Performance Issues in U.S.–China Joint Ventures

Based on an in-depth study of U.S.-China joint ventures, this article offers some insights into the performance of such international business relationships. While the conventional literature treats government as an amorphous aspea of the political-legal environment, in this case government is an active participant and influence in the performance of international joint ventures (UVs). It has both a constraining and enabling effect on LJV structure, strategy, and performance. For example, limits can be placed on ownership shares of joint ventures and on prices of the output. At the same time, government can cooperate with LJVs and foreign parent companies by creating partners for foreign parent companies, acting as major customers, and improving financial performance by lowering taxes

A simple screening approach to reduce B*5701-associated abacavir hypersensitivity on the basis of sequence variation in HIV reverse transcriptase

Background. Abacavir hypersensitivity is strongly associated with the human leukocyte antigen (HLA)–B*5701 allele; however, the cost of routine high-resolution HLA typing before initiation of therapy remains prohibitive. We propose a simple approach to reduce B*5701-associated abacavir hypersensitivity based on the screening of human immunodeficiency virus (HIV) reverse transcriptase (RT) for a signature B*5701-associated cytotoxic T lymphocyte escape mutation at RT codon 245. Methods. The correlation between HLA-B*5701 and RT codon 245 variation was investigated in 392 HIV-infected, antiretroviral-naive adults who were initiating highly active antiretroviral therapy. The relationship between codon 245 variation and premature abacavir discontinuation was investigated in a larger cohort of treated individuals (n = 982). Associations between HLA-B*5701 and codon 245 variants were determined using Fisher's exact test or the χ2 test. Results. A very strong association between HLA-B*5701 and RT codon 245 variation was observed. Only 1 (4.2%) of 24 subjects with B*5701 harbored virus with the clade B “wild-type” amino acid 245V, compared with 278 (75.5%) of 368 who did not have B*5701 (P < .001). The sensitivity and specificity of codon 245 substitutions for predicting HLA-B*5701 were 96% and 75%, respectively, and the positive and negative predictive values were 20% and 99.6%, respectively. This association remained robust even after antiretroviral treatment was administered (negative predictive value, 100%; n = 269). In abacavir-treated individuals (n = 982), codon 245 substitutions were predictive of premature abacavir discontinuation (P = .02). Conclusions. As HIV RT sequence is incidentally obtained as a part of routine drug-resistance testing, the examination of sequence variation at RT codon 245 could be adopted as a simple, low-cost screening method to identify individuals who could be safely treated with abacavir and/or who could benefit from HLA characterization

Correlates of protective cellular immunity revealed by analysis of population-level immune escape pathways in HIV-1

HLA class I-associated polymorphisms identified at the population level mark viral sites under immune pressure by individual HLA alleles. As such, analysis of their distribution, frequency, location, statistical strength, sequence conservation, and other properties offers a unique perspective from which to identify correlates of protective cellular immunity. We analyzed HLA-associated HIV-1 subtype B polymorphisms in 1,888 treatment-naïve, chronically infected individuals using phylogenetically informed methods and identified characteristics of HLA-associated immune pressures that differentiate protective and nonprotective alleles. Over 2,100 HLA-associated HIV-1 polymorphisms were identified, approximately one-third of which occurred inside or within 3 residues of an optimally defined cytotoxic T-lymphocyte (CTL) epitope. Differential CTL escape patterns between closely related HLA alleles were common and increased with greater evolutionary distance between allele group members. Among 9-mer epitopes, mutations at HLA-specific anchor residues representedthe most frequently detected escape type: these occurred nearly 2-fold more frequently than expected by chance and were computationally predicted to reduce peptide-HLA binding nearly 10-fold on average. Characteristics associated with protective HLA alleles (defined using hazard ratios for progression to AIDS from natural history cohorts) included the potential to mount broad immune selection pressures across all HIV-1 proteins except Nef, the tendency to drive multisite and/or anchor residue escape mutations within known CTL epitopes, and the ability to strongly select mutations in conserved regions within HIV's structural and functional proteins. Thus, the factors defining protective cellular immune responsesmay be more complex than simply targeting conserved viral regions. The results provide new information to guide vaccine design and immunogenicity studies

Uncommon pathways of immune escape attenuate HIV-1 integrase replication capacity

An attenuation of the HIV-1 replication capacity (RC) has been observed for immune-mediated escape mutations in Gag restricted by protective HLA alleles. However, the extent to which escape mutations affect other viral proteins during natural infection is not well understood. We generated recombinant viruses encoding plasma HIV-1 RNA integrase sequences from antiretroviral-naive individuals with early (n = 88) and chronic (n = 304) infections and measured the in vitro RC of each. In contrast to data from previous studies of Gag, we observed little evidence that host HLA allele expression was associated with integrase RC. A modest negative correlation was observed between the number of HLA-B-associated integrase polymorphisms and RC in chronic infection (R = -0.2; P = 0.003); however, this effect was not driven by mutations restricted by protective HLA alleles. Notably, the integrase variants S119R, G163E, and I220L, which represent uncommon polymorphisms associated with HLA-C*05, -A*33, and -B*52, respectively, correlated with lower RC (all q < 0.2). We identified a novel C*05-restricted epitope (HTDNGSNF(114-121)) that likely contributes to the selection of the S119R variant, the polymorphism most significantly associated with lower RC in patient sequences. An NL4-3 mutant encoding the S119R polymorphism displayed a similar to 35%-reduced function that was rescued by a single compensatory mutation of A91E. Together, these data indicate that substantial HLA-driven attenuation of integrase is not a general phenomenon during HIV-1 adaptation to host immunity. However, uncommon polymorphisms selected by HLA alleles that are not conventionally regarded to be protective may be associated with impaired protein function. Vulnerable epitopes in integrase might therefore be considered for future vaccine strategies

Why are Nigeria-Cameroon chimpanzees (Pan troglodytes