ImportanceHerpes simplex virus type 1 (HSV-1) is the leading cause of first-episode genital herpes in many countries.ObjectiveTo inform counseling messages regarding genital HSV-1 transmission, oral and genital viral shedding patterns... more
ImportanceHerpes simplex virus type 1 (HSV-1) is the leading cause of first-episode genital herpes in many countries.ObjectiveTo inform counseling messages regarding genital HSV-1 transmission, oral and genital viral shedding patterns among persons with first-episode genital HSV-1 infection were assessed. The trajectory of the development of HSV-specific antibody and T-cell responses was also characterized.Design, Setting, and ParticipantsProspective cohort followed up for up to 2 years, with 82 participants followed up between 2013 and 2018. Participants were recruited from sexual health and primary care clinics in Seattle, Washington. Persons with laboratory-documented first-episode genital HSV-1 infection, without HIV infection or current pregnancy, were referred for enrollment.ExposuresFirst-episode genital HSV-1 infection.Main Outcomes and MeasuresGenital and oral HSV-1 shedding and lesion rates at 2 months, 11 months, and up to 2 years after initial genital HSV-1 infection. Pa...
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Liver-humanized mouse models have become the gold standard for the in vivo study of hepatitis B virus (HBV), yet their complexity and cost have prohibited widespread use of existing models in research. Here, we show that the NSG-PiZ... more
Liver-humanized mouse models have become the gold standard for the in vivo study of hepatitis B virus (HBV), yet their complexity and cost have prohibited widespread use of existing models in research. Here, we show that the NSG-PiZ liver-humanized mouse model, which is relatively inexpensive and simple to establish, can support chronic HBV infection.
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Research Interests: Immunology, Biology, Medicine, Probability, Multivariate Analysis, and 15 moreHumans, Chronic Disease, Female, Blood, Male, Cytomegalovirus, Incidence, Clinical Sciences, Middle Aged, Adult, Inheritance Patterns, Hematopoietic Stem Cell Transplantation, Acute Disease, Cardiovascular medicine and haematology, and Paediatrics and reproductive medicine
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ABSTRACTHerpes simplex virus (HSV) establishes latency in ganglionic neurons of the peripheral nervous system, from which it can reactivate, causing recurrent disease and possible transmission to a new host. Current anti-HSV therapy does... more
ABSTRACTHerpes simplex virus (HSV) establishes latency in ganglionic neurons of the peripheral nervous system, from which it can reactivate, causing recurrent disease and possible transmission to a new host. Current anti-HSV therapy does not eliminate latent HSV, and thus is only suppressive rather than curative. We developed a potentially curative approach to latent HSV infection and pathogenesis, based on gene editing using HSV-specific meganucleases delivered by adeno-associated virus (AAV) vectors. Our results demonstrated that a dual meganuclease therapy, composed of two anti-HSV-1 meganucleases delivered by a triple AAV serotype combination (AAV9, AAV-Dj/8, AAV-Rh10), can eliminate up to 97% of latent HSV DNA from ganglia in both ocular and vaginal mouse models of latent HSV infection. Using a novel pharmacological approach to reactivate latent HSV-1 in mice with the bromodomain inhibitor JQ-1, we demonstrated that this reduction in ganglionic viral load leads to a significant...
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Hepatitis B virus (HBV) is a pathogen of major public health importance that is largely incurable once a chronic hepatitis B (CHB) infection is established. Only humans and great apes are fully permissive to HBV replication, and this... more
Hepatitis B virus (HBV) is a pathogen of major public health importance that is largely incurable once a chronic hepatitis B (CHB) infection is established. Only humans and great apes are fully permissive to HBV replication, and this species restriction has impacted HBV research by limiting the utility of small animal models of HBV. To combat the species restriction of HBV and enable more HBV studies in vivo, liver-humanized mouse models have been developed that harbor primary human hepatocytes (PHH) and are fully permissive to HBV infection and replication. Unfortunately, these models can be difficult to establish and are expensive commercially, which has limited their academic use. As an alternative mouse model to study HBV, we evaluated liver-humanized NSG-PiZ mice and showed that they are fully permissive to HBV and can develop CHB. Mice were infected with a precore mutant clinical isolate that has now been serially passaged through 3 generations of mice without loss of fitness....
