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Biomedical subjects

Nathan D Wolfe

Publications and source records attributed to Nathan D Wolfe.

At least 19 recordsLinked to original sources
PubMed2006

Cross-clade reactivity of HIV-1-specific T-cell responses in HIV-1-infected individuals from Botswana and Cameroon.

An effective HIV type 1 (HIV-1) vaccine will likely require elicitation of broadly reactive cell-mediated immune (CMI) responses against divergent HIV-1 clades. We compared anti-HIV-1 T-cell immune responses among 363 unvaccinated adults infected with diverse HIV-1 clades. Response rates to clade B Gag and/or clade B Nef in Botswana (95%) and Cameroon (98%) were similar when compared with those in countries previously studied, including Brazil (92%), Thailand (96%), South Africa (96%), Malawi (100%), and the United States (100%). Substantial cross-clade cell-mediated immune responses in Botswana and Cameroon confirm previous findings in a larger, more genetically diverse collection of HIV-1 samples.

Adolescent↗
PubMed2006

Common and divergent immune response signaling pathways discovered in peripheral blood mononuclear cell gene expression patterns in presymptomatic and clinically apparent malaria.

Using genome-wide expression profiles from persons either experimentally challenged with malaria-infected mosquitoes or naturally infected with Plasmodium falciparum malaria, we present details of the transcriptional changes that occur with infection and that either are commonly shared between subjects with presymptomatic and clinically apparent malaria or distinguish these two groups. Toll-like receptor signaling through NF-kappaB pathways was significantly upregulated in both groups, as were downstream genes that function in phagocytosis and inflammation, including the cytokines tumor necrosis factor alpha, gamma interferon (IFN-gamma), and interleukin-1beta (IL-1beta). The molecular program derived from these signatures illuminates the closely orchestrated interactions that regulate gene expression by transcription factors such as IRF-1 in the IFN-gamma signal transduction pathway. Modulation of transcripts in heat shock and glycolytic enzyme genes paralleled the intensity of infection. Major histocompatibility complex class I molecules and genes involved in class II antigen presentation are significantly induced in 90% of malaria-infected persons regardless of group. Differences between early presymptomatic infection and natural infection involved genes that regulate the induction of apoptosis through mitogen-activated protein (MAP) kinases and signaling pathways through the endogenous pyrogen IL-1beta, a major inducer of fever. The induction of apoptosis in peripheral blood mononuclear cells from patients with naturally acquired infection impacted the mitochondrial control of apoptosis and the activation of MAP kinase pathways centered around MAPK14 (p38alpha and p38beta). Our findings confirm and extend findings regarding aspects of the earliest responses to malaria infection at the molecular level, which may be informative in elucidating how innate and adaptive immune responses may be modulated in different stages of infection.

Adult↗
PubMed2006

Ancient origin and molecular features of the novel human T-lymphotropic virus type 3 revealed by complete genome analysis.

Human T-lymphotropic virus type 3 (HTLV-3) is a new virus recently identified in two primate hunters in Central Africa. Limited sequence analysis shows that HTLV-3 is distinct from HTLV-1 and HTLV-2 but is genetically similar to simian T-lymphotropic virus type 3 (STLV-3). We report here the first complete HTLV-3 sequence obtained by PCR-based genome walking using uncultured peripheral blood lymphocytes from an HTLV-3-infected person. The HTLV-3(2026ND) genome is 8,917 bp long and is genetically equidistant from HTLV-1 and HTLV-2, sharing about 62% identity. Phylogenetic analysis of all gene regions confirms this relationship and shows that HTLV-3 falls within the diversity of STLV-3, suggesting a primate origin. However, HTLV-3(2026ND) is unique, sharing only 87% to 92% sequence identity with STLV-3. SimPlot and phylogenetic analysis did not reveal any evidence of genetic recombination with either HTLV-1, HTLV-2, or STLV-3. Molecular dating estimates that the ancestor of HTLV-3 is as old as HTLV-1 and HTLV-2, with an inferred divergence time of 36,087 to 54,067 years ago. HTLV-3 has a prototypic genomic structure, with all enzymatic, regulatory, and structural proteins preserved. Like STLV-3, HTLV-3 is missing a third 21-bp transcription element found in the long terminal repeats of HTLV-1 and HTLV-2 but instead contains a unique activator protein-1 transcription factor upstream of the 21-bp repeat elements. A PDZ motif, like that in HTLV-1, which is important for cellular signal transduction and transformation, is present in the C terminus of the HTLV-3 Tax protein. A basic leucine zipper region located in the antisense strand of HTLV-1, believed to play a role in viral replication and oncogenesis, was also found in the complementary strand of HTLV-3. The ancient origin of HTLV-3, the broad distribution of STLV-3 in Africa, and the propensity of STLVs to cross species into humans all suggest that HTLV-3 may be prevalent and support the need for expanded surveillance for this virus.

