific Nef CD8+ polyfunctional T cell responses and antigen were detected in tissues post mortem in completely-protected macaques indicating post-challenge control of infection. Within the parameters of the study design, on-going occult-phase replication may not be absolutely required for protective immunity.

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“…9 Thus, in a recent elegant study authors combined deep sequencing technology and comprehensive CD8 T cell epitope mapping and demonstrated that the initial CD8 T cell response in the acute phase of the live attenuated simian immunodeficiency virus infection (SIVDnef, one of the most effective vaccines in inducing protection against wild-type lentiviral challenge) is mounted predominantly against more variable epitopes, followed by viral escape. 48 Interestingly, epitope escape expands the CD8 T cell repertoire that targets highly conserved epitopes (defined as anentropic specificity) generating de novo responses to the escaped epitope variants during the vaccination period. 48 The first and the second waves of HIV vaccine development, aimed to induce nAbs and CTL response, respectively, did not address the issue of antigenic variability, and candidate vaccines' capacity to induce immune responses able to recognize variant (mutated) epitopes has not been tested.…”

Section: Hivmentioning

confidence: 99%

“…48 Interestingly, epitope escape expands the CD8 T cell repertoire that targets highly conserved epitopes (defined as anentropic specificity) generating de novo responses to the escaped epitope variants during the vaccination period. 48 The first and the second waves of HIV vaccine development, aimed to induce nAbs and CTL response, respectively, did not address the issue of antigenic variability, and candidate vaccines' capacity to induce immune responses able to recognize variant (mutated) epitopes has not been tested. 42,[49][50][51] Clinical trials were halted because of lack of efficacy, and subsequent careful statistical analysis demonstrated that in some cases vaccination in fact enhanced HIV acquisition.…”

Section: Hivmentioning

confidence: 99%

Antigenic variability: Obstacles on the road to vaccines against traditionally difficult targets

Servín-Blanco

Zamora-Alvarado

Gevorkian

et al. 2016

Human Vaccines & Immunotherapeutics

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Despite the impressive impact of vaccines on public health, the success of vaccines targeting many important pathogens and cancers has to date been limited. The burden of infectious diseases today is mainly caused by antigenically variable pathogens (AVPs), which escape immune responses induced by prior infection or vaccination through changes in molecular structures recognized by antibodies or T cells. Extensive genetic and antigenic variability is the major obstacle for the development of new or improved vaccines against "difficult" targets. Alternative, qualitatively new approaches leading to the generation of disease-and patient-specific vaccine immunogens that incorporate complex permanently changing epitope landscapes of intended targets accompanied by appropriate immunomodulators are urgently needed. In this review, we highlight some of the most critical common issues related to the development of vaccines against many pathogens and cancers that escape protective immune responses owing to antigenic variation, and discuss recent efforts to overcome the obstacles by applying alternative approaches for the rational design of new types of immunogens.

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CD8 T Cell Response Maturation Defined by Anentropic Specificity and Repertoire Depth Correlates with SIVΔnef-induced Protection

Cited by 20 publications

References 50 publications

Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

Role of Occult and Post-acute Phase Replication in Protective Immunity Induced with a Novel Live Attenuated SIV Vaccine

Antigenic variability: Obstacles on the road to vaccines against traditionally difficult targets

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