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Persons with HIV infection are frequently coinfected with chronic herpesviruses, which periodically replicate and produce viable herpes virions, particularly in anogenital and cervical tissues. Persistent protein expression results in... more
Persons with HIV infection are frequently coinfected with chronic herpesviruses, which periodically replicate and produce viable herpes virions, particularly in anogenital and cervical tissues. Persistent protein expression results in proliferation of CD8 + and CD4 + T cells, and the latter could potentially expand and sustain HIV tissue reservoirs. We found HSV genital shedding rates were positively correlated with HIV DNA concentrations and HIV divergence from ancestral sequences in tissues. Our work suggests that immune responses to common coinfections, such as herpesviruses, may sustain HIV tissue reservoirs during suppressive ART, suggesting future cure strategies should study interventions to suppress replication or reactivation of chronic herpes infections.
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RNA viruses that replicate in the cytoplasm often disrupt nucleocytoplasmic transport to preferentially translate their own transcripts and prevent host antiviral responses. The Sarbecovirus accessory protein ORF6 has previously been... more
RNA viruses that replicate in the cytoplasm often disrupt nucleocytoplasmic transport to preferentially translate their own transcripts and prevent host antiviral responses. The Sarbecovirus accessory protein ORF6 has previously been shown to be the major inhibitor of interferon production in both SARS-CoV and SARS-CoV-2. SARS-CoV-2 ORF6 was recently shown to co-purify with the host mRNA export factors Rae1 and Nup98. Here, we demonstrate SARS-CoV-2 ORF6 strongly represses protein expression of co-transfected reporter constructs and imprisons host mRNA in the nucleus, which is associated with its ability to co-purify with Rae1 and Nup98. These protein-protein interactions map to the C-terminus of ORF6 and can be abolished by a single amino acid mutation in Met58. Overexpression of Rae1 restores reporter expression in the presence of SARS-CoV-2 ORF6. We further identify an ORF6 mutant containing a 9-amino acid deletion, ORF6 Δ22-30, in multiple SARS-CoV-2 clinical isolates that can s...
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We evaluate gene editing of HSV in a well-established mouse model, using adeno-associated virus (AAV)-delivered meganucleases, as a potentially curative approach to treat latent HSV infection. Here we show that AAV-delivered... more
We evaluate gene editing of HSV in a well-established mouse model, using adeno-associated virus (AAV)-delivered meganucleases, as a potentially curative approach to treat latent HSV infection. Here we show that AAV-delivered meganucleases, but not CRISPR/Cas9, mediate highly efficient gene editing of HSV, eliminating over 90% of latent virus from superior cervical ganglia. Single-cell RNA sequencing demonstrates that both HSV and individual AAV serotypes are non-randomly distributed among neuronal subsets in ganglia, implying that improved delivery to all neuronal subsets may lead to even more complete elimination of HSV. As predicted, delivery of meganucleases using a triple AAV serotype combination results in the greatest decrease in ganglionic HSV loads. The levels of HSV elimination observed in these studies, if translated to humans, would likely significantly reduce HSV reactivation, shedding, and lesions. Further optimization of meganuclease delivery and activity is likely pos...
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Human herpesvirus 6 (HHV-6) genome equivalents were quantitated in peripheral blood mononuclear cells (PBMCs) and saliva from 20 healthy individuals by the polymerase chain reaction (PCR). Nineteen of 20 subjects (95%) harbored HHV-6 DNA:... more
Human herpesvirus 6 (HHV-6) genome equivalents were quantitated in peripheral blood mononuclear cells (PBMCs) and saliva from 20 healthy individuals by the polymerase chain reaction (PCR). Nineteen of 20 subjects (95%) harbored HHV-6 DNA: 18 (90%) had HHV-6 in their PBMCs and 18 had HHV-6 in their saliva. Quantitative PCR revealed HHV-6 DNA levels ranging from negative to 4,000 HHV-6 genome equivalents per 10(6) PBMCs and from negative to 200,000 HHV-6 genome equivalents per ml of saliva. Longitudinal saliva samples from 15 HHV-6-seropositive subjects revealed salivary HHV-6 DNA persistence in 13 subjects. HHV-6 antibodies were detected in 17 of 19 subjects, with titers ranging from 1:400 to 1:51,200 (geometric mean titer, 1:2,500). Antibody titers did not correlate with HHV-6 DNA levels in PBMCs or saliva (P = 0.27 and P = 0.44, respectively). One subject with persistent HHV-6 DNA lacked detectable HHV-6 antibodies. The high prevalence of HHV-6 DNA in PBMCs and saliva supports the ...
