HSV-2 ΔgD elicits FcγR-effector antibodies that protect against clinical isolates

Petro, Christopher D.; Weinrick, Brian; Khajoueinejad, Nazanin; Burn, Clare; Sellers, R. F.; Jacobs, William R.; Herold, Betsy C.

doi:10.1172/jci.insight.88529

Cited by 63 publications

(101 citation statements)

References 42 publications

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“…6 ). This protection was observed despite the lack of HSV-specific CD4 T or B cell memory, elements of the immune response that are often considered crucial for protection against HSV-2 (32–35). It is possible that a new focus on vaccine strategies that elicit memory CD8 T cells within the genital mucosa, the site of first exposure to STIs, will increase vaccine efficacy.…”

Section: Discussionmentioning

confidence: 97%

Cervicovaginal tissue residence imprints a distinct differentiation program upon memory CD8 T cells

Davé¹,

Cardozo-Ojeda

Mair³

et al. 2019

Preprint

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26The memory CD8 T cell compartment in human cervicovaginal tissue (CVT) is phenotypically 27 and functionally distinct compared to other non-lymphoid tissues. To determine if these 28 distinctive features are driven by residence in the tissue itself, rather than a consequence of 29 local antigenic insults, we used a mouse model to assess memory CD8 T cell differentiation in 30 the CVT. Following systemic immunization to elicit a CD8 T cell response to a herpes simplex 31 virus (HSV) epitope, HSV-specific memory CD8 T cells were stably maintained in other tissues 32 but gradually declined in the CVT over 5 months post-immunization, correlating with a delay in 33 viral control upon HSV challenge. While memory cells in the periphery and small intestine 34 maintained a fairly stable phenotype after 30 days, memory CD8 T cells in the CVT gradually 35 acquired a CD103 + , TCF-1 -, granzyme B + phenotype over the 5 month time span. Notably, a 36 sizable and phenotypically similar population of CD8 T cells was also found in human CVT. Our 37 data indicate that the CVT environment itself considerably affects memory CD8 T cell 38 maintenance and differentiation, and call for a reassessment of the prevalent model of memory 39 T cell maintenance which does not currently account for tissue-specific divergence. 40Pathogens that infect mucosal barrier surfaces represent a significant global health 43 burden, yet immune cell function within reproductive mucosal tissues remains understudied. In 44 addition, the phenotypic and functional characteristics of memory T cells in cervicovaginal tissue 45 (CVT) compared to other mucosal and lymphoid organs is poorly understood, despite the 46 potentially broad importance of this cellular population in the context of sexually-transmitted 47 infections. 48We recently reported that memory CD8 T cells in the human CVT displayed unique 49 phenotypical and functional features including the presence of a subset of CD69 -CD103 -50 inflammatory CD8 T cells (1). Importantly, the majority of memory CD8 T cells in the CVT of 51 healthy women typically expressed CD103 and CD69, which are biomarkers associated with 52 tissue-residence (2-4), suggesting that most memory CD8 T cells in the human CVT stably 53 reside there. Tissue-residence itself can affect functional and phenotypical properties of T cells 54 (5)(6)(7)(8)(9)(10)(11)(12)(13), which is thought to be a consequence of exposure to metabolites, cytokines, and other 55 factors present in the tissue environment in steady state conditions(14, 15) (16). However, it is 56 unclear if the distinctive features of memory CD8 T cells in the CVT are a consequence of 57 recurring local infections and antigenic insults or driven by residence in the tissue itself. To 58 address this question, we used a mouse model system to assess memory CD8 T cell 59 differentiation and maintenance in the CVT. Specifically, we used a systemic immunization 60 strategy to induce HSV-specific memory CD8 T cells. We then tracked these antigen-specific T 61 cells across tissu...