Amino Acid Sequence↗
PubMed2006

Seroprevalence and distribution of Flaviviridae, Togaviridae, and Bunyaviridae arboviral infections in rural Cameroonian adults.

Arboviruses from the families Flaviviridae, Togaviridae, and Bunyaviridae are suspected to cause widespread morbidity in sub-Saharan African populations, but little research been done to document the burden and distribution of these pathogens. We tested serum samples from 256 Cameroonian adults from nine rural villages for the presence of Dengue-2 (DEN-2), West Nile (WN), Yellow fever (YF), Chikungunya (CHIK), O'nyong-nyong (ONN), Sindbis (SIN), and Tahyna (TAH) infection using standard plaque-reduction neutralization tests (PRNT). Of these samples, 12.5% were DEN-2 positive, 6.6% were WN positive, 26.9% were YF positive, 46.5% were CHIK seropositive, 47.7% were ONN positive, 7.8% were SIN positive, and 36.3% were TAH positive. DEN-2, YF, and CHIK seroprevalence rates were lower among individuals living in dwellings with grass or thatched roofs versus corrugated tin and in villages isolated from urban centers. Seroprevalence rates of YF and CHIK increased with age. These results suggest that inter-epidemic arboviral infection is common in central African populations.

Adolescent↗
PubMed2005

Improved measles surveillance in Cameroon reveals two major dynamic patterns of incidence.

OBJECTIVE: To characterize the province-specific incidence patterns of measles in Cameroon and determine if an increase in measles incidence during the period January 2000-June 2001 is consistent with coincident epidemics in several regions with different inter-epidemic periods. METHOD: Periodic behavior of the monthly measles incidence time-series from each province of Cameroon was analyzed using time-series analysis and cluster techniques. Cumulative incidence in each province of Cameroon over a five-year period was associated with birth rates, and vaccination coverage. RESULTS: Distinct patterns of measles incidence were found in two different areas of Cameroon. The three northern-most provinces experience major epidemics every year. Seven southern provinces show evidence of experiencing major epidemics every third year. In January 2000, Cameroon experienced coincident peaks in these two cycles and thus an increase in measles incidence countrywide over the previous year. Higher cumulative province-specific incidence rates were associated with higher birth rates and lower routine vaccination coverage rates. CONCLUSION: Within one country, two dramatically different dynamic patterns of measles incidence were observed. Long-term surveillance data is crucial to the evaluation of measles immunization campaigns. The availability of a five-year record of measles incidence in Cameroon reveals an interesting dynamic pattern of measles incidence that accounts for the increase in countrywide incidence in 2000-2001.

Cameroon↗
PubMed2005

The phylogenetic and evolutionary history of a novel alpha-globin-type gene in orangutans (Pongo pygmaeus).

