PLoS Articles
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UNC-authored articles published by the Public Library of Science (PLoS)
Works (2111)
1751. Prediction of extended high viremia among newly HIV-1-infected persons in sub-Saharan Africa
- Title Tesim:
- Prediction of extended high viremia among newly HIV-1-infected persons in sub-Saharan Africa
- Creator:
- Inambao, Mubiana, Gilmour, Jill, Anzala, Omu, Kamali, Anatoli, Lakhi, Shabir, Hunter, Eric, Bekker, Linda-Gail, Sanders, Eduard J., Price, Matthew A., Allen, Susan, Powers, Kimberly A., Latka, Mary H., Kilembe, William, Karita, Etienne, and Fast, Patricia E.
- Date of publication:
- 2018
- Abstract Tesim:
- Objective Prompt identification of newly HIV-infected persons, particularly those who are most at risk of extended high viremia (EHV), allows important clinical and transmission prevention benefits. We sought to determine whether EHV could be predicted during early HIV infection (EHI) from clinical, demographic, and laboratory indicators in a large HIV-1 incidence study in Africa. Design Adults acquiring HIV-1 infection were enrolled in an EHI study assessing acute retroviral syndrome (ARS) symptoms and viral dynamics. Methods Estimated date of infection (EDI) was based on a positive plasma viral load or p24 antigen test prior to seroconversion, or the mid-point between negative and positive serological tests. EHV was defined as mean untreated viral load ≥5 log10 copies/ml 130-330 days post-EDI. We used logistic regression to develop risk score algorithms for predicting EHV based on sex, age, number of ARS symptoms, and CD4 and viral load at diagnosis. Results Models based on the full set of five predictors had excellent performance both in the full population (c-statistic = 0.80) and when confined to persons with each of three HIV-1 subtypes(c-statistic = 0.80-0.83 within subtypes A, C, and D). Reduced models containing only 2-4 predictors performed similarly. In a risk score algorithm based on the final full-population model, predictor scores were one for male sex and enrollment CD4<350 cells/mm3, and two for having enrollment viral load >4.9 log10 copies/ml. With a risk score cut-point of two, this algorithm was 85% sensitive (95% CI: 76%-91%) and 61% specific (55%-68%) in predicting EHV. Conclusions Simple risk score algorithms can reliably identify persons with EHI in sub-Saharan Africa who are likely to sustain high viral loads if treatment is delayed. These algorithms may be useful for prioritizing intensified efforts around care linkage and retention, treatment initiation,adherence support, and partner services to optimize clinical and prevention outcomes.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Epidemiology
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/8r2r-3h57
- Identifier:
- https://dx.doi.org/10.1371/journal.pone.0192785
- ISSN:
- 1932-6203
- Journal Issue:
- 4
- Journal Title:
- PLoS ONE
- Journal Volume:
- 13
- Keyword:
- human, Africa south of the Sahara, estimated date of infection, infection prevention, viremia, CD4 antigen, acute HIV infection, female, cohort analysis, extended high viremia, sensitivity and specificity, Human immunodeficiency virus infected patient, algorithm, male, incidence, virus load, major clinical study, Human immunodeficiency virus infection, predictive value, risk assessment, epidemiological data, adult, and copy number variation
- Language Label:
- English
- License Label:
- Attribution 3.0 United States
- ORCID:
- Other Affiliation:
- Person:
- Inambao, Mubiana, Gilmour, Jill, Anzala, Omu, Kamali, Anatoli, Lakhi, Shabir, Hunter, Eric, Bekker, Linda-Gail, Sanders, Eduard J., Price, Matthew A., Allen, Susan, Powers, Kimberly A., Latka, Mary H., Kilembe, William, Karita, Etienne, and Fast, Patricia E.
