Publications by authors named "Beatrice H Hahn"

268 Publications

Author Correction: Adaptation of Plasmodium falciparum to humans involved the loss of an ape-specific erythrocyte invasion ligand.

Nat Commun 2021 Feb 16;12(1):1188. Epub 2021 Feb 16.

Malaria Programme, Wellcome Sanger Institute,Wellcome Genome Campus, Cambridge, CB10 1SA, UK.

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http://dx.doi.org/10.1038/s41467-021-21491-yDOI Listing
February 2021

Convalescent plasma-mediated resolution of COVID-19 in a patient with humoral immunodeficiency.

Cell Rep Med 2021 Jan 5;2(1):100164. Epub 2020 Dec 5.

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Convalescent plasma (CP) is widely used to treat COVID-19, but without formal evidence of efficacy. Here, we report the beneficial effects of CP in a severely ill COVID-19 patient with prolonged pneumonia and advanced chronic lymphocytic leukemia (CLL), who was unable to generate an antiviral antibody response of her own. On day 33 after becoming symptomatic, the patient received CP containing high-titer (ID > 5,000) neutralizing antibodies (NAbs), defervesced, and improved clinically within 48 h and was discharged on day 37. Hence, when present in sufficient quantities, NAbs to SARS-CoV-2 have clinical benefit even if administered relatively late in the disease course. However, analysis of additional CP units revealed widely varying NAb titers, with many recipients exhibiting endogenous NAb responses far exceeding those of the administered units. To obtain the full therapeutic benefits of CP immunotherapy, it will thus be important to determine the neutralizing activity in both CP units and transfusion candidates.
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http://dx.doi.org/10.1016/j.xcrm.2020.100164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817775PMC
January 2021

Heightened resistance to host type 1 interferons characterizes HIV-1 at transmission and after antiretroviral therapy interruption.

Sci Transl Med 2021 Jan;13(576)

Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Type 1 interferons (IFN-I) are potent innate antiviral effectors that constrain HIV-1 transmission. However, harnessing these cytokines for HIV-1 cure strategies has been hampered by an incomplete understanding of their antiviral activities at later stages of infection. Here, we characterized the IFN-I sensitivity of 500 clonally derived HIV-1 isolates from the plasma and CD4 T cells of 26 individuals sampled longitudinally after transmission or after antiretroviral therapy (ART) and analytical treatment interruption. We determined the concentration of IFNα2 and IFNβ that reduced viral replication in vitro by 50% (IC) and found consistent changes in the sensitivity of HIV-1 to IFN-I inhibition both across individuals and over time. Resistance of HIV-1 isolates to IFN-I was uniformly high during acute infection, decreased in all individuals in the first year after infection, was reacquired concomitant with CD4 T cell loss, and remained elevated in individuals with accelerated disease. HIV-1 isolates obtained by viral outgrowth during suppressive ART were relatively IFN-I sensitive, resembling viruses circulating just before ART initiation. However, viruses that rebounded after treatment interruption displayed the highest degree of IFNα2 and IFNβ resistance observed at any time during the infection course. These findings indicate a dynamic interplay between host innate responses and the evolving HIV-1 quasispecies, with the relative contribution of IFN-I to HIV-1 control affected by both ART and analytical treatment interruption. Although elevated at transmission, host innate pressures are the highest during viral rebound, limiting the viruses that successfully become reactivated from latency to those that are IFN-I resistant.
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http://dx.doi.org/10.1126/scitranslmed.abd8179DOI Listing
January 2021

Natural cystatin C fragments inhibit GPR15-mediated HIV and SIV infection without interfering with GPR15L signaling.

Proc Natl Acad Sci U S A 2021 Jan;118(3)

Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany;

GPR15 is a G protein-coupled receptor (GPCR) proposed to play a role in mucosal immunity that also serves as a major entry cofactor for HIV-2 and simian immunodeficiency virus (SIV). To discover novel endogenous GPR15 ligands, we screened a hemofiltrate (HF)-derived peptide library for inhibitors of GPR15-mediated SIV infection. Our approach identified a C-terminal fragment of cystatin C (CysC95-146) that specifically inhibits GPR15-dependent HIV-1, HIV-2, and SIV infection. In contrast, GPR15L, the chemokine ligand of GPR15, failed to inhibit virus infection. We found that cystatin C fragments preventing GPR15-mediated viral entry do not interfere with GPR15L signaling and are generated by proteases activated at sites of inflammation. The antiretroviral activity of CysC95-146 was confirmed in primary CD4 T cells and is conserved in simian hosts of SIV infection. Thus, we identified a potent endogenous inhibitor of GPR15-mediated HIV and SIV infection that does not interfere with the physiological function of this GPCR.
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http://dx.doi.org/10.1073/pnas.2023776118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826402PMC
January 2021

Research and Conservation in the Greater Gombe Ecosystem: Challenges and Opportunities.

Biol Conserv 2020 Dec 16;252. Epub 2020 Nov 16.

The Jane Goodall Institute, Vienna, VA, 22182 USA.