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Tenofovir is a potent anti-HIV agent that decreased risk of HSV-2 acquisition in HIV pre-exposure prophylaxis trials. Whether tenofovir has utility in established HSV-2 disease is unclear. We randomized immunocompetent women with... more
Tenofovir is a potent anti-HIV agent that decreased risk of HSV-2 acquisition in HIV pre-exposure prophylaxis trials. Whether tenofovir has utility in established HSV-2 disease is unclear. We randomized immunocompetent women with symptomatic HSV-2 infection to oral tenofovir disoproxil fumarate (TDF)/placebo vaginal gel, oral placebo/tenofovir (TFV) vaginal gel, or double placebo (ratio 2:2:1) in a one-way cross-over trial. Women collected genital swabs twice daily for HSV PCR during 4-week lead-in and 5-week treatment phases. The primary intent-to-treat endpoint was within-person comparison of genital HSV shedding and lesion rates. 64 women completed the lead-in phase and were randomized. Neither TDF nor TFV gel decreased overall shedding or lesion rate in the primary analysis; TFV gel decreased quantity of HSV DNA by -0.50 (-0.86-0.13) log10 copies/mL. In the per-protocol analysis, TDF reduced shedding (RR=0.74, p=0.006) and lesion rates (RR=0.75, p=0.032); quantity of virus sh...
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We evaluated a genital herpes prophylactic vaccine containing HSV-2 glycoproteins C (gC2) and D (gD2) to stimulate humoral immunity and UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) as T-cell immunogens. HSV-2 gC2 and gD2... more
We evaluated a genital herpes prophylactic vaccine containing HSV-2 glycoproteins C (gC2) and D (gD2) to stimulate humoral immunity and UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) as T-cell immunogens. HSV-2 gC2 and gD2 proteins were expressed in baculovirus, while UL19 and UL47 gene were expressed in replication defective adenovirus vectors. The adenovirus vectors containing UL19/UL47 stimulated CD4(+) and CD8(+) human and murine T-cell responses. Guinea pigs were either i) mock immunized; ii) immunized with gC2/gD2 with CpG/alum as adjuvants; iii) immunized with adenovirus vectors UL19/UL47; or iv) immunized with combined gC2/gD2-CpG/alum and adenovirus vectors UL19/UL47. Immunization with gC2/gD2 produced potent neutralizing antibodies, while UL19 and UL47 also stimulated antibody responses. After intravaginal HSV-2 challenge, the mock and adenovirus UL19/UL47 groups developed severe acute disease, while 2/8 animals in the gC2/gD2 alone and none in the combined ...
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Cytotoxic CD8+ T cells play a critical role in controlling herpes simplex virus (HSV) infection and reactivation. However, little is known about the spatiotemporal dynamics of CD8+ T cells during HSV lesion evolution or about their... more
Cytotoxic CD8+ T cells play a critical role in controlling herpes simplex virus (HSV) infection and reactivation. However, little is known about the spatiotemporal dynamics of CD8+ T cells during HSV lesion evolution or about their involvement in immune surveillance after lesion resolution. Using quantum dot–conjugated peptide–major histocompatibility complex multimers, we investigated the in vivo localization of HSV-2–specific CD8+ T cells in sequential biopsies of human genital skin during acute, resolving, and healed stages of HSV-2 reactivation. Our studies revealed that functionally active CD8+ T cells selectively infiltrated to the site of viral reactivation. After lesion healing in concert with complete reepithelialization and loss of HSV DNA from skin biopsies, HSV-2–specific CD8+ T cells persisted for more than two months at the dermal–epidermal junction, adjacent to peripheral nerve endings. In two out of the six sequentially studied individuals, HSV-2 DNA reappeared in cl...