- Rights Statement Label:
- In Copyright
- Source:
- 8336h730c
1752. Longitudinal patterns of unmet need for contraception among women living with HIV on antiretroviral therapy in South Africa
- Title Tesim:
- Longitudinal patterns of unmet need for contraception among women living with HIV on antiretroviral therapy in South Africa
- Creator:
- Schwartz, Sheree R., Chi, Benjamin H., Pettifor, Audrey E., Rucinski, Katherine B., Black, Vivian, Pence, Brian W., Powers, Kimberly A., and Rees, Helen
- Date of publication:
- 2018
- Abstract Tesim:
- Objectives: Fertility intentions and contraceptive use are often not assessed in the context of clinical HIV care, representing a possible programming gap if women's family planning needs change over time. We aimed to identify longitudinal patterns of unmet need for contraception over a 12-month period among women living with HIV taking antiretroviral therapy (ART). Study design: 850 non-pregnant, HIV-positive women aged 18-35 on or initiating ART in Johannesburg, South Africa, were enrolled into a prospective cohort study in 2009-2010. Fertility intentions and contraceptive use were assessed during routine HIV care visits via an interviewer-administered questionnaire, and women were referred for on-site contraceptive counseling. We used group-based trajectory modeling to identify patterns of unmet need for contraception over 12 months, first in the entire population and then in a subset of recent ART initiators. Results: In the full population we identified four patterns of unmet need for contraception over one year. Half of the enrolled women were predicted to have a consistently high probability of unmet need, 22.9% a consistently low probability, 16.7% a decreasing probability, and 10.4% an increasing probability over time. Contraceptive method discontinuation and rapidly changing fertility intentions were the primary drivers of changing (increasing or decreasing) unmet need over follow-up. Results were similar in recent ART initiators. Conclusions: Half of women were estimated to have a high probability of unmet need that persisted over time, and more than a quarter were estimated to experience patterns of changing unmet need over 12 months. Family planning needs should be assessed more regularly in HIV-positive women to prevent unintended pregnancies and support safer conception among women trying to conceive.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Obstetrics and Gynecology and Department of Epidemiology
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/86h4-ge88
- Identifier:
- https://dx.doi.org/10.1371/journal.pone.0209114
- ISSN:
- 1932-6203
- Journal Issue:
- 12
- Journal Title:
- PLoS ONE
- Journal Volume:
- 13
- Keyword:
- controlled study, major clinical study, longitudinal study, counseling, human cell, South Africa, female fertility, patient care, unplanned pregnancy, antiretroviral therapy, cohort analysis, health care need, human immunodeficiency virus infection, human, Female, contraception, clinical assessment, prospective study, probability, contraceptive behavior, family planning, and adult
- Language Label:
- English
- License Label:
- Attribution 3.0 United States
- ORCID:
- Other Affiliation:
- University of the Witwatersrand and
- Person:
- Schwartz, Sheree R., Chi, Benjamin H., Pettifor, Audrey E., Rucinski, Katherine B., Black, Vivian, Pence, Brian W., Powers, Kimberly A., and Rees, Helen
- Rights Statement Label:
- In Copyright
- Source:
- 3j333761m
1753. Mutations in H5N1 influenza virus hemagglutinin that confer binding to human tracheal airway epithelium
- Title Tesim:
- Mutations in H5N1 influenza virus hemagglutinin that confer binding to human tracheal airway epithelium
- Creator:
- Shelton, Holly, Scull, Margaret A., Ayora-Talavera, Guadalupe, Pickles, Raymond, Barclay, Wendy S., Ren, Junyuan, and Jones, Ian M.
- Date of publication:
- 2009
- Abstract Tesim:
- The emergence in 2009 of a swine-origin H1N1 influenza virus as the first pandemic of the 21st Century is a timely reminder of the international public health impact of influenza viruses, even those associated with mild disease. The widespread distribution of highly pathogenic H5N1 influenza virus in the avian population has spawned concern that it may give rise to a human influenza pandemic. The mortality rate associated with occasional human infection by H5N1 virus approximates 60%, suggesting that an H5N1 pandemic would be devastating to global health and economy. To date, the H5N1 virus has not acquired the propensity to transmit efficiently between humans. The reasons behind this are unclear, especially given the high mutation rate associated with influenza virus replication. Here we used a panel of recombinant H5 hemagglutinin (HA) variants to demonstrate the potential for H5 HA to bind human airway epithelium, the predominant target tissue for influenza virus infection and spread. While parental H5 HA exhibited limited binding to human tracheal epithelium, introduction of selected mutations converted the binding profile to that of a current human influenza strain HA. Strikingly, these amino-acid changes required multiple simultaneous mutations in the genomes of naturally occurring H5 isolates. Moreover, H5 HAs bearing intermediate sequences failed to bind airway tissues and likely represent mutations that are an evolutionary ‘‘dead end.’’ We conclude that, although genetic changes that adapt H5 to human airways can be demonstrated, they may not readily arise during natural virus replication. This genetic barrier limits the likelihood that current H5 viruses will originate a human pandemic.
