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An abstract of the article "Killer Immunoglobulin-Like Receptor Genes and Heterosexual HIV-1 Transmission," by Aimee Merino, Rakhi Malhotra, Matt Morton, Joseph Mulenga, Susan Allen, Eric Hunter, Jianming Tang and Richard Kaslow is presented.

Motivation: Killer immunoglobulin-like receptor (KIR) genes vary considerably in their presence or absence on a specific regional haplotype. Because presence or absence of these genes is largely detected using locus-specific genotyping technology, the distinction between homozygosity and hemizygosity is often ambiguous. The performance of methods for haplotype inference (e.g. PL-EM, PHASE) for KIR genes may be compromised due to the large portion of ambiguous data. At the same time, many haplotypes or partial haplotype patterns have been previously identified and can be incorporated to facilitate haplotype inference for unphased genotype data. To accommodate the increased ambiguity of present–absent genotyping of KIR genes, we developed a hybrid approach combining a greedy algorithm with the Expectation-Maximization (EM) method for haplotype inference based on previously identified haplotypes and haplotype patterns. Results: We implemented this algorithm in a software package named HAPLO-IHP (Haplotype inference using identified haplotype patterns) and compared its performance with that of HAPLORE and PHASE on simulated KIR genotypes. We compared five measures in order to evaluate the reliability of haplotype assignments and the accuracy in estimating haplotype frequency. Our method outperformed the two existing techniques by all five measures when either 60 % or 25 % of previously identified haplotypes were incorporated into the analyses. Availability: The HAPLO-IHP is available at http://www.soph.uab.edu/Statgenetics/People/KZhang/HAPLO-IHP/index.html Contact: KZhang@ms.soph.uab.edu Supplementary information: Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Due to a great increase in the plasticity of deep marine shale reservoirs in southern Sichuan under high-temperature and high-pressure conditions, the single brittleness evaluation method is difficult to effectively characterize its fracability, which significantly limits the selection of sweet spots and fracturing reconstruction in the area. In the case of the deep marine shale reservoir of the Wufeng-Longmaxi formations in the southern Sichuan Basin, through triaxial high-temperature and high-pressure experiments, fracture toughness and X-ray diffraction experiments, the mechanical properties and its influencing factors in the shale reservoir are studied, and the rock fracture morphology under various loading conditions is quantified. According to the morphological characteristics of shale, the analysis of influencing factors and comprehensive quantitative evaluation of the brittleness has been carried out. The deep marine shale resource in the southern Sichuan Basin is likely to be characterized by its high elastic modulus and low I fracture toughness. The mineral composition, temperature, pressure, and degree of bedding development are the primary factors for determining the brittleness; with high quartz mineral content (>50%), low confining pressure (<20 MPa), medium and low temperature (<60 °C) and high density of the shale bedding, the fractal dimension of the sample after the experiment is higher; whereas the geometry of cracks are mainly complex shear cracks, and brittleness is higher. The analytic hierarchy approach establishes a comprehensive evaluation index by analyzing the relationship between the normalized rock mechanical parameters, the stress–strain curve's brittleness index, and the fractal dimension. The brittleness of deep marine shale can be more accurately described by this evaluation index. The primary target layer for future shale gas exploitation, the 3¹ sublayer of the first member of the Longmaxi Formation, is shown to have a high brittleness index. [ABSTRACT FROM AUTHOR]

CD8+ T cell responses restricted by MHC-E, a nonclassical MHC molecule, have been associated with protection in an SIV/rhesus macaque model. The biological relevance of HLA-E-restricted CD8+ T cell responses in HIV infection, however, remains unknown. In this study, CD8+ T cells responding to HIV-1 Gag peptides presented by HLA-E were analyzed. Using in vitro assays, we observed HLA-E-restricted T cell responses to what we believe to be a newly identified subdominant Gag-KL9 as well as a well-described immunodominant Gag-KF11 epitope in T cell lines derived from chronically HIV-infected patients and also primed from healthy donors. Blocking of the HLA-E/KF11 binding by the B7 signal peptide resulted in decreased CD8+ T cell responses. KF11 presented via HLA-E in HIV-infected cells was recognized by antigen-specific CD8+ T cells. Importantly, bulk CD8+ T cells obtained from HIV-infected individuals recognized infected cells via HLA-E presentation. Ex vivo analyses at the epitope level showed a higher responder frequency of HLA-E-restricted responses to KF11 compared with KL9. Taken together, our findings of HLA-E-restricted HIV-specific immune responses offer intriguing and possibly paradigm-shifting insights into factors that contribute to the immunodominance of CD8+ T cell responses in HIV infection. [ABSTRACT FROM AUTHOR]