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Objective. To compare genital HSV shedding among HIV-positive and HIV-negative women.Methods. Women with and without known HIV infection who delivered at the University of Washington Medical Center between 1989–1996 had HSV serologies... more
Objective. To compare genital HSV shedding among HIV-positive and HIV-negative women.Methods. Women with and without known HIV infection who delivered at the University of Washington Medical Center between 1989–1996 had HSV serologies done as part of clinical care. Genital swabs from HSV-2-seropositive women were evaluated by real-time quantitative HSV DNA PCR.Results. HSV-2 seroprevalence was 71% and 30% among 75 HIV-positive and 3051 HIV-negative women, respectively, (P<.001). HSV was detected at delivery in the genital tract of 30.8% of HIV-seropositive versus 9.5% of HIV-negative women (RR=3.2, 95% CI 1.6 to 6.5,P=.001). The number of virion copies shed per mL was similar (log 3.54 for HIV positive versus 3.90 for HIV negative,P=.99).Conclusions. Our study demonstrated that HIV-, HSV-2-coinfected women are more likely to shed HSV at delivery.
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Allogeneic conventional hematopoietic cell transplantation (HCT) can be curative treatment for lymphoid malignancies, but it has been characterized by high nonrelapse mortality (NRM). Here, we compared outcomes among patients with... more
Allogeneic conventional hematopoietic cell transplantation (HCT) can be curative treatment for lymphoid malignancies, but it has been characterized by high nonrelapse mortality (NRM). Here, we compared outcomes among patients with lymphoma or chronic lymphocytic leukemia given either nonmyeloablative (n = 152) or myeloablative (n = 68) conditioning. Outcomes were stratified by the HCT-specific comorbidity index. Patients in the nonmyeloablative group were older, had more previous treatment and more comorbidities, more frequently had unrelated donors, and more often had malignancy in remission compared with patients in the myeloablative group. Patients with indolent versus aggressive malignancies were equally distributed among both cohorts. After HCT, patients without comorbidities both in the nonmyeloablative and myeloablative cohorts had comparable NRM (P = .74), overall survival (P = .75), and progression-free survival (P = .40). No significant differences were observed (P = .91, ...
Research Interests: Risk assessment, Adolescent, Medicine, Comorbidity, Multivariate Analysis, and 15 moreLymphoma, Humans, Internal Medicine, Chronic Lymphocytic Leukemia, Blood, Incidence, Clinical Sciences, Aged, Middle Aged, Adult, Retrospective Studies, Risk Assessment, Hematopoietic Stem Cell Transplantation, Cardiovascular medicine and haematology, and Paediatrics and reproductive medicine
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Herpes simplex virus-2 (HSV-2) is a common sexually transmitted infection with a highly variable clinical course. Many infections quickly become subclinical, with episodes of spontaneous virus reactivation. To study the host/HSV-2... more
Herpes simplex virus-2 (HSV-2) is a common sexually transmitted infection with a highly variable clinical course. Many infections quickly become subclinical, with episodes of spontaneous virus reactivation. To study the host/HSV-2 interactions an animal model of subclinical HSV-2 infection is needed. In an effort to develop a relevant model, rhesus macaques (RM) were inoculated intravaginally with two or three HSV-2 strains (186, 333 and/or G); total dose 1x10 pfu HSV-2 per animal. Infectious HSV-2 and HSV-2 DNA was consistently shed in vaginal swabs for the first 7-14 days after each inoculation. Proteins associated with wound healing, innate immunity and inflammation were significantly increased in cervical secretions immediately after HSV-2 inoculation. Histologic evidence of acute herpesvirus pathology including: acantholysis in the squamous epithelium, ballooning degeneration of, and intranuclear inclusion bodies, in epithelial cells, with HSV antigen in mucosal epithelial cell...