The study of chimpanzees in Gombe National Park, Tanzania, started by Jane Goodall in 1960, provided pioneering accounts of chimpanzee behavior and ecology. With funding from multiple sources, including the Jane Goodall Institute (JGI) and grants from private foundations and federal programs, the project has continued for sixty years, providing a wealth of information about our evolutionary cousins. These chimpanzees face two main challenges to their survival: infectious disease - including simian immunodeficiency virus (SIVcpz), which can cause Acquired Immune Deficiency Syndrome (AIDS) in chimpanzees - and the deforestation of land outside the park. A health monitoring program has increased understanding of the pathogens affecting chimpanzees and has promoted measures to characterize and reduce disease risk. Deforestation reduces connections between Gombe and other chimpanzee populations, which can cause loss of genetic diversity. To promote habitat restoration, JGI facilitated participatory village land use planning, in which communities voluntarily allocated land to a network of Village Land Forest Reserves. Expected benefits to people include stabilizing watersheds, improving water supplies, and ensuring a supply of forest resources. Surveys and genetic analyses confirm that chimpanzees persist on village lands and remain connected to the Gombe population. Many challenges remain, but the regeneration of natural forest on previously degraded lands provides hope that conservation solutions can be found that benefit both people and wildlife. Conservation work in the Greater Gombe Ecosystem has helped promote broader efforts to plan and work for conservation elsewhere in Tanzania and across Africa.
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http://dx.doi.org/10.1016/j.biocon.2020.108853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743041PMC
December 2020

Recapitulation of HIV-1 Env-antibody coevolution in macaques leading to neutralization breadth.

Science 2021 01 19;371(6525). Epub 2020 Nov 19.

Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Neutralizing antibodies elicited by HIV-1 coevolve with viral envelope proteins (Env) in distinctive patterns, in some cases acquiring substantial breadth. We report that primary HIV-1 envelope proteins-when expressed by simian-human immunodeficiency viruses in rhesus macaques-elicited patterns of Env-antibody coevolution very similar to those in humans, including conserved immunogenetic, structural, and chemical solutions to epitope recognition and precise Env-amino acid substitutions, insertions, and deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a 208-strain panel, revealed a V2 apex mode of recognition like that of human broadly neutralizing antibodies (bNAbs) PGT145 and PCT64-35S. Another rhesus antibody bound the CD4 binding site by CD4 mimicry, mirroring human bNAbs 8ANC131, CH235, and VRC01. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design.
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http://dx.doi.org/10.1126/science.abd2638DOI Listing
January 2021

SARS-CoV-2-specific peripheral T follicular helper cells correlate with neutralizing antibodies and increase during convalescence.

medRxiv 2020 Oct 12. Epub 2020 Oct 12.

T-cell immunity is likely to play a role in protection against SARS-CoV-2 by helping generate neutralizing antibodies. We longitudinally studied CD4 T-cell responses to the M, N, and S structural proteins of SARS-CoV-2 in 21 convalescent individuals. Within the first two months following symptom onset, a majority of individuals (81%) mount at least one CD4 T-cell response, and 48% of individuals mount detectable SARS-CoV-2-specific peripheral T follicular helper cells (pTfh, defined as CXCR5+PD1+ CD4 T cells). SARS-CoV-2-specific pTfh responses across all three protein specificities correlate with antibody neutralization with the strongest correlation observed for S protein-specific responses. When examined over time, pTfh responses increase in frequency and magnitude in convalescence, and robust responses with magnitudes greater than 5% were detected only at the second convalescent visit, an average of 38 days post-symptom onset. These data deepen our understanding of antigen-specific pTfh responses in SARS-CoV-2 infection, suggesting that M and N protein-specific pTfh may also assist in the development of neutralizing antibodies and that pTfh response formation may be delayed in SARS-CoV-2 infection.
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http://dx.doi.org/10.1101/2020.10.07.20208488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553179PMC
October 2020

Urine as a high-quality source of host genomic DNA from wild populations.

Mol Ecol Resour 2021 Jan 17;21(1):170-182. Epub 2020 Oct 17.

Center for Evolution and Medicine, Arizona State University, Tempe, AZ, USA.

The ability to generate genomic data from wild animal populations has the potential to give unprecedented insight into the population history and dynamics of species in their natural habitats. However, for many species, it is impossible legally, ethically or logistically to obtain tissue samples of quality sufficient for genomic analyses. In this study we evaluate the success of multiple sources of genetic material (faeces, urine, dentin and dental calculus) and several capture methods (shotgun, whole-genome, exome) in generating genome-scale data in wild eastern chimpanzees (Pan troglodytes schweinfurthii) from Gombe National Park, Tanzania. We found that urine harbours significantly more host DNA than other sources, leading to broader and deeper coverage across the genome. Urine also exhibited a lower rate of allelic dropout. We found exome sequencing to be far more successful than both shotgun sequencing and whole-genome capture at generating usable data from low-quality samples such as faeces and dental calculus. These results highlight urine as a promising and untapped source of DNA that can be noninvasively collected from wild populations of many species.
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http://dx.doi.org/10.1111/1755-0998.13260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746602PMC
January 2021

Ape Origins of Human Malaria.

Annu Rev Microbiol 2020 09;74:39-63

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; email:

African apes harbor at least twelve species, some of which have been a source of human infection. It is now well established that emerged following the transmission of a gorilla parasite, perhaps within the last 10,000 years, while emerged earlier from a parasite lineage that infected humans and apes in Africa before the Duffy-negative mutation eliminated the parasite from humans there. Compared to their ape relatives, both human parasites have greatly reduced genetic diversity and an excess of nonsynonymous mutations, consistent with severe genetic bottlenecks followed by rapid population expansion. A putative new species widespread in chimpanzees, gorillas, and bonobos places the origin of in Africa. Here, we review what is known about the origins and evolutionary history of all human-infective species, the time and circumstances of their emergence, and the diversity, host specificity, and zoonotic potential of their ape counterparts.
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http://dx.doi.org/10.1146/annurev-micro-020518-115628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643433PMC
September 2020

Recommendations for measuring HIV reservoir size in cure-directed clinical trials.