- Resource type:
- Article
- Admin Note:
- deposited with permission of Raymond Pickles
- Affiliation Label Tesim:
- Cystic Fibrosis and Pulmonary Diseases Research and Treatment Center
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/vn9j-bn19
- Identifier:
- https://dx.doi.org/10.1371/journal.pone.0007836
- ISSN:
- 1932-6203
- Journal Issue:
- 11
- Journal Title:
- PLoS ONE
- Journal Volume:
- 4
- Keyword:
- genetic variability, respiratory epithelium, Spodoptera, virus strain, Hemagglutinin Glycoproteins, controlled study, influenza, Neuraminidase, Salmonella typhimurium, human, pandemic, sequence analysis, sialidase, epithelium, human tissue, Suidae, codon, armyworm, protein expression, nonhuman, gene mutation, chemistry, animal, Influenza virus hemagglutinin, binding site, genome, amino acid sequence, hemagglutinin, mutation, metabolism, nucleotide sequence, virus isolation, Orthomyxoviridae, protein binding, genetics, cytolology, Aves, influenza virus A H5N1, ligand, trachea, and enzymology
- Language Label:
- English
- License Label:
- Attribution 3.0 United States
- ORCID:
- Other Affiliation:
- Imperial College London, , and University of Reading
- Person:
- Shelton, Holly, Scull, Margaret A., Ayora-Talavera, Guadalupe, Pickles, Raymond, Barclay, Wendy S., Ren, Junyuan, and Jones, Ian M.
- Rights Statement Label:
- In Copyright
- Source:
- jq085q964
1754. Cyclophilin-B Modulates Collagen Cross-linking by Differentially Affecting Lysine Hydroxylation in the Helical and Telopeptidyl Domains of Tendon Type I Collagen
- Title Tesim:
- Cyclophilin-B Modulates Collagen Cross-linking by Differentially Affecting Lysine Hydroxylation in the Helical and Telopeptidyl Domains of Tendon Type I Collagen
- Creator:
- Kurie, Jonathan M., Srisawasdi, Sirivimol, Marini, Joan C., Nagasawa, Masako, Yamauchi, Mitsuo, Cabral, Wayne A., Taga, Yuki, Hattori, Shunji, Sumida, Noriko, Terajima, Masahiko, Chen, Yulong, and Hou-Fu, Guo
- Date of publication:
- 2016
- Abstract Tesim:
- Covalent intermolecular cross-linking provides collagen fibrils with stability. The cross-linking chemistry is tissue-specific and determined primarily by the state of lysine hydroxylation at specific sites. A recent study on cyclophilin B (CypB) null mice, a model of recessive osteogenesis imperfecta, demonstrated that lysine hydroxylation at the helical cross-linking site of bone type I collagen was diminished in these animals (Cabral, W. A., Perdivara, I., Weis, M., Terajima, M., Blissett, A. R., Chang, W., Perosky, J. E., Makareeva, E. N., Mertz, E. L., Leikin, S., Tomer, K. B., Kozloff, K. M., Eyre, D. R., Yamauchi, M., and Marini, J. C. (2014) PLoS Genet. 10, e1004465). However, the extent of decrease appears to be tissue- and molecular site-specific, the mechanism of which is unknown. Here we report that although CypB deficiency resulted in lower lysine hydroxylation in the helical cross-linking sites, it was increased in the telopeptide cross-linking sites in tendon type I collagen. This resulted in a decrease in the lysine aldehyde-derived cross-links but generation of hydroxylysine aldehyde-derived cross-links. The latter were absent from the wild type and heterozygous mice. Glycosylation of hydroxylysine residues was moderately increased in the CypB null tendon. We found that CypB interacted with all lysyl hydroxylase isoforms (isoforms 1–3) and a putative lysyl hydroxylase-2 chaperone, 65-kDa FK506-binding protein. Tendon collagen in CypB null mice showed severe size and organizational abnormalities. The data indicate that CypB modulates collagen cross-linking by differentially affecting lysine hydroxylation in a site-specific manner, possibly via its interaction with lysyl hydroxylases and associated molecules. This study underscores the critical importance of collagen post-translational modifications in connective tissue formation.