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Herpes simplex viruses (HSVs) are difficult to sequence due to their large DNA genome, high GC content, and the presence of repeats. To date, most HSV genomes have been recovered from culture isolates, raising concern that these genomes... more
Herpes simplex viruses (HSVs) are difficult to sequence due to their large DNA genome, high GC content, and the presence of repeats. To date, most HSV genomes have been recovered from culture isolates, raising concern that these genomes may not accurately represent circulating clinical strains. We report the development and validation of a DNA oligonucleotide hybridization panel to recover nearly complete HSV genomes at abundances up to 50,000-fold lower than previously reported. Using copy number information on herpesvirus and host DNA background via quantitative PCR, we developed a protocol for pooling for cost-effective recovery of more than 50 HSV-1 or HSV-2 genomes per MiSeq run. We demonstrate the ability to recover >99% of the HSV genome at >100× coverage in 72 h at viral loads that allow whole-genome recovery from latently infected ganglia. We also report a new computational pipeline for rapid HSV genome assembly and annotation. Using the above tools and a series of 17...
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Quantitative PCR is the diagnostic pillar for clinical virology testing, and reference materials are necessary for accurate, comparable quantitation between clinical laboratories. Accurate quantitation of HHV-6 is important for detection... more
Quantitative PCR is the diagnostic pillar for clinical virology testing, and reference materials are necessary for accurate, comparable quantitation between clinical laboratories. Accurate quantitation of HHV-6 is important for detection of viral reactivation and inherited chromosomally integrated HHV-6 in immunocompromised patients. Reference materials in clinical virology commonly consist of laboratory-adapted viral strains that may be affected by the culture process. We performed next-generation sequencing to make relative copy number measurements at single nucleotide resolution of eight candidate HHV-6A and seven HHV-6B reference strains and DNA materials from the HHV-6 Foundation and Advanced Biotechnologies. 11 of 17 (65%) HHV6 candidate reference materials showed multiple copies of the origin of replication upstream of the U41 gene by next-generation sequencing. These large tandem repeats arose independently in culture-adapted HHV-6A and HHV-6B strains, measuring 1254 bp and ...
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Homo sapiens harbor two distinct, medically significant species of simplexviruses, herpes simplex virus (HSV)-1 and HSV-2, with estimated divergence 6-8 million years ago (MYA). Unexpectedly, we found that circulating HSV-2 strains can... more
Homo sapiens harbor two distinct, medically significant species of simplexviruses, herpes simplex virus (HSV)-1 and HSV-2, with estimated divergence 6-8 million years ago (MYA). Unexpectedly, we found that circulating HSV-2 strains can contain HSV-1 DNA segments in three distinct genes. Using over 150 genital swabs from North and South America and Africa, we detected recombinants worldwide. Common, widely distributed gene UL39 genotypes are parsimoniously explained by an initial >457 basepair (bp) HSV-1 × HSV-2 crossover followed by back-recombination to HSV-2. Blocks of >244 and >539 bp of HSV-1 DNA within genes UL29 and UL30, respectively, have reached near fixation, with a minority of strains retaining sequences we posit as ancestral HSV-2. Our data add to previous in vitro and animal work, implying that in vivo cellular co-infection with HSV-1 and HSV-2 yields viable interspecies recombinants in the natural human host.
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Cytomegalovirus (CMV) is acquired by the oral route in children, and primary infection is associated with abundant mucosal replication as well as the establishment of latency in myeloid cells that results in lifelong infection. The... more
Cytomegalovirus (CMV) is acquired by the oral route in children, and primary infection is associated with abundant mucosal replication as well as the establishment of latency in myeloid cells that results in lifelong infection. The efficiency of primary CMV infection in humans following oral exposure, however, is unknown. We consistently detected self-limited, low-level oral CMV shedding events, which we termed transient CMV infections, in a prospective birth cohort of 30 highly exposed CMV-uninfected infants. We estimated the likelihood of transient oral CMV infections by comparing their observed frequency to that of established primary infections, characterized by persistent high-level shedding, viremia and seroconversion. We developed mathematical models of viral dynamics upon initial oral CMV infection, and validated them using clinical shedding data. Transient infections comprised 76-88% of oral CMV shedding events. For this high percentage of transient infections to occur, we ...