Nat Med 2020 09 7;26(9):1339-1350. Epub 2020 Sep 7.

The Wistar Institute, Philadelphia, PA, USA.

Therapeutic strategies are being clinically tested either to eradicate latent HIV reservoirs or to achieve virologic control in the absence of antiretroviral therapy. Attaining this goal will require a consensus on how best to measure the numbers of persistently infected cells with the potential to cause viral rebound after antiretroviral-therapy cessation in assessing the results of cure-directed strategies in vivo. Current measurements assess various aspects of the HIV provirus and its functionality and produce divergent results. Here, we provide recommendations from the BEAT-HIV Martin Delaney Collaboratory on which viral measurements should be prioritized in HIV-cure-directed clinical trials.
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http://dx.doi.org/10.1038/s41591-020-1022-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703694PMC
September 2020

The Origin of COVID-19 and Why It Matters.

Am J Trop Med Hyg 2020 Sep;103(3):955-959

Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

The COVID-19 pandemic is among the deadliest infectious diseases to have emerged in recent history. As with all past pandemics, the specific mechanism of its emergence in humans remains unknown. Nevertheless, a large body of virologic, epidemiologic, veterinary, and ecologic data establishes that the new virus, SARS-CoV-2, evolved directly or indirectly from a β-coronavirus in the sarbecovirus (SARS-like virus) group that naturally infect bats and pangolins in Asia and Southeast Asia. Scientists have warned for decades that such sarbecoviruses are poised to emerge again and again, identified risk factors, and argued for enhanced pandemic prevention and control efforts. Unfortunately, few such preventive actions were taken resulting in the latest coronavirus emergence detected in late 2019 which quickly spread pandemically. The risk of similar coronavirus outbreaks in the future remains high. In addition to controlling the COVID-19 pandemic, we must undertake vigorous scientific, public health, and societal actions, including significantly increased funding for basic and applied research addressing disease emergence, to prevent this tragic history from repeating itself.
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http://dx.doi.org/10.4269/ajtmh.20-0849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470595PMC
September 2020

Hitting the sweet spot: exploiting HIV-1 glycan shield for induction of broadly neutralizing antibodies.

Curr Opin HIV AIDS 2020 09;15(5):267-274

T-6 Theoretical Biology & Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico.

Purpose Of Review: The surface of the HIV-1 Env glycoprotein, the target of neutralizing antibodies, is extensively covered by N-linked glycans that create a glycan shield. Broadly neutralizing antibodies (bNAbs), the primary targets of HIV-1 vaccine design, have to negotiate this glycan shield. Here, we review the barriers and opportunities that the HIV-1 glycan shield presents for vaccine induction of bNAbs.

Recent Findings: Glycan shields can impact the nature of the antibody response and influence the development of neutralization breadth in HIV-1 infections. The architecture of the glycan shield arising from glycan interactions and dynamics have been modeled, and its fine structure, that is, the site-wise glycan heterogeneity, has been determined for some isolates. Although the extent of glycan shielding is conserved, the precise number, location and processing of glycans, however, is strain-dependent. New insights continue to reveal how such differences can impact bNAb activity and development. Novel approaches have exploited the glycan shield for designing immunogens that bind the germline precursors of bNAbs, a critical roadblock for vaccine-induction of bNAbs.

Summary: The HIV-1 glycan shield can significantly impact the induction and maturation of bNAbs, and a better understanding of how to manipulate it will improve immunogen design.
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http://dx.doi.org/10.1097/COH.0000000000000639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877895PMC
September 2020

Convergent Evolution of HLA-C Downmodulation in HIV-1 and HIV-2.

mBio 2020 07 14;11(4). Epub 2020 Jul 14.

Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany

HLA-C-mediated antigen presentation induces the killing of human immunodeficiency virus (HIV)-infected CD4 T cells by cytotoxic T lymphocytes (CTLs). To evade killing, many HIV-1 group M strains decrease HLA-C surface levels using their accessory protein Vpu. However, some HIV-1 group M isolates lack this activity, possibly to prevent the activation of natural killer (NK) cells. Analyzing diverse primate lentiviruses, we found that Vpu-mediated HLA-C downregulation is not limited to pandemic group M but is also found in HIV-1 groups O and P as well as several simian immunodeficiency viruses (SIVs). We show that Vpu targets HLA-C primarily at the protein level, independently of its ability to suppress NF-κB-driven gene expression, and that in some viral lineages, HLA-C downregulation may come at the cost of efficient counteraction of the restriction factor tetherin. Remarkably, HIV-2, which does not carry a gene, uses its accessory protein Vif to decrease HLA-C surface expression. This Vif activity requires intact binding sites for the Cullin5/Elongin ubiquitin ligase complex but is separable from its ability to counteract APOBEC3G. Similar to HIV-1 Vpu, the degree of HIV-2 Vif-mediated HLA-C downregulation varies considerably among different virus isolates. In agreement with opposing selection pressures , we show that the reduction of HLA-C surface levels by HIV-2 Vif is accompanied by increased NK cell-mediated killing. In summary, our results highlight the complex role of HLA-C in lentiviral infections and demonstrate that HIV-1 and HIV-2 have evolved at least two independent mechanisms to decrease HLA-C levels on infected cells. Genome-wide association studies suggest that HLA-C expression is a major determinant of viral load set points and CD4 T cell counts in HIV-infected individuals. On the one hand, efficient HLA-C expression enables the killing of infected cells by cytotoxic T lymphocytes (CTLs). On the other hand, HLA-C sends inhibitory signals to natural killer (NK) cells and enhances the infectivity of newly produced HIV particles. HIV-1 group M viruses modulate HLA-C expression using the accessory protein Vpu, possibly to balance CTL- and NK cell-mediated immune responses. Here, we show that the second human immunodeficiency virus, HIV-2, can use its accessory protein Vif to evade HLA-C-mediated restriction. Furthermore, our mutational analyses provide insights into the underlying molecular mechanisms. In summary, our results reveal how the two human AIDS viruses modulate HLA-C, a key component of the antiviral immune response.
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http://dx.doi.org/10.1128/mBio.00782-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360927PMC
July 2020