- Resource type:
- Article
- Affiliation Label Tesim:
- School of Dentistry
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/cmhj-sd29
- Identifier:
- PMID: 26934917, Onescience id: ee33cde8616687310047dfe1a537b82d0e9ce3f2, Publisher DOI: https://doi.org/10.1074/jbc.M115.699470, and PMCID: PMC4850290
- ISSN:
- 0021-9258 and 1083-351X
- Journal Issue:
- 18
- Journal Title:
- The Journal of Biological Chemistry
- Journal Volume:
- 291
- Keyword:
- Collagen, molecular chaperone, cyclophilin, post-translational modification (PTM), Tendons, glycosylation, Lysine, hydroxylysine (Hyl), Animals, Cyclophilins, tendon, Hydroxylation, Collagen Type I, and collagen
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Department of Thoracic; Head and Neck Medical Oncology; University of Texas; M.D. Anderson Cancer Center, Department of Operative Dentistry; Chulalongkorn University, Bone and Extracellular Matrix Branch; NICHD; National Institutes of Health, Division of Bio-Prosthodontics; Niigata University; Graduate School of Medical and Dental Sciences, and Nippi Research Institute of Biomatrix
- Person:
- Kurie, Jonathan M., Srisawasdi, Sirivimol, Marini, Joan C., Nagasawa, Masako, Yamauchi, Mitsuo, Cabral, Wayne A., Taga, Yuki, Hattori, Shunji, Sumida, Noriko, Terajima, Masahiko, Chen, Yulong, and Hou-Fu, Guo
- Rights Statement Label:
- In Copyright
- Source:
- 1z40m0110
1755. The microbiome and the hallmarks of cancer
- Title Tesim:
- The microbiome and the hallmarks of cancer
- Creator:
- Fulbright, Laura E., Ellermann, Melissa, and Arthur, Janelle C.
- Date of publication:
- 2017
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Microbiology and Immunology
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/gchk-ee21
- Identifier:
- Publisher DOI: https://doi.org/10.1371/journal.ppat.1006480, PMCID: PMC5608396, PMID: 28934351, and Onescience id: 518b9718ff97cfdda17d70544558bbf94416e8e4
- ISSN:
- 1553-7374 and 1553-7366
- Journal Issue:
- 9
- Journal Title:
- PLoS Pathogens
- Journal Volume:
- 13
- Keyword:
- Microbiome, Genomic signal processing, Carcinogenesis, Cell metabolism, Mouse models, Colorectal cancer, Gastrointestinal tract, and Inflammation
- Language Label:
- English
- ORCID:
- 0000-0003-3212-3390, 0000-0002-8942-6889, and
- Other Affiliation:
- University of North Carolina at Chapel Hill and School of Medicine
- Page Start:
- e1006480
- Person:
- Fulbright, Laura E., Ellermann, Melissa, and Arthur, Janelle C.
- Rights Statement Label:
- In Copyright
- Source:
- xp68kn546
1756. T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy
- Title Tesim:
- T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy
- Creator:
- Simmens, Samuel, Eron, Joseph J., Walker, Bruce D., Benko, Erika, Bosch, Ronald J., Jones, Kimberley L., Mellors, John W., Gandhi, Rajesh T., McMahon, Deborah K., Bosque, Alberto, Macedo, Amanda B., Cyktor, Joshua C., Lalama, Christina M., Jones, R. Brad, Chan, Dora, Kovacs, Colin, Truong, Ronald, Huang, Szu-Han, and Thomas, Allison S.
- Date of publication:
- 2017
- Abstract Tesim:
- HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART), these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of latency, we observed that a Nef-specific CD8+ T-cell clone exhibited low-level recognition of infected cells prior to reactivation and robust recognition shortly thereafter. A Gag-specific CD8+ T-cell clone failed to recognized infected cells under these conditions, corresponding with a lack of detectable Gag expression. We measured HIV-specific T-cell responses in 96 individuals who had been suppressed on ART for a median of 7 years, and observed a significant, direct correlation between cell-associated HIV DNA levels and magnitudes of IFN-γ-producing Nef/Tat/Rev-specific T-cell responses. This correlation was confirmed in an independent cohort (n = 18). Correlations were not detected between measures of HIV persistence and T-cell responses to other HIV antigens. The correlation with Nef/Tat/Rev-specific T-cells was attributable to Nef-specific responses, the breadth of which also correlated with HIV DNA levels. These results suggest that ongoing Nef expression in ART-treated individuals drives preferential maintenance and/or expansion of T-cells reactive to this protein, implying sensing of infected cells by the immune system. The direct correlation, however, suggests that recognition does not result in efficient elimination of infected cells. These results raise the possibility that enhancing the cytolytic activity of Nef-specific T-cells may lead to reductions in infected cell frequencies, even in the absence of therapeutic latency reversal.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Medicine