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Research Interests: Incidence Geometry, Biology, Infectious Diseases, Adolescent, Breastfeeding, and 15 moreBiological Sciences, Humans, Child, Female, Male, Cytomegalovirus, Infant, Incidence, Adult, Asymptomatic, Herpes Simplex Virus, Cohort Studies, Child preschool, Human Cytomegalovirus, and Medical and Health Sciences
Human herpesvirus-8 (HHV-8), the etiologic agent of Kaposi sarcoma (KS), establishes lifelong latent infection with periodic lytic replication ("shedding") at mucosal sites, especially the oropharynx. Patterns of HHV-8 shedding... more
Human herpesvirus-8 (HHV-8), the etiologic agent of Kaposi sarcoma (KS), establishes lifelong latent infection with periodic lytic replication ("shedding") at mucosal sites, especially the oropharynx. Patterns of HHV-8 shedding are not well understood, and require elucidation to better predict risk of HHV-8 related malignancies in those infected. We sought to characterize patterns of HHV-8 oropharyngeal shedding among diverse cohorts that enrolled HHV-8 seropositive persons. We quantified HHV-8 oral shedding using PCR among HHV-8 seropositive persons who collected at least 14 days of oral swabs in 22 studies on 3 continents. We excluded persons taking antivirals during sampling or any prior use of antiretrovirals in those who were HIV-infected. 248 participants were enrolled from the US, Peru, Cameroon, Uganda, and Kenya; 61 % were men, 58 % were HIV seropositive, and 16 % had KS. Overall, 3,123 of 10,557 samples (29.6 %) had HHV-8 detected. Quantity of virus shed was high...
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The presence of inherited chromosomally integrated human herpesvirus 6 (ciHHV-6) in hematopoietic cell transplant (HCT) donors or recipients confounds molecular testing for HHV-6 reactivation, which occurs in 30-50% of transplants. Here... more
The presence of inherited chromosomally integrated human herpesvirus 6 (ciHHV-6) in hematopoietic cell transplant (HCT) donors or recipients confounds molecular testing for HHV-6 reactivation, which occurs in 30-50% of transplants. Here we describe a multiplex droplet digital PCR clinical diagnostic assay that concurrently distinguishes between HHV-6 species (A or B) and identifies inherited ciHHV-6. By applying this assay to recipient post-HCT plasma and serum samples, we demonstrate reactivation of HHV-6B in 25% (4/16) of HCT recipients with donor or recipient-derived inherited ciHHV-6A, underscoring the need for diagnostic testing for HHV-6 infection even in the presence of ciHHV-6.
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Long-term storage of biological specimens at low temperatures is costly and impractical in resource limited settings, where the disease burden of chronic viral infections is highest, and the need for research greatest. We examined the... more
Long-term storage of biological specimens at low temperatures is costly and impractical in resource limited settings, where the disease burden of chronic viral infections is highest, and the need for research greatest. We examined the necessity of cold storage by comparing the quantity of HHV-8 DNA recovered from swab samples before and after 9-11 months of storage at temperatures of -20°C, 4°C and 37°C. Quantitative levels of HHV-8 DNA remained consistent for laboratory or mucosal swab samples regardless of storage temperature. Freezer storage is determined to be not necessary for mucosal samples destined for HHV-8 DNA quantification.
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Newer diagnostic methods may link more idiopathic pneumonia syndrome (IPS) cases to an infectious agent. Bronchoalveolar lavage (BAL) samples from 69 hematopoietic cell transplant (HCT) recipients with IPS diagnosed between 1992 and 2006... more
Newer diagnostic methods may link more idiopathic pneumonia syndrome (IPS) cases to an infectious agent. Bronchoalveolar lavage (BAL) samples from 69 hematopoietic cell transplant (HCT) recipients with IPS diagnosed between 1992 and 2006 were tested for 28 pathogens (three bacteria and 25 viruses) by quantitative PCR and for Aspergillus by galactomannan assay. Research BALs from 21 asymptomatic HCT patients served as controls. Among 69 HCT patients with IPS, 39 (56.5%) had a pathogen detected. The most frequent pathogens were human herpesvirus-6 (HHV-6) (N=20 [29%]) followed by human rhinovirus (HRV), cytomegalovirus (CMV) and Aspergillus (N=8 [12%] in each). HHV-6 and HRV were rarely detected in controls, while CMV and Aspergillus were occasionally detected with low pathogen load. Patients with pathogens had worse day-100 survival than those without (HR 1.88; p=0.03). Mortality in patients with only pathogens of 'uncertain' significance in lung was similar to that in patien...