The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site.

mBio 2020 05 26;11(3). Epub 2020 May 26.

Centre de Recherche du CHUM, Montreal, Quebec, Canada

The HIV-1 envelope glycoproteins (Env) undergo conformational changes upon interaction of the gp120 exterior glycoprotein with the CD4 receptor. The gp120 inner domain topological layers facilitate the transition of Env to the CD4-bound conformation. CD4 engages gp120 by introducing its phenylalanine 43 (Phe43) in a cavity ("the Phe43 cavity") located at the interface between the inner and outer gp120 domains. Small CD4-mimetic compounds (CD4mc) can bind within the Phe43 cavity and trigger conformational changes similar to those induced by CD4. Crystal structures of CD4mc in complex with a modified CRF01_AE gp120 core revealed the importance of these gp120 inner domain layers in stabilizing the Phe43 cavity and shaping the CD4 binding site. Our studies reveal a complex interplay between the gp120 inner domain and the Phe43 cavity and generate useful information for the development of more-potent CD4mc. The Phe43 cavity of HIV-1 envelope glycoproteins (Env) is an attractive druggable target. New promising compounds, including small CD4 mimetics (CD4mc), were shown to insert deeply into this cavity. Here, we identify a new network of residues that helps to shape this highly conserved CD4 binding pocket and characterize the structural determinants responsible for Env sensitivity to small CD4 mimetics.
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http://dx.doi.org/10.1128/mBio.00280-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251204PMC
May 2020

Sexual dimorphism in chimpanzee (Pan troglodytes schweinfurthii) and human age-specific fertility.

J Hum Evol 2020 07 23;144:102795. Epub 2020 May 23.

Department of Evolutionary Anthropology, Duke University, USA.

Across vertebrates, species with intense male mating competition and high levels of sexual dimorphism in body size generally exhibit dimorphism in age-specific fertility. Compared with females, males show later ages at first reproduction and earlier reproductive senescence because they take longer to attain adult body size and musculature, and maintain peak condition for a limited time. This normally yields a shorter male duration of effective breeding, but this reduction might be attenuated in species that frequently use coalitionary aggression. Here, we present comparative genetic and demographic data on chimpanzees from three long-term study communities (Kanyawara: Kibale National Park, Uganda; Mitumba and Kasekela: Gombe National Park, Tanzania), comprising 581 male risk years and 112 infants, to characterize male age-specific fertility. For comparison, we update estimates from female chimpanzees in the same sites and append a sample of human foragers (the Tanzanian Hadza). Consistent with the idea that aggressive mating competition favors youth, chimpanzee males attained a higher maximum fertility than females, followed by a steeper decline with age. Males did not show a delay in reproduction compared with females, however, as adolescents in both sites successfully reproduced by targeting young, subfecund females, who were less attractive to adults. Gombe males showed earlier reproductive senescence and a shorter duration of effective breeding than Gombe females. By contrast, older males in Kanyawara generally continued to reproduce, apparently by forming coalitions with the alpha. Hadza foragers showed a distinct pattern of sexual dimorphism in age-specific fertility as, compared with women, men gained conceptions later but continued reproducing longer. In sum, both humans and chimpanzees showed sexual dimorphism in age-specific fertility that deviated from predictions drawn from primates with more extreme body size dimorphism, suggesting altered dynamics of male-male competition in the two lineages. In both species, coalitions appear important for extending male reproductive careers.
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http://dx.doi.org/10.1016/j.jhevol.2020.102795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337577PMC
July 2020

CpG Frequency in the 5' Third of the Gene Determines Sensitivity of Primary HIV-1 Strains to the Zinc-Finger Antiviral Protein.

mBio 2020 01 14;11(1). Epub 2020 Jan 14.

Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany

CpG dinucleotide suppression has been reported to allow HIV-1 to evade inhibition by the zinc-finger antiviral protein (ZAP). Here, we show that primate lentiviruses display marked differences in CpG frequencies across their genome, ranging from 0.44% in simian immunodeficiency virus SIVwrc from Western red colobus to 2.3% in SIVmon infecting mona monkeys. Moreover, functional analyses of a large panel of human and simian immunodeficiency viruses revealed that the magnitude of CpG suppression does not correlate with their susceptibility to ZAP. However, we found that the number of CpG dinucleotides within a region of ∼700 bases at the 5' end of the gene determines ZAP sensitivity of primary HIV-1 strains but not of HIV-2. Increased numbers of CpGs in this region were associated with reduced mRNA expression and viral protein production. ZAP sensitivity profiles of chimeric simian-human immunodeficiency viruses (SHIVs) expressing different HIV-1 genes were highly similar to those of the corresponding HIV-1 strains. The frequency of CpGs in the identified region correlated with differences in clinical progression rates. Thus, the CpG frequency in a specific part of , rather than the overall genomic CpG content, governs the susceptibility of HIV-1 to ZAP and might affect viral pathogenicity Evasion of the zinc-finger antiviral protein (ZAP) may drive CpG dinucleotide suppression in HIV-1 and many other viral pathogens but the viral determinants of ZAP sensitivity are poorly defined. Here, we examined CpG suppression and ZAP sensitivity in a large number of primate lentiviruses and demonstrate that their genomic frequency of CpGs varies substantially and does not correlate with ZAP sensitivity. We further show that the number of CpG residues in a defined region at the 5' end of the gene together with structural features plays a key role in HIV-1 susceptibility to ZAP and correlates with differences in clinical progression rates in HIV-1-infected individuals. Our identification of a specific part of as a major determinant of HIV-1 susceptibility to ZAP restriction provides a basis for future studies of the underlying inhibitory mechanisms and their potential relevance in the pathogenesis of AIDS.
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http://dx.doi.org/10.1128/mBio.02903-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960287PMC
January 2020

Sexually transmitted founder HIV-1 viruses are relatively resistant to Langerhans cell-mediated restriction.

PLoS One 2019 19;14(12):e0226651. Epub 2019 Dec 19.

Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.

A single HIV-1 variant establishes infection of the host after sexual contact. Identifying the phenotypic characteristics of these Transmitted Founder (T/F) viruses is important to understand the restriction mechanisms during transmission. Langerhans cells (LCs) are the mucosal dendritic cell subset that has been shown to have a protective role in HIV-1 transmission. Immature LCs efficiently capture and degrade HIV-1 via langerin-mediated restriction. Here we have investigated the capacity of T/F HIV-1 strains to infect mucosal Langerhans cells (LCs). Notably, most T/F variants efficiently infected immature LCs derived from skin and vaginal tissue in contrast to chronic HIV-1 laboratory strains. Next we screened a panel of T/F viruses and their matched 6-month consensus sequence viruses. Interestingly most T/F variants infected immature LCs whereas donor-matched 6-month consensus sequence viruses had lost the ability to infect LCs. However, we also identified 6-month consensus sequence viruses that had retained an ability to infect LCs similar to that of the donor-matched T/F virus. Moreover, some T/F viruses and 6-month consensus sequence viruses were unable to infect immature LCs. Further analyses indicated that T/F viruses are less sensitive to langerin-mediated restriction. These data suggest that T/F HIV-1 variants have the ability to infect immature LCs, which will facilitate transmission.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226651PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922402PMC
April 2020

Contribution of proteasome-catalyzed peptide -splicing to viral targeting by CD8 T cells in HIV-1 infection.

Proc Natl Acad Sci U S A 2019 12 20;116(49):24748-24759. Epub 2019 Nov 20.

Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom;

Peptides generated by proteasome-catalyzed splicing of noncontiguous amino acid sequences have been shown to constitute a source of nontemplated human leukocyte antigen class I (HLA-I) epitopes, but their role in pathogen-specific immunity remains unknown. CD8 T cells are key mediators of HIV type 1 (HIV-1) control, and identification of novel epitopes to enhance targeting of infected cells is a priority for prophylactic and therapeutic strategies. To explore the contribution of proteasome-catalyzed peptide splicing (PCPS) to HIV-1 epitope generation, we developed a broadly applicable mass spectrometry-based discovery workflow that we employed to identify spliced HLA-I-bound peptides on HIV-infected cells. We demonstrate that HIV-1-derived spliced peptides comprise a relatively minor component of the HLA-I-bound viral immunopeptidome. Although spliced HIV-1 peptides may elicit CD8 T cell responses relatively infrequently during infection, CD8 T cells primed by partially overlapping contiguous epitopes in HIV-infected individuals were able to cross-recognize spliced viral peptides, suggesting a potential role for PCPS in restricting HIV-1 escape pathways. Vaccine-mediated priming of responses to spliced HIV-1 epitopes could thus provide a novel means of exploiting epitope targets typically underutilized during natural infection.
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http://dx.doi.org/10.1073/pnas.1911622116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900506PMC
December 2019

Ancient Introgression between Two Ape Malaria Parasite Species.

Genome Biol Evol 2019 11;11(11):3269-3274

Institute of Evolutionary Biology, and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom.

The Laverania clade comprises the human malaria parasite Plasmodium falciparum as well as at least seven additional parasite species that infect wild African apes. A recent analysis of Laverania genome sequences (Otto TD, et al. 2018. Genomes of all known members of a Plasmodium subgenus reveal paths to virulent human malaria. Nat Microbiol. 3: 687-697) reported three instances of interspecies gene transfer, one of which had previously been described. Generating gene sequences from additional ape parasites and re-examining sequencing reads generated in the Otto et al. study, we identified one of the newly described gene transfers as an assembly artifact of sequences derived from a sample coinfected by two parasite species. The second gene transfer between ancestors of two divergent chimpanzee parasite lineages was confirmed, but involved a much larger number of genes than originally described, many of which encode exported proteins that remodel, or bind to, erythrocytes. Because successful hybridization between Laverania species is very rare, it will be important to determine to what extent these gene transfers have shaped their host interactions.
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http://dx.doi.org/10.1093/gbe/evz244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145702PMC
November 2019

Adaptation of Plasmodium falciparum to humans involved the loss of an ape-specific erythrocyte invasion ligand.

Nat Commun 2019 10 4;10(1):4512. Epub 2019 Oct 4.