The alpha-globin genes are implicated in human resistance to malaria, a disease caused by Plasmodium parasites. This study is the first to analyze DNA sequences from a novel alpha-globin-type gene in orangutans, a species affected by Plasmodium. Phylogenetic methods show that the gene is a duplication of an alpha-globin gene and is located 5' of alpha-2 globin. The alpha-globin-type gene is notable for having four amino acid replacements relative to the orangutan's alpha-1 and alpha-2 globin genes, with no synonymous differences. Pairwise K(a)/K(s) methods and likelihood ratio tests (LRTs) revealed that the evolutionary history of the alpha-globin-type gene has been marked by either neutral or positive evolution, but not purifying selection. A comparative analysis of the amino acid replacements of the alpha-globin-type gene with human hemoglobinopathies and hemoglobin structure showed that two of the four replaced sites are members of the same molecular bond, one that is crucial to the proper functioning of the hemoglobin molecule. This suggested an adaptive evolutionary change. Functionally, this locus may result in a thalassemia-like phenotype in orangutans, possibly as an adaptation to combat Plasmodium.

Amino Acid Sequence↗
PubMed2005

Outbreak of a West African recombinant of HIV-1 in Tashkent, Uzbekistan.

OBJECTIVES: This research describes the genetic diversity of HIV-1 in Uzbekistan. METHODS: During 2002 and 2003, blood from HIV-positive patients in Uzbekistan was collected, and part of the proviral pol gene and nearly full-length genomes were sequenced and analyzed. RESULTS: Among 142 Uzbek strains, most clustered genetically with the subtype A strain common in the former Soviet Union. Most of these subtype A-infected drug-naive subjects (65.6%) had an accessory drug resistance mutation, A62V, in the reverse transcriptase gene. Thirteen of the strains (9.2%) clustered with CRF02_AG, an HIV strain common in West Africa. People infected with CRF02_AG were all residents of Tashkent and sampled in 2002. The CRF02_AG strains were monophyletic and probably descended from a single ancestor. Two strains were recombinant between CRF02_AG and subtype A, with each having a different subtype structure. The CRF02_AG and the subtype A elements of the recombinants were monophyletic with Uzbek CRF02_AG and subtype A. New full-length genomes of 12 Uzbek strains suggested that neither the subtype A and nor the CRF02_AG strains in this epidemic were mosaics with other subtypes or circulating recombinant forms. CONCLUSION: A genetic analysis of Uzbek HIV strains demonstrated the predominance of subtype A in the epidemic. An outbreak of a West African strain of HIV-1, CRF02_AG, occurred in Tashkent, Uzbekistan in 2002, however. The cocirculation of the 2 strains has resulted in new recombinants that are apparently unique to Uzbekistan.

Africa↗
PubMed2005

Emergence of unique primate T-lymphotropic viruses among central African bushmeat hunters.

The human T-lymphotropic viruses (HTLVs) types 1 and 2 originated independently and are related to distinct lineages of simian T-lymphotropic viruses (STLV-1 and STLV-2, respectively). These facts, along with the finding that HTLV-1 diversity appears to have resulted from multiple cross-species transmissions of STLV-1, suggest that contact between humans and infected nonhuman primates (NHPs) may result in HTLV emergence. We investigated the diversity of HTLV among central Africans reporting contact with NHP blood and body fluids through hunting, butchering, and keeping primate pets. We show that this population is infected with a wide variety of HTLVs, including two previously unknown retroviruses: HTLV-4 is a member of a phylogenetic lineage that is distinct from all known HTLVs and STLVs; HTLV-3 falls within the phylogenetic diversity of STLV-3, a group not previously seen in humans. We also document human infection with multiple STLV-1-like viruses. These results demonstrate greater HTLV diversity than previously recognized and suggest that NHP exposure contributes to HTLV emergence. Our discovery of unique and divergent HTLVs has implications for HTLV diagnosis, blood screening, and potential disease development in infected persons. The findings also indicate that cross-species transmission is not the rate-limiting step in pandemic retrovirus emergence and suggest that it may be possible to predict and prevent disease emergence by surveillance of populations exposed to animal reservoirs and interventions to decrease risk factors, such as primate hunting.

Base Sequence↗
PubMed2005

Seroprevalence of human T cell leukemia virus in HIV antibody-negative populations in rural Cameroon.