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ABSTRACT Background: HSV-1 infection has a wide severity spectrum in the immunocompetent host, from asymptomatic seropositivity to frequent orolabial lesions. To gain insight into virus and host genotype contributions to disease... more
ABSTRACT Background: HSV-1 infection has a wide severity spectrum in the immunocompetent host, from asymptomatic seropositivity to frequent orolabial lesions. To gain insight into virus and host genotype contributions to disease phenotype, we evaluated HSV-1 genotypes and immunity in mono- (MZ) and dizygotic (DZ) twins. Methods: HSV-1 seropositive twin pairs collected daily oral swabs for quantitative HSV-1 PCR and kept symptom diaries for 60 days. Associations of shedding rates were assessed by estimating correlations. We categorized the viral strain as identical or different in each pair with DNA available for genotyping from both. The identity and breadth of HSV-1 antigens recognized by circulating CD4 T-cells were determined using a complete HSV-1 ORF (open reading frame) set. CD4 T-cell responses were scored as present or absent to each ORF. We used a bootstrap method to estimate the distribution of agreements in ORF responses between individuals. Results: We enrolled 29 MZ and 22 DZ twin pairs. The overall shedding rate was 10.3% of days (median 9.3%; range 0-47%). There was a positive correlation between shedding rates within twin pairs (r=0.33, p=0.015) but not among unrelated individuals (r=-0.086; p=0.5). Genotyping showed that 15/14 twin pairs had the same/different HSV-1 strain, respectively. The correlation for shedding rates in all twin pairs was higher in those with the same virus (r=0.55, p=0.033) versus different (r=-0.169, p=0.56). 8 MZ pairs were analyzed for CD4 T-cell responses. The median number of ORFs recognized per person was 19 (range 6-35). The bootstrapped mean percent agreement in ORF response between unrelated pairs was 71% (5th/95th percentile, 67%/75% respectively). The percent agreement between the original 8 pairs of MZ twins was 77% (p=0.003 for difference from bootstrapped dataset). Conclusion: A relationship between HSV-1 shedding and host genotype is supported by our observation of a higher correlation in HSV-1 shedding between twin pairs than between unrelated individuals and similar CD4 T-cell responses between MZ twins. These data and the higher correlation in shedding rates among twins with the same versus different virus suggests that both viral and host genetics contribute to HSV-1 severity.
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Background. Despite high herpes simplex virus type 2 (HSV-2) incidence and prevalence among women in Africa, we are unaware of published neonatal herpes reports. To assess neonatal HSV transmission potential in South Africa, we... more
Background. Despite high herpes simplex virus type 2 (HSV-2) incidence and prevalence among women in Africa, we are unaware of published neonatal herpes reports. To assess neonatal HSV transmission potential in South Africa, we investigated the frequency of the strongest risk factors: HSV acquisition in late pregnancy and HSV shedding during labor.Methods. Women admitted in early labor to a hospital in Soweto underwent HSV serologic testing and genital swab collection for HSV PCR. HSV-2 seronegative women were assessed for seroconversion 4–6 weeks after delivery.Results. Of 390 women enrolled, 229 (58.7%) were HSV-2 seropositive. Genital HSV-2 was detected in 17.2% of HSV-2 seropositive women, including 26 of 115 HIV-positive and 13 of 110 HIV-negative women (22.6% versus 11.8%; RR, 1.91; 95% CI, 1.04–3.53;P=0.038), but in none of 161 HSV-2 seronegative women. Among the 91 HSV-2 seronegative women followed after delivery, none seroconverted.Conclusions. HSV-2 reactivation is common ...