Malaria Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SA, UK.

Plasmodium species are frequently host-specific, but little is currently known about the molecular factors restricting host switching. This is particularly relevant for P. falciparum, the only known human-infective species of the Laverania sub-genus, all other members of which infect African apes. Here we show that all tested P. falciparum isolates contain an inactivating mutation in an erythrocyte invasion associated gene, PfEBA165, the homologues of which are intact in all ape-infective Laverania species. Recombinant EBA165 proteins only bind ape, not human, erythrocytes, and this specificity is due to differences in erythrocyte surface sialic acids. Correction of PfEBA165 inactivating mutations by genome editing yields viable parasites, but is associated with down regulation of both PfEBA165 and an adjacent invasion ligand, which suggests that PfEBA165 expression is incompatible with parasite growth in human erythrocytes. Pseudogenization of PfEBA165 may represent a key step in the emergence and evolution of P. falciparum.
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http://dx.doi.org/10.1038/s41467-019-12294-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778099PMC
October 2019

Primary HIV-1 Strains Use Nef To Downmodulate HLA-E Surface Expression.

J Virol 2019 10 30;93(20). Epub 2019 Sep 30.

Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany

Human immunodeficiency virus type 1 (HIV-1) has evolved elaborate ways to evade immune cell recognition, including downregulation of classical HLA class I (HLA-I) from the surfaces of infected cells. Recent evidence identified HLA-E, a nonclassical HLA-I, as an important part of the antiviral immune response to HIV-1. Changes in HLA-E surface levels and peptide presentation can prompt both CD8 T-cell and natural killer (NK) cell responses to viral infections. Previous studies reported unchanged or increased HLA-E levels on HIV-1-infected cells. Here, we examined HLA-E surface levels following infection of CD4 T cells with primary HIV-1 strains and observed that a subset downregulated HLA-E. Two primary strains of HIV-1 that induced the strongest reduction in surface HLA-E expression were chosen for further testing. Expression of single Nef or Vpu proteins in a T-cell line, as well as tail swap experiments exchanging the cytoplasmic tail of HLA-A2 with that of HLA-E, demonstrated that Nef modulated HLA-E surface levels and targeted the cytoplasmic tail of HLA-E. Furthermore, infection of primary CD4 T cells with HIV-1 mutants showed that a lack of functional Nef (and Vpu to some extent) impaired HLA-E downmodulation. Taken together, the results of this study demonstrate for the first time that HIV-1 can downregulate HLA-E surface levels on infected primary CD4 T cells, potentially rendering them less vulnerable to CD8 T-cell recognition but at increased risk of NKG2A NK cell killing. For almost two decades, it was thought that HIV-1 selectively downregulated the highly expressed HLA-I molecules HLA-A and HLA-B from the cell surface in order to evade cytotoxic-T-cell recognition, while leaving HLA-C and HLA-E molecules unaltered. It was stipulated that HIV-1 infection thereby maintained inhibition of NK cells via inhibitory receptors that bind HLA-C and HLA-E. This concept was recently revised when a study showed that primary HIV-1 strains reduce HLA-C surface levels, whereas the cell line-adapted HIV-1 strain NL4-3 lacks this ability. Here, we demonstrate that infection with distinct primary HIV-1 strains results in significant downregulation of surface HLA-E levels. Given the increasing evidence for HLA-E as an important modulator of CD8 T-cell and NKG2A NK cell functions, this finding has substantial implications for future immunomodulatory approaches aimed at harnessing cytotoxic cellular immunity against HIV.
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http://dx.doi.org/10.1128/JVI.00719-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798123PMC
October 2019

Upregulation of BST-2 by Type I Interferons Reduces the Capacity of Vpu To Protect HIV-1-Infected Cells from NK Cell Responses.

mBio 2019 06 18;10(3). Epub 2019 Jun 18.

Centre de Recherche du CHUM, Montreal, Quebec, Canada

The HIV-1 accessory protein Vpu enhances viral release by counteracting the restriction factor BST-2. Furthermore, Vpu promotes NK cell evasion by downmodulating cell surface NTB-A and PVR, known ligands of the NK cell receptors NTB-A and DNAM-1, respectively. While it has been established that Vpu's transmembrane domain (TMD) is required for the interaction and intracellular sequestration of BST-2, NTB-A, and PVR, it remains unclear how Vpu manages to target these proteins simultaneously. In this study, we show that upon upregulation, BST-2 is preferentially downregulated by Vpu over its other TMD substrates. We found that type I interferon (IFN)-mediated BST-2 upregulation greatly impairs the ability of Vpu to downregulate NTB-A and PVR. Our results suggest that occupation of Vpu by BST-2 affects its ability to downregulate other TMD substrates. Accordingly, knockdown of BST-2 increases Vpu's potency to downmodulate NTB-A and PVR in the presence of type I IFN treatment. Moreover, we show that expression of human BST-2, but not that of the macaque orthologue, decreases Vpu's capacity to downregulate NTB-A. Importantly, we show that type I IFNs efficiently sensitize HIV-1-infected cells to NTB-A- and DNAM-1-mediated direct and antibody-dependent NK cell responses. Altogether, our results reveal that type I IFNs decrease Vpu's polyfunctionality, thus reducing its capacity to protect HIV-1-infected cells from NK cell responses. The restriction factor BST-2 and the NK cell ligands NTB-A and PVR are among a growing list of membrane proteins found to be downregulated by HIV-1 Vpu. BST-2 antagonism enhances viral release, while NTB-A and PVR downmodulation contributes to NK cell evasion. However, it remains unclear how Vpu can target multiple cellular factors simultaneously. Here we provide evidence that under physiological conditions, BST-2 is preferentially targeted by Vpu over NTB-A and PVR. Specifically, we show that type I IFNs decrease Vpu's polyfunctionality by upregulating BST-2, thus reducing its capacity to protect HIV-1-infected cells from NK cell responses. This indicates that there is a hierarchy of Vpu substrates upon IFN treatment, revealing that for the virus, targeting BST-2 as part of its resistance to IFN takes precedence over evading NK cell responses. This reveals a potential weakness in HIV-1's immunoevasion mechanisms that may be exploited therapeutically to harness NK cell responses against HIV-1.
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http://dx.doi.org/10.1128/mBio.01113-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581860PMC
June 2019