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Section: Discussionmentioning

confidence: 97%

Cervicovaginal tissue residence imprints a distinct differentiation program upon memory CD8 T cells

Davé¹,

Cardozo-Ojeda

Mair³

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…It is possible that antibody-dependent cellular cytotoxicity contributed significantly to vaccine protection as reported for HSV-2 ΔgD2, a gD2 null live virus vaccine [41, 42]. Alternatively, blocking cell-to-cell spread mediated by antibodies to gE2, or enhanced antigen presentation facilitated by blocking the interaction of gC2 with C3b may account for the improved protection by the trivalent vaccine [10, 21].…”

Section: Discussionmentioning

confidence: 99%

An HSV-2 Trivalent Vaccine Is Immunogenic in Rhesus Macaques and Highly Efficacious in Guinea Pigs

et al. 2017

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A genital herpes vaccine is urgently needed to prevent pain and suffering, reduce the incidence of neonatal herpes, and decrease the risk of HIV acquisition and transmission that accompanies genital infection. We evaluated a trivalent HSV-2 subunit antigen vaccine administered with CpG and alum in rhesus macaques and guinea pigs. The vaccine contains glycoproteins C, D and E (gC2, gD2, gE2) to block virus entry by gD2 and immune evasion by gC2 and gE2. In rhesus macaques, the trivalent vaccine induced plasma and mucosa neutralizing antibodies, antibodies that block gC2 and gE2 immune evasion activities, and stimulated CD4 T cell responses. After intravaginal challenge, a self-limited vaginal infection of brief duration was detected by histopathology and immunohistochemistry in naïve, but not in trivalent immunized macaques. Vaccine efficacy was evaluated in female guinea pigs. Animals were mock immunized, or immunized with gD2, the trivalent vaccine or the trivalent vaccine followed by a booster dose of gD2 (trivalent + gD2). The trivalent and trivalent + gD2 groups were 97% and 99% efficacious, respectively in preventing genital lesions and both outperformed gD2 alone. As a marker of transmission risk, vaginal swabs were evaluated daily for HSV-2 DNA and replication competent virus between five and seven weeks after challenge. HSV-2 DNA shedding was reduced in all groups compared with mock. Shedding of replication competent virus occurred on fewer days in the trivalent than gD2 immunized animals while the trivalent + gD2 group had no shedding of replication competent virus. Overall, the trivalent group had genital lesions on < 1% days and shedding of replication competent virus on 0.2% days. The vaccine has outstanding potential for prevention of genital herpes in humans.

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“…Although Petro et al . described a much higher divergence in a small number cultured clinical isolates, additional sequencing will be required to extend this finding and determine the genomic distance between strains (48). The global diversity of HSV glycoproteins has been described, with a unique amino acid signature gG2 involving amino acids 291, 338, 372, and 546 in specimens from East Africa (49).…”

Section: Discussionmentioning

confidence: 99%

Highly conserved intragenic HSV-2 sequences: Results from next-generation sequencing of HSV-2 UL and US regions from genital swabs collected from 3 continents

et al. 2017

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Introduction Understanding the variability in circulating herpes simplex virus type 2 (HSV-2) genomic sequences is critical to the development of HSV-2 vaccines. Methods Genital lesion swabs containing ≥107 log10 copies HSV DNA collected from Africa, the USA, and South America underwent next-generation sequencing, followed by K-mer based filtering and de novo genomic assembly. Sites of heterogeneity within coding regions in unique long and unique short (UL_US) regions were identified. Phylogenetic trees were created using maximum likelihood reconstruction. Results Among 46 samples from 38 persons, 1468 intragenic base-pair substitutions were identified. The maximum nucleotide distance between strains for concatenated UL_US segments was 0.4%. Phylogeny did not reveal geographic clustering. The most variable proteins had non-synonymous mutations in <3% of amino acids. Conclusions Unenriched HSV-2 DNA can undergo next-generation sequencing to identify intragenic variability. The use of clinical swabs for sequencing expands the information that can be gathered directly from these specimens.

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HSV-2 ΔgD elicits FcγR-effector antibodies that protect against clinical isolates

Cited by 63 publications

References 42 publications

Cervicovaginal tissue residence imprints a distinct differentiation program upon memory CD8 T cells

Cervicovaginal tissue residence imprints a distinct differentiation program upon memory CD8 T cells

An HSV-2 Trivalent Vaccine Is Immunogenic in Rhesus Macaques and Highly Efficacious in Guinea Pigs

Highly conserved intragenic HSV-2 sequences: Results from next-generation sequencing of HSV-2 UL and US regions from genital swabs collected from 3 continents

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