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/q4bq-1y47
- Identifier:
- Onescience id: 48aba164561138f7a122629f5bd33fc1611116c1, PMID: 28931091, Publisher DOI: https://doi.org/10.1371/journal.ppat.1006629, and PMCID: PMC5624641
- ISSN:
- 1553-7374 and 1553-7366
- Journal Issue:
- 9
- Journal Title:
- PLoS Pathogens
- Journal Volume:
- 13
- Keyword:
- RNA viruses, Blood cells, Medical Microbiology, Organisms, T cells, T Cells, Medicine and Health Sciences, Cytotoxic T cells, Cell Biology, Pathogens, Animal Cells, Viruses, Biology and life sciences, White blood cells, Cellular Types, Cell biology, Retroviruses, Lentivirus, Microbiology, Animal cells, Biology and Life Sciences, White Blood Cells, Immunodeficiency Viruses, HIV, Viral Pathogens, Blood Cells, Cellular types, Pathology and Laboratory Medicine, Immune Cells, Immune cells, Medicine, Immunology, and Microbial Pathogens
- Language Label:
- English
- ORCID:
- 0000-0001-7830-8003, 0000-0002-4938-0644, , 0000-0001-9136-0877, 0000-0002-8800-2160, 0000-0003-3601-4837, 0000-0001-6711-481X, 0000-0003-4470-1231, 0000-0002-7777-3293, and 0000-0003-1420-3186
- Other Affiliation:
- Department of Epidemiology and Biostatistics; George Washington University; Milken Institute School of Public Health, Ragon Institute of MIT; MGH and Harvard, Howard Hughes Medical Institute, Division of Infectious Diseases; Department of Medicine; University of Pittsburgh School of Medicine, Harvard TH Chan School of Public Health, Department of Microbiology Immunology and Tropical Medicine; George Washington University, Massachusetts General Hospital, and Maple Leaf Medical Clinic
- Page Start:
- e1006629
- Person:
- Simmens, Samuel, Eron, Joseph J., Walker, Bruce D., Benko, Erika, Bosch, Ronald J., Jones, Kimberley L., Mellors, John W., Gandhi, Rajesh T., McMahon, Deborah K., Bosque, Alberto, Macedo, Amanda B., Cyktor, Joshua C., Lalama, Christina M., Jones, R. Brad, Chan, Dora, Kovacs, Colin, Truong, Ronald, Huang, Szu-Han, and Thomas, Allison S.
- Rights Statement Label:
- In Copyright
- Source:
- 3b591f53f
1757. Sp100 colocalizes with HPV replication foci and restricts the productive stage of the infectious cycle
- Title Tesim:
- Sp100 colocalizes with HPV replication foci and restricts the productive stage of the infectious cycle
- Creator:
- Khurana, Simran, McBride, Alison A., Warburton, Alix, Stepp, Wesley H., and Stamos, James D.
- Date of publication:
- 2017
- Abstract Tesim:
- We have shown previously that Sp100 (a component of the ND10 nuclear body) represses transcription, replication and establishment of incoming human papillomavirus (HPV) DNA in the early stages of infection. In this follow up study, we show that Sp100 does not substantially regulate viral infection in the maintenance phase, however at late stages of infection Sp100 interacts with amplifying viral genomes to repress viral processes. We find that Sp100 localizes to HPV16 replication foci generated in primary keratinocytes, to HPV31 replication foci that form in differentiated cells, and to HPV16 replication foci in CIN 1 cervical biopsies. To analyze this further, Sp100 was down regulated by siRNA treatment of differentiating HPV31 containing cells and levels of viral transcription and replication were assessed. This revealed that Sp100 represses viral transcription and replication in differentiated cells. Analysis of Sp100 binding to viral chromatin showed that Sp100 bound across the viral genome, and that binding increased at late stages of infection. Therefore, Sp100 represses the HPV life cycle at both early and late stages of infection.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Surgery
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/9shc-r737
- Identifier:
- PMID: 28968443, PMCID: PMC5638619, Publisher DOI: https://doi.org/10.1371/journal.ppat.1006660, and Onescience id: eb3b9f2c04bf596c30c6504326a5206379125a2c
- ISSN:
- 1553-7366 and 1553-7374
- Journal Issue:
- 10
- Journal Title:
- PLoS Pathogens
- Journal Volume:
- 13
- Keyword:
- Transcription Factors, Host-Pathogen Interactions, DNA Replication, Virus Replication, Autoantigens, Antigens, Nuclear, Humans, Genome, Viral, Human papillomavirus 16, and Keratinocytes
- Language Label:
- English
- ORCID:
- , 0000-0001-5607-5157, and 0000-0001-7321-1640
- Other Affiliation:
- Laboratory of Viral Diseases; National Institute of Allergy and Infectious Diseases; National Institutes of Health
- Page Start:
- e1006660
- Person:
- Khurana, Simran, McBride, Alison A., Warburton, Alix, Stepp, Wesley H., and Stamos, James D.