IFI16 Targets the Transcription Factor Sp1 to Suppress HIV-1 Transcription and Latency Reactivation.

Cell Host Microbe 2019 06 4;25(6):858-872.e13. Epub 2019 Jun 4.

Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany. Electronic address:

The interferon γ-inducible protein 16 (IFI16) is known as immune sensor of retroviral DNA intermediates. We show that IFI16 restricts HIV-1 independently of immune sensing by binding and inhibiting the host transcription factor Sp1 that drives viral gene expression. This antiretroviral activity and ability to bind Sp1 require the N-terminal pyrin domain and nuclear localization of IFI16, but not the HIN domains involved in DNA binding. Highly prevalent clade C HIV-1 strains are more resistant to IFI16 and less dependent on Sp1 than other HIV-1 subtypes. Furthermore, inhibition of Sp1 by IFI16 or pharmacologically by Mithramycin A suppresses reactivation of latent HIV-1 in CD4 T cells. Finally, IFI16 also inhibits retrotransposition of LINE-1, known to engage Sp1, and murine IFI16 homologs restrict Friend retrovirus replication in mice. Thus, IFI16 restricts retroviruses and retrotransposons by interfering with Sp1-dependent gene expression, and evasion from this restriction may facilitate spread of HIV-1 subtype C.
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http://dx.doi.org/10.1016/j.chom.2019.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681451PMC
June 2019

The Chimpanzee SIV Envelope Trimer: Structure and Deployment as an HIV Vaccine Template.

Cell Rep 2019 05;27(8):2426-2441.e6

Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative, Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02114, USA. Electronic address:

Epitope-targeted HIV vaccine design seeks to focus antibody responses to broadly neutralizing antibody (bnAb) sites by sequential immunization. A chimpanzee simian immunodeficiency virus (SIV) envelope (Env) shares a single bnAb site, the variable loop 2 (V2)-apex, with HIV, suggesting its possible utility in an HIV immunization strategy. Here, we generate a chimpanzee SIV Env trimer, MT145K, which displays selective binding to HIV V2-apex bnAbs and precursor versions, but no binding to other HIV specificities. We determine the structure of the MT145K trimer by cryo-EM and show that its architecture is remarkably similar to HIV Env. Immunization of an HIV V2-apex bnAb precursor Ab-expressing knockin mouse with the chimpanzee MT145K trimer induces HIV V2-specific neutralizing responses. Subsequent boosting with an HIV trimer cocktail induces responses that exhibit some virus cross-neutralization. Overall, the chimpanzee MT145K trimer behaves as expected from design both in vitro and in vivo and is an attractive potential component of a sequential immunization regimen to induce V2-apex bnAbs.
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http://dx.doi.org/10.1016/j.celrep.2019.04.082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533203PMC
May 2019

Syndromic Surveillance of Respiratory Disease in Free-Living Chimpanzees.

Ecohealth 2019 06 5;16(2):275-286. Epub 2019 Mar 5.

Veterinary Population Medicine, University of Minnesota, 495 Animal Science/Veterinary Medicine, 1988 Fitch Ave, St. Paul, MN, 55108, USA.

Disease surveillance in wildlife is rapidly expanding in scope and methodology, emphasizing the need for formal evaluations of system performance. We examined a syndromic surveillance system for respiratory disease detection in Gombe National Park, Tanzania, from 2004 to 2012, with respect to data quality, disease trends, and respiratory disease detection. Data quality was assessed by examining community coverage, completeness, and consistency. The data were examined for baseline trends; signs of respiratory disease occurred at a mean frequency of less than 1 case per week, with most weeks containing zero observations of abnormalities. Seasonal and secular (i.e., over a period of years) trends in respiratory disease frequency were not identified. These baselines were used to develop algorithms for outbreak detection using both weekly counts and weekly prevalence thresholds and then compared retrospectively on the detection of 13 respiratory disease clusters from 2005 to 2012. Prospective application of outbreak detection algorithms to real-time syndromic data would be useful in triggering a rapid outbreak response, such as targeted diagnostic sampling, enhanced surveillance, or mitigation.
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http://dx.doi.org/10.1007/s10393-019-01400-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684380PMC
June 2019

CD4 receptor diversity in chimpanzees protects against SIV infection.

Proc Natl Acad Sci U S A 2019 02 4;116(8):3229-3238. Epub 2019 Feb 4.

Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104;

Human and simian immunodeficiency viruses (HIV/SIVs) use CD4 as the primary receptor to enter target cells. Here, we show that the chimpanzee CD4 is highly polymorphic, with nine coding variants present in wild populations, and that this diversity interferes with SIV envelope (Env)-CD4 interactions. Testing the replication fitness of SIVcpz strains in CD4 T cells from captive chimpanzees, we found that certain viruses were unable to infect cells from certain hosts. These differences were recapitulated in CD4 transfection assays, which revealed a strong association between CD4 genotypes and SIVcpz infection phenotypes. The most striking differences were observed for three substitutions (Q25R, Q40R, and P68T), with P68T generating a second N-linked glycosylation site (N66) in addition to an invariant N32 encoded by all chimpanzee CD4 alleles. In silico modeling and site-directed mutagenesis identified charged residues at the CD4-Env interface and clashes between CD4- and Env-encoded glycans as mechanisms of inhibition. CD4 polymorphisms also reduced Env-mediated cell entry of monkey SIVs, which was dependent on at least one D1 domain glycan. CD4 allele frequencies varied among wild chimpanzees, with high diversity in all but the western subspecies, which appeared to have undergone a selective sweep. One allele was associated with lower SIVcpz prevalence rates in the wild. These results indicate that substitutions in the D1 domain of the chimpanzee CD4 can prevent SIV cell entry. Although some SIVcpz strains have adapted to utilize these variants, CD4 diversity is maintained, protecting chimpanzees against infection with SIVcpz and other SIVs to which they are exposed.
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http://dx.doi.org/10.1073/pnas.1821197116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386711PMC
February 2019

HIV-1 Neutralizing Antibody Signatures and Application to Epitope-Targeted Vaccine Design.

Cell Host Microbe 2019 01;25(1):59-72.e8

Los Alamos National Laboratory, Los Alamos, NM 87545, USA; New Mexico Consortium, Los Alamos, NM 87545, USA. Electronic address:

Eliciting HIV-1-specific broadly neutralizing antibodies (bNAbs) remains a challenge for vaccine development, and the potential of passively delivered bNAbs for prophylaxis and therapeutics is being explored. We used neutralization data from four large virus panels to comprehensively map viral signatures associated with bNAb sensitivity, including amino acids, hypervariable region characteristics, and clade effects across four different classes of bNAbs. The bNAb signatures defined for the variable loop 2 (V2) epitope region of HIV-1 Env were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine, and immunization of guinea pigs with V2-SET vaccines resulted in increased breadth of NAb responses compared with Env 459C alone. These data demonstrate that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens capable of eliciting antibody responses with greater neutralization breadth.
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http://dx.doi.org/10.1016/j.chom.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331341PMC
January 2019

Completeness of HIV-1 Envelope Glycan Shield at Transmission Determines Neutralization Breadth.

Cell Rep 2018 10;25(4):893-908.e7

Theoretical Biology & Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA. Electronic address:

Densely arranged N-linked glycans shield the HIV-1 envelope (Env) trimer from antibody recognition. Strain-specific breaches in this shield (glycan holes) can be targets of vaccine-induced neutralizing antibodies that lack breadth. To understand the interplay between glycan holes and neutralization breadth in HIV-1 infection, we developed a sequence- and structure-based approach to identify glycan holes for individual Env sequences that are shielded in most M-group viruses. Applying this approach to 12 longitudinally followed individuals, we found that transmitted viruses with more intact glycan shields correlated with development of greater neutralization breadth. Within 2 years, glycan acquisition filled most glycan holes present at transmission, indicating escape from hole-targeting neutralizing antibodies. Glycan hole filling generally preceded the time to first detectable breadth, although time intervals varied across hosts. Thus, completely glycan-shielded viruses were associated with accelerated neutralization breadth development, suggesting that Env immunogens with intact glycan shields may be preferred components of AIDS vaccines.
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http://dx.doi.org/10.1016/j.celrep.2018.09.087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426304PMC
October 2018

CHIIMP: An automated high-throughput microsatellite genotyping platform reveals greater allelic diversity in wild chimpanzees.

Ecol Evol 2018 Aug 16;8(16):7946-7963. Epub 2018 Jul 16.

Departments of Microbiology and Medicine Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania.

Short tandem repeats (STRs), also known as microsatellites, are commonly used to noninvasively genotype wild-living endangered species, including African apes. Until recently, capillary electrophoresis has been the method of choice to determine the length of polymorphic STR loci. However, this technique is labor intensive, difficult to compare across platforms, and notoriously imprecise. Here we developed a MiSeq-based approach and tested its performance using previously genotyped fecal samples from long-term studied chimpanzees in Gombe National Park, Tanzania. Using data from eight microsatellite loci as a reference, we designed a bioinformatics platform that converts raw MiSeq reads into locus-specific files and automatically calls alleles after filtering stutter sequences and other PCR artifacts. Applying this method to the entire Gombe population, we confirmed previously reported genotypes, but also identified 31 new alleles that had been missed due to sequence differences and size homoplasy. The new genotypes, which increased the allelic diversity and heterozygosity in Gombe by 61% and 8%, respectively, were validated by replicate amplification and pedigree analyses. This demonstrated inheritance and resolved one case of an ambiguous paternity. Using both singleplex and multiplex locus amplification, we also genotyped fecal samples from chimpanzees in the Greater Mahale Ecosystem in Tanzania, demonstrating the utility of the MiSeq-based approach for genotyping nonhabituated populations and performing comparative analyses across field sites. The new automated high-throughput analysis platform (available at https://github.com/ShawHahnLab/chiimp) will allow biologists to more accurately and effectively determine wildlife population size and structure, and thus obtain information critical for conservation efforts.
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http://dx.doi.org/10.1002/ece3.4302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145012PMC
August 2018