T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis

Identification of T-cell subsets that are infected in vivo is essential to understanding the pathogenesis of human immunodeficiency virus (HIV) disease; however, this goal has been beset with technical challenges. Here, we used polychromatic flow cytometry to sort multiple T-cell subsets to 99.8% purity, followed by quantitative PCR to quantify HIV gag DNA directly ex vivo. We show that resting memory CD4(+) T cells are the predominantly infected cells but that terminally differentiated memory CD4(+) T cells contain 10-fold fewer copies of HIV DNA. Memory CD8(+) T cells can also be infected upon upregulation of CD4; however, this is infrequent and HIV-specific CD8(+) T cells are not infected preferentially. Na?ve CD4(+) T-cell infection is rare and principally confined to those peripheral T cells that have proliferated. Furthermore, the virus is essentially absent from na?ve CD8(+) T cells, suggesting that the thymus is not a major source of HIV-infected T cells in the periphery. These data illuminate the underlying mechanisms that distort T-cell homeostasis in HIV infection.     

Immunologic pressure within class I-restricted cognate human immunodeficiency virus epitopes during highly active antiretroviral therapy

Cytotoxic T lymphocytes (CTL) and highly active antiretroviral therapy (HAART) are known to exert strong evolutionary pressures on the virus population during human immunodeficiency virus (HIV) infection. However, it is not known whether CTL responses continue to substantially affect viral evolution during treatment. To study the effect of immunologic pressure on viral sequences during HAART, we identified 10 targeted HIV-specific CD8+-T-cell epitopes in five treatment-naive patients, sequenced each epitope in plasma-derived viruses, and then identified evidence of immunologic pressure at these epitopes by comparing the frequency of viral variants in plasma to the frequency of the CD8+-T-cell response for each variant identified. For one of the five patients, evidence of viral evolution was found during therapy. The sequence of the CTL-targeted epitope changed from an apparent escape variant prior to the initiation of therapy, to the sequence that is best recognized by the CTL response after the initiation of therapy, and then finally to a new escape variant during continued therapy. These data show that CTL-mediated pressure can continue to affect viral evolution after the initiation of HAART, even when treatment drives the viral load below detectable levels, and suggest that antiretroviral therapy may preferentially inhibit those virus variants that escape the CTL response.     

Interaction between the CD8 coreceptor and major histocompatibility complex class I stabilizes T cell receptor-antigen complexes at the cell surface

The off-rate (k(off)) of the T cell receptor (TCR)/peptide-major histocompatibility complex class I (pMHCI) interaction, and hence its half-life, is the principal kinetic feature that determines the biological outcome of TCR ligation. However, it is unclear whether the CD8 coreceptor, which binds pMHCI at a distinct site, influences this parameter. Although biophysical studies with soluble proteins show that TCR and CD8 do not bind cooperatively to pMHCI, accumulating evidence suggests that TCR associates with CD8 on the T cell surface. Here, we titrated and quantified the contribution of CD8 to TCR/pMHCI dissociation in membrane-constrained interactions using a panel of engineered pMHCI mutants that retain faithful TCR interactions but exhibit a spectrum of affinities for CD8 of >1,000-fold. Data modeling generates a "stabilization factor" that preferentially increases the predicted TCR triggering rate for low affinity pMHCI ligands, thereby suggesting an important role for CD8 in the phenomenon of T cell cross-reactivity.     

Is metabolic activity by biofilms with sulfate-reducing bacterial consortia essential for long-term propagation of pitting corrosion of stainless steel?

Concentric electrodes have been fabricated from 304 stainless steel in which a small anode (0.031 cm²) and large cathode (4.87 cm²) are induced by the application of a current density of 11A cm^–2 at the anode. It has previously been shown that reproducible pitting and maintenance of a galvanic current occurs only in the presence of a consortium of bacteria containing sulphate-reducing bacteria (SRB). Actively corroding systems that had maintained a galvanic current for at least 24 h after the applied current was removed were treated with inhibitors of the SRB. The only inhibitor tested which had any marked effect on the galvanic current was sodium molybdate which is a known inhibitor of corrosion as well as SRB.     