In individuals with HIV-1 infection, depletion of CD4+ T cells is often accompanied by a malfunction of CD8+ T cells that are persistently activated and/or exhausted. While the dynamics and correlates of CD4 counts have been well documented, the same does not apply to CD8 counts. Here, we examined the CD8 counts in a cohort of 497 Africans with primary HIV-1 infection evaluated in monthly to quarterly follow-up visits for up to 3 years in the absence of antiretroviral therapy. Statistical models revealed that (i) CD8 counts were relatively steady in the 3- to 36-month period of infection and similar between men and women; (ii) neither geography nor heterogeneity in the HIV-1 set-point viral load could account for the roughly 10-fold range of CD8 counts in the cohort (P > 0.25 in all tests); and (iii) factors independently associated with relatively high CD8 counts included demographics (age ≤ 40 years, adjusted P = 0.010) and several human leukocyte antigen class I (HLA-I) alleles, including HLA-A*03:01 (P = 0.013), B*15:10 (P = 0.007), and B*58:02 (P < 0.001). Multiple sensitivity analyses provided supporting evidence for these novel relationships. Overall, these findings suggest that factors associated with the CD8 count have little overlap with those previously reported for other HIV-1-related outcome measures, including viral load, CD4 count, and CD4/CD8 ratio. [ABSTRACT FROM AUTHOR]

Two human leukocyte antigen (HLA) variants, HLA-B*57 and -B*81, are consistently known as favorable host factors in human immunodeficiency virus type 1 (HIV-1)-infected Africans and African-Americans. In our analyses of prospective data from 538 recent HI V-1 seroconverters and cross-sectional data from 292 subjects with unknown duration of infection, HLA-B*57 (mostly B*57:03) and -B*81 (exclusively B*81:01 ) had mostly discordant associations with virologie and immunologic manifestations before antiretroviral therapy. Specifically, relatively low viral load (VL) in HLA-B*57-positive subjects (P ≤ 0.03 in various models) did not translate to early advantage in CD4+ T-cell (CD4) counts (P ≥ 0.37). In contrast, individuals with HLA-B*81 showed little deviation from the normal set point VL (P > 0.18) while maintaining high CD4 count during early and chronic infection (P = 0.01 ). These observations suggest that discordance between VL and CD4 count can occur in the presence of certain HLA alleles and that effective control of HIV-1 viremia is not always a prerequisite for favorable prognosis (delayed immunodeficiency). Of note, steady CD4 count associated with HLA-B*81 in HIV-1-infected Africans may depend on the country of origin, as observations differed slightly between subgroups enrolled in southern Africa (Zambia) and eastern Africa (Kenya, Rwanda, and Uganda). [ABSTRACT FROM AUTHOR]

In HIV-1 infection, the early set-point viral load strongly predicts both viral transmission and disease progression. The factors responsible for the wide spectrum of set-point viral loads are complex and likely reflect an interplay between the transmitted virus and genetically defined factors in both the transmitting source partner and the seroconverter. Indeed, analysis of 195 transmission pairs from Lusaka, Zambia, revealed that the viral loads in transmitting source partners contributed only 2% of the variance in early set-point viral loads of seroconverters (P = 0.046 by univariable analysis). In multivariable models, early set-point viral loads in seroconverting partners were a complex function of (i) the viral load in the source partner, (ii) the gender of the seroconverter, (iii) specific HLA class I alleles in the newly infected partner, and (iv) sharing of HLA-I alleles between partners in a transmission pair. Each of these factors significantly and independently contributed to the set-point viral load in the newly infected partner, accounting for up to 37% of the variance observed and suggesting that many factors operate in concert to define the early virological phenotype in HIV-1 infection. [ABSTRACT FROM AUTHOR]

The article summarizes research conducted by Jonathan M. Carlson and others into the heterosexual transmission of the HIV-1 virus. Their work tested the hypothesis that the transmitting virus from the donor is selected based upon certain genetic characteristics. Results indicated that selection biases exist.

A hallmark of human immunodeficiency virus type 1 (HIV-1) pathogenesis is the rapid loss of CD4 T cells leading to generalized immune dysfunction, including an exhausted CD8 T cell phenotype. Understanding the necessary factors that govern the functional quality and protective potential of antiviral T cell responses would facilitate rational vaccine design and improve therapeutic strategies to combat persistent infections. Mouse models of chronic viral infection demonstrate that interleukin-21 (IL-21), produced primarily by CD4 T cells, is required for the generation and maintenance of functionally competent CD8 T cells and viral containment. We reasoned that preserved IL-21 production during HIV-1 infection would be associated with enhanced CD8 T cell function, allowing improved viral control. Here we analyzed the ability of CD4 and CD8 T cells to produce several cytokines in addition to IL-21 ex vivo following stimulation with overlapping HIV-1 peptides. Both CD4 and CD8 T cells were able to produce IL-21 in response to HIV-1 infection, with the latter cell type more closely associated with viral control. Furthermore, IL-21-producing HIV-1-specific CD4 T cells (compared to those producing other cytokines) were the best indicator of functional CD8 T cells. Our results demonstrate that HIV-1-specific IL-21-producing CD8 T cells are induced following primary infection and enriched in elite controllers, suggesting a critical role for these cells in the maintenance of viremia control. [ABSTRACT FROM AUTHOR]