Seven hundred forty-seven serum samples collected from humans in 4 separate rural village areas in Cameroon were examined for antibody to human T cell leukemia viruses (HTLVs) by use of an enzyme immunoassay followed by a Western blot assay. Of the 88 serum samples that the enzyme immunoassay found to be repeatedly reactive, the HTLV status of 49 samples was confirmed by Western blot assay to be HTLV type I, and the status of 6 samples was confirmed to be HTLV type II.

Cameroon↗
PubMed2005

The population genetics of the alpha-2 globin locus of orangutans (Pongo pygmaeus).

In this study, the molecular population genetics of the orangutan's alpha-2 globin (HBA2) gene were investigated in order to test for the action of natural selection. Haplotypes from 28 orangutan chromosomes were collected from a 1.46-kilobase region of the alpha-2 globin locus. While many aspects of the data were consistent with neutrality, the observed heterogeneous distribution of polymorphisms was inconsistent with neutral expectations. Furthermore, a single amino acid variant, found in both the Bornean and the Sumatran orangutan subspecies, was associated with different alternative synonymous variants in each subspecies, suggesting that the allele may have spread separately through the two subspecies after two distinct origination events. This variant is not in Hardy-Weinberg equilibrium (HWE). These observations are consistent with neutral models that incorporate population structure and models that invoke selection. The orangutan Plasmodium parasite is a plausible selective agent that may underlie the variation at alpha-2 globin in orangutans.

Animals↗
PubMed2005

HIV type 1 CRF13_cpx revisited: identification of a new sequence from Cameroon and signal for subsubtype J2.

A nearly full-length genome sequence of an HIV-1 isolate originating from Cameroon, 02CM.3226MN, was found to cluster together with previously reported CRF13 sequences 96CM-4164 and 96CM-1849. Similarity plotting, bootscanning, breakpoint analysis, and phylogenetic trees confirmed similar genomic structures with almost identical breakpoint positions among these three isolates. Thus, CRF13 now fulfills the HIV-1 nomenclature requirements. A X2 analysis across all three genomes simultaneously was applied to more accurately determine breakpoints and address the uncertainty in such estimates. Some fragments were found to be difficult to classify, as indicated by a low branching index (BI), due to limited knowledge about parental and reference subtype sequences. One fragment with low BI association to reference subtype J sequences (BI = 0.27, cut-off for subtype classification >0.55) was found to be closer to J fragments of CRF11 similar to the way that A1-A2 and F1-F2 subsubtypes associate. This suggests that subtype J may need to be reclassified into subsubtypes J1 and J2. The CRF13 genome consists of fragments from subtypes A1, G, and both J1 and J2 as well as CRF01 and one region that was left unclassified.

Cameroon↗
PubMed2005

Bushmeat hunting, deforestation, and prediction of zoonoses emergence.

Understanding the emergence of new zoonotic agents requires knowledge of pathogen biodiversity in wildlife, human-wildlife interactions, anthropogenic pressures on wildlife populations, and changes in society and human behavior. We discuss an interdisciplinary approach combining virology, wildlife biology, disease ecology, and anthropology that enables better understanding of how deforestation and associated hunting leads to the emergence of novel zoonotic pathogens.

Animals↗
PubMed2005

Central African hunters exposed to simian immunodeficiency virus.

HIV-seronegative Cameroonians with exposure to nonhuman primates were tested for simian immunodeficiency virus (SIV) infection. Seroreactivity was correlated with exposure risk (p<0.001). One person had strong humoral and weak cellular immune reactivity to SIVcol peptides. Humans are exposed to and possibly infected with SIV, which has major public health implications.

Animals↗
PubMed2004

Naturally acquired simian retrovirus infections in central African hunters.