Birds and biogeography of Mount Mecula in Mozambique’s Niassa National Reserve

The montane forests of northern Mozambique’s isolated massifs are inhabited by numerous range-restricted and threatened bird species, but until recently were extremely little-known. We report on a first avifaunal survey of the isolated montane habitats of Mt Mecula (1 442 m), Niassa National Reserve, notable as the only currently protected montane area in northern Mozambique. Mount Mecula’s moist forest is small (approximately 136 ha in total) and patchy, and although known botanically to have some montane affinities, was found to support an avifauna more typical of riparian forests of medium to low altitude. The only montane forest species recorded was Lemon Dove Aplopelia larvata. Other montane elements included Vincent’s Bunting Emberiza (capensis) vincenti, one of six species recorded new to the Niassa National Reserve list. Overall, it appears that despite its intermediate location, Mt Mecula does not represent a biogeographical ‘stepping stone’ for montane forest bird species. This probably owes to its remoteness from the Eastern Arc Mountains of Tanzania to the north and the massifs of other parts of northern Mozambique, to the south and west.     

With no gap to mind: a shallow genealogy within the world's most widespread small pelagic fish

Species‐delimitation studies across wide geographic ranges often reveal insights that ultimately improve our understanding of biogeographic and evolutionary processes. Here we investigated species delimitation and the global coastal pelagic population structures of the marine sardine species from the economically important subgenus Sardinella (Clupeidae). The main purpose of this study was to relate morphological and genetic discontinuities to biogeography, in a taxonomic and systematic context. Morphological examinations have first reduced the currently recognized five species of the subgenus to two distinct morphospecies with parapatric relationship. Genetic analyses further showed a remarkable shallow genealogy across a global scale, yet to be encountered among small pelagic fishes. Additional three species‐delimitation analyses have failed to delimit the five putative species, indicating the possible existence of only a single cosmopolitan species with two ecophenotypic variations, thus entitling Sardinella aurita as the world's most widespread small pelagic fish. Subsequent population‐structure investigations revealed distinct geographical intraspecific sub‐divisions, flagging the West Pacific Ocean through gene‐flow computations as the probable source of future speciation for the subgenus. Considering its utmost importance to fisheries, this finding of a remarkable global genetic homogeneity should attract future attention among population geneticists and fishery researchers.     

CCR2 identifies a stable population of human effector memory CD4+ T cells equipped for rapid recall response

Because T cells act primarily through short-distance interactions, homing receptors can identify colocalizing cells that serve common functions. Expression patterns for multiple chemokine receptors on CD4(+) T cells from human blood suggested a hierarchy of receptors that are induced and accumulate during effector/memory cell differentiation. We characterized CD4(+)CD45RO(+) T cells based on expression of two of these receptors, CCR5 and CCR2, the principal subsets being CCR5(-)CCR2(-) (～70%), CCR5(+)CCR2(-) (～25%), and CCR5(+)CCR2(+) (～5%). Relationships among expression of CCR5 and CCR2 and CD62L, and the subsets' proliferation histories, suggested a pathway of progressive effector/memory differentiation from the CCR5(-)CCR2(-) to CCR5(+)CCR2(-) to CCR5(+)CCR2(+) cells. Sensitivity and rapidity of TCR-mediated activation, TCR signaling, and effector cytokine production by the subsets were consistent with such a pathway. The subsets also showed increasing responsiveness to IL-7, and the CCR5(+)CCR2(+) cells were CD127(bright) and invariably showed the greatest response to tetanus toxoid. CCR5(+)CCR2(+) cells also expressed the largest repertoire of chemokine receptors and migrated to the greatest number of chemokines. By contrast, the CCR5(+)CCR2(-) cells had the greatest percentages of regulatory T cells, activated/cycling cells, and CMV-reactive cells, and were most susceptible to apoptosis. Our results indicate that increasing memory cell differentiation can be uncoupled from susceptibility to death, and is associated with an increase in chemokine responsiveness, suggesting that vaccination (or infection) can produce a stable population of effector-capable memory cells that are highly enriched in the CCR5(+)CCR2(+) subset and ideally equipped for rapid recall responses in tissue.