- Rights Statement Label:
- In Copyright
- Source:
- 5d86p560k
1758. Rare HIV-1 transmitted/founder lineages identified by deep viral sequencing contribute to rapid shifts in dominant quasispecies during acute and early infection
- Title Tesim:
- Rare HIV-1 transmitted/founder lineages identified by deep viral sequencing contribute to rapid shifts in dominant quasispecies during acute and early infection
- Creator:
- Poltavee, Kultida, O’Sullivan, Anne Marie, Nitayaphan, Sorachai, Tovanabutra, Sodsai, Eller, Michael A., Cicala, Claudia, Warren, Joanna A., Michael, Nelson L., Arthos, James, O’Connell, Robert J., Billings, Erik, Shaw, George M., Merbah, Melanie, Kim, Jerome H., Goonetilleke, Nilu, Kibuuka, Hannah, Oropeza, Celina, Fischer, Will, Thomas, Rasmi, Marovich, Mary A., Rao, Mangala, Rolland, Morgane, Peachman, Kristina K., Eller, Leigh A., Gao, Feng, Robb, Merlin L., Leviyang, Sivan, Costanzo, Margaret C., Krebs, Shelly J., Sinei, Samuel, Maganga, Lucas, Bose, Meera, Kijak, Gustavo H., Sanders-Buell, Eric, Slike, Bonnie, Harbolick, Elizabeth A., Pham, Phuc, Li, Hui, Korber, Bette T., and Chenine, Agnes-Laurence
- Date of publication:
- 2017
- Abstract Tesim:
- In order to inform the rational design of HIV-1 preventive and cure interventions it is critical to understand the events occurring during acute HIV-1 infection (AHI). Using viral deep sequencing on six participants from the early capture acute infection RV217 cohort, we have studied HIV-1 evolution in plasma collected twice weekly during the first weeks following the advent of viremia. The analysis of infections established by multiple transmitted/founder (T/F) viruses revealed novel viral profiles that included: a) the low-level persistence of minor T/F variants, b) the rapid replacement of the major T/F by a minor T/F, and c) an initial expansion of the minor T/F followed by a quick collapse of the same minor T/F to low frequency. In most participants, cytotoxic T-lymphocyte (CTL) escape was first detected at the end of peak viremia downslope, proceeded at higher rates than previously measured in HIV-1 infection, and usually occurred through the exploration of multiple mutational pathways within an epitope. The rapid emergence of CTL escape variants suggests a strong and early CTL response. Minor T/F viral strains can contribute to rapid and varied profiles of HIV-1 quasispecies evolution during AHI. Overall, our results demonstrate that early, deep, and frequent sampling is needed to investigate viral/host interaction during AHI, which could help identify prerequisites for prevention and cure of HIV-1 infection.
- Resource type:
- Article
- Affiliation Label Tesim:
- School of Medicine
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/fcht-sf53
- Identifier:
- PMCID: PMC5552316, Publisher DOI: https://doi.org/10.1371/journal.ppat.1006510, Onescience id: 8d3a7039b1b0dd8924150285baa18f19fd6b878a, and PMID: 28759651
- ISSN:
- 1553-7374 and 1553-7366
- Journal Issue:
- 7
- Journal Title:
- PLoS Pathogens
- Journal Volume:
- 13
- Keyword:
- Cohort Studies, Male, High-Throughput Nucleotide Sequencing, Adolescent, T-Lymphocytes, Cytotoxic, Humans, Adult, Young Adult, Immune Evasion, Middle Aged, Female, HIV Infections, and HIV-1
- Language Label:
- English
- ORCID:
- , 0000-0001-6935-1405, 0000-0001-5882-5548, 0000-0002-2293-1944, 0000-0003-4579-4062, 0000-0002-8315-3146, and 0000-0002-2026-5757
- Other Affiliation:
- U.S. Military HIV Research Program; Walter Reed Army Institute of Research, Henry M. Jackson Foundation for the Advancement of Military Medicine, Armed Forces Research Institute of Medical Sciences, Laboratory of Immunoregulation National Institute of Allergy and Infectious Diseases; National Institutes of Health, Perelman School of Medicine; University of Pennsylvania, International Vaccine Institute, Makerere University-Walter Reed Project, Theoretical Biology; Los Alamos National Laboratory, Vaccine Research Program; National Institute of Allergy and Infectious Diseases; National Institutes of Health, Duke Human Vaccine Institute; Duke University Medical Center, Department of Mathematics and Statistics; Georgetown University, Walter Reed Project, Mbeya Medical Research Programme, and GSK Vaccines
- Page Start:
- e1006510
- Person:
- Poltavee, Kultida, O’Sullivan, Anne Marie, Nitayaphan, Sorachai, Tovanabutra, Sodsai, Eller, Michael A., Cicala, Claudia, Warren, Joanna A., Michael, Nelson L., Arthos, James, O’Connell, Robert J., Billings, Erik, Shaw, George M., Merbah, Melanie, Kim, Jerome H., Goonetilleke, Nilu, Kibuuka, Hannah, Oropeza, Celina, Fischer, Will, Thomas, Rasmi, Marovich, Mary A., Rao, Mangala, Rolland, Morgane, Peachman, Kristina K., Eller, Leigh A., Gao, Feng, Robb, Merlin L., Leviyang, Sivan, Costanzo, Margaret C., Krebs, Shelly J., Sinei, Samuel, Maganga, Lucas, Bose, Meera, Kijak, Gustavo H., Sanders-Buell, Eric, Slike, Bonnie, Harbolick, Elizabeth A., Pham, Phuc, Li, Hui, Korber, Bette T., and Chenine, Agnes-Laurence
- Rights Statement Label:
- In Copyright
- Source:
- cv43p270g
1759. NS5A inhibitors unmask differences in functional replicase complex half-life between different hepatitis C virus strains
- Title Tesim:
- NS5A inhibitors unmask differences in functional replicase complex half-life between different hepatitis C virus strains
- Creator:
- Perelson, Alan S., Yamane, Daisuke, McGivern, David R., Benzine, Tiffany, Lovell, William C., Lemon, Stanley M., Neddermann, Petra, Ke, Ruian, Brandt, Ryan, and De Francesco, Raffaele
- Date of publication:
- 2017
- Abstract Tesim:
- Hepatitis C virus (HCV) RNA is synthesized by the replicase complex (RC), a macromolecular assembly composed of viral non-structural proteins and cellular co-factors. Inhibitors of the HCV NS5A protein block formation of new RCs but do not affect RNA synthesis by pre-formed RCs. Without new RC formation, existing RCs turn over and are eventually lost from the cell. We aimed to use NS5A inhibitors to estimate the half-life of the functional RC of HCV. We compared different cell culture-infectious strains of HCV that may be grouped based on their sensitivity to lipid peroxidation: robustly replicating, lipid peroxidation resistant (LPOR) viruses (e.g. JFH-1 or H77D) and more slowly replicating, lipid peroxidation sensitive (LPOS) viruses (e.g. H77S.3 and N.2). In luciferase assays, LPOS HCV strains declined under NS5A inhibitor therapy with much slower kinetics compared to LPOR HCV strains. This difference in rate of decline was not observed for inhibitors of the NS5B RNA-dependent RNA polymerase suggesting that the difference was not simply a consequence of differences in RNA stability. In further analyses, we compared two isoclonal HCV variants: the LPOS H77S.3 and the LPOR H77D that differ only by 12 amino acids. Differences in rate of decline between H77S.3 and H77D following NS5A inhibitor addition were not due to amino acid sequences in NS5A but rather due to a combination of amino acid differences in the non-structural proteins that make up the HCV RC. Mathematical modeling of intracellular HCV RNA dynamics suggested that differences in RC stability (half-lives of 3.5 and 9.9 hours, for H77D and H77S.3, respectively) are responsible for the different kinetics of antiviral suppression between LPOS and LPOR viruses. In nascent RNA capture assays, the rate of RNA synthesis decline following NS5A inhibitor addition was significantly faster for H77D compared to H77S.3 indicating different half-lives of functional RCs.