BACKGROUND: Hunting and butchering of wild non-human primates infected with simian immunodeficiency virus (SIV) is thought to have sparked the HIV pandemic. Although SIV and other primate retroviruses infect laboratory workers and zoo workers, zoonotic retrovirus transmission has not been documented in natural settings. We investigated zoonotic infection in individuals living in central Africa. METHODS: We obtained behavioural data, plasma samples, and peripheral blood lymphocytes from individuals living in rural villages in Cameroon. We did serological testing, PCR, and sequence analysis to obtain evidence of retrovirus infection. FINDINGS: Zoonotic infections with simian foamy virus (SFV), a retrovirus endemic in most Old World primates, were identified in people living in central African forests who reported direct contact with blood and body fluids of wild non-human primates. Ten (1%) of 1099 individuals had antibodies to SFV. Sequence analysis from these individuals revealed three geographically-independent human SFV infections, each of which was acquired from a distinct non-human primate lineage: De Brazza's guenon (Cercopithecus neglectus), mandrill (Mandrillus sphinx), and gorilla (Gorilla gorilla), two of which (De Brazza's guenon and mandrill) are naturally infected with SIV. INTERPRETATION: Our findings show that retroviruses are actively crossing into human populations, and demonstrate that people in central Africa are currently infected with SFV. Contact with non-human primates, such as happens during hunting and butchering, can play a part in the emergence of human retroviruses and the reduction of primate bushmeat hunting has the potential to decrease the frequency of disease emergence.

Animals↗
PubMed2004

Development and application of a high-throughput HIV type 1 genotyping assay to identify CRF02_AG in West/West Central Africa.

In West/West Central Africa, CRF02_AG is the most prevalent HIV-1 strain and circulates in the milieu of rare subtypes, circulating recombinant forms (CRFs), and unique recombinant forms (URFs). The molecular complexity of HIV-1 epidemics in this region and the need to extensively sample large populations, such as in the case of vaccine trials, pose seemingly conflicting requirements between full-genome sequencing and high-throughput low-resolution assays. Here we describe the development and evaluation of a multiregion hybridization assay (MHAcrf02) for the efficient genotyping of CRF02_AG in West/West Central Africa. Subtype A, G, and CRF02_AG-specific fluorescent probes were designed flanking five recombination breakpoints in CRF02_AG and were used in real-time PCRs. A panel representing West/West Central African HIV-1 genetic diversity was evaluated by MHAcrf02. The sample set, previously characterized by full-genome sequencing, included CRF02_AG and CRF02_AG-containing recombinants (n = 28), other subtypes, CRFs, and URFs (n = 34). DNA from peripheral blood mononuclear cells, cocultures, and plasmids was used as template. When the patterns of probe reactivity were evaluated. CRF02_AG was identified with a 100% specificity and sensitivity. In conclusion, MHAcrf02 will permit more efficient characterization of HIV-1 in West/West Central Africa, where CRF02_AG is an important strain. Together with other regional genotyping assays MHAcrf02 will contribute to the development of a global picture of HIV-1 diversity and geographic distribution, providing a strong foundation for intervention, including vaccine development.

Africa, Central↗
PubMed2004

Unhealthy landscapes: Policy recommendations on land use change and infectious disease emergence.

Anthropogenic land use changes drive a range of infectious disease outbreaks and emergence events and modify the transmission of endemic infections. These drivers include agricultural encroachment, deforestation, road construction, dam building, irrigation, wetland modification, mining, the concentration or expansion of urban environments, coastal zone degradation, and other activities. These changes in turn cause a cascade of factors that exacerbate infectious disease emergence, such as forest fragmentation, disease introduction, pollution, poverty, and human migration. The Working Group on Land Use Change and Disease Emergence grew out of a special colloquium that convened international experts in infectious diseases, ecology, and environmental health to assess the current state of knowledge and to develop recommendations for addressing these environmental health challenges. The group established a systems model approach and priority lists of infectious diseases affected by ecologic degradation. Policy-relevant levels of the model include specific health risk factors, landscape or habitat change, and institutional (economic and behavioral) levels. The group recommended creating Centers of Excellence in Ecology and Health Research and Training, based at regional universities and/or research institutes with close links to the surrounding communities. The centers' objectives would be 3-fold: a) to provide information to local communities about the links between environmental change and public health; b) to facilitate fully interdisciplinary research from a variety of natural, social, and health sciences and train professionals who can conduct interdisciplinary research; and c) to engage in science-based communication and assessment for policy making toward sustainable health and ecosystems.

Agriculture↗