- Resource type:
- Article
- Affiliation Label Tesim:
- University of North Carolina at Chapel Hill
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/ek6n-ys15
- Identifier:
- Onescience id: 791ad392c685c8e587562604cb738dc245d47417, Publisher DOI: https://doi.org/10.1371/journal.ppat.1006343, PMID: 28594932, and PMCID: PMC5464671
- ISSN:
- 1553-7374 and 1553-7366
- Journal Issue:
- 6
- Journal Title:
- PLoS Pathogens
- Journal Volume:
- 13
- Keyword:
- Hepatitis C, Viral Nonstructural Proteins, Virus Assembly, Half-Life, Humans, Hepacivirus, Virus Replication, Kinetics, and NS-5 protein, hepatitis C virus
- Language Label:
- English
- ORCID:
- 0000-0002-2455-0002, , and 0000-0001-8625-6581
- Other Affiliation:
- Theoretical Biology and Biophysics; Los Alamos National Laboratory, Department of Microbiology and Cell Biology; Tokyo Metropolitan Institute of Medical Science, Department of Medicine, INGM -Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi, GCP-Service International, and Department of Mathematics; North Carolina State University
- Page Start:
- e1006343
- Person:
- Perelson, Alan S., Yamane, Daisuke, McGivern, David R., Benzine, Tiffany, Lovell, William C., Lemon, Stanley M., Neddermann, Petra, Ke, Ruian, Brandt, Ryan, and De Francesco, Raffaele
- Rights Statement Label:
- In Copyright
- Source:
- g445ck11s
1760. NLRX1 negatively modulates type I IFN to facilitate KSHV reactivation from latency
- Title Tesim:
- NLRX1 negatively modulates type I IFN to facilitate KSHV reactivation from latency
- Creator:
- Guo, Haitao, Yang, Fan, Ma, Zhe, Ting, Jenny P-Y, Dittmer, Dirk P., Hopcraft, Sharon E., Damania, Blossom, and Petrucelli, Alex
- Date of publication:
- 2017
- Abstract Tesim:
- Kaposi’s sarcoma-associated herpesvirus (KSHV) is a herpesvirus that is linked to Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD). KSHV establishes persistent latent infection in the human host. KSHV undergoes periods of spontaneous reactivation where it can enter the lytic replication phase of its lifecycle. During KSHV reactivation, host innate immune responses are activated to restrict viral replication. Here, we report that NLRX1, a negative regulator of the type I interferon response, is important for optimal KSHV reactivation from latency. Depletion of NLRX1 in either iSLK.219 or BCBL-1 cells significantly suppressed global viral transcription levels compared to the control group. Concomitantly, fewer viral particles were present in either cells or supernatant from NLRX1 depleted cells. Further analysis revealed that upon NLRX1 depletion, higher IFNβ transcription levels were observed, which was also associated with a transcriptional upregulation of JAK/STAT pathway related genes in both cell lines. To investigate whether IFNβ contributes to NLRX1’s role in KSHV reactivation, we treated control and NLRX1 depleted cells with a TBK1 inhibitor (BX795) or TBK1 siRNA to block IFNβ production. Upon BX795 or TBK1 siRNA treatment, NLRX1 depletion exhibited less inhibitory effects on reactivation and infectious virion production, suggesting that NLRX1 facilitates KSHV lytic replication by negatively regulating IFNβ responses. Our data suggests that NLRX1 plays a positive role in KSHV lytic replication by suppressing the IFNβ response during the process of KSHV reactivation, which might serve as a potential target for restricting KSHV replication and transmission.
- Resource type:
- Article
- Affiliation Label Tesim:
- University of North Carolina at Chapel Hill
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/szpn-x318
- Identifier:
- PMID: 28459883, Onescience id: dd2ab3fea69fb742b063aec0d8f31cefff300f3f, Publisher DOI: https://doi.org/10.1371/journal.ppat.1006350, and PMCID: PMC5426799
- ISSN:
- 1553-7374 and 1553-7366
- Journal Issue:
- 5
- Journal Title:
- PLoS Pathogens
- Journal Volume:
- 13
- Keyword:
- Interferon Type I, Mitochondrial Proteins, Lymphoma, Primary Effusion, Herpesvirus 8, Human, DNA Replication, Humans, Sarcoma, Kaposi, Cell Line, Multi-centric Castleman's Disease, Gene Expression Regulation, Virus Latency, Castleman Disease, and Virus Activation
- Language Label:
- English
- ORCID:
- , 0000-0002-7222-2556, and 0000-0002-2564-3913
- Other Affiliation:
- Department of Microbiology and Immunology
- Page Start:
- e1006350
- Person:
- Guo, Haitao, Yang, Fan, Ma, Zhe, Ting, Jenny P-Y, Dittmer, Dirk P., Hopcraft, Sharon E., Damania, Blossom, and Petrucelli, Alex
- Rights Statement Label:
- In Copyright
- Source:
- t722hg122
Collection Details
- Total items
-
2111
- Size
-
unknown
- Date created
-
February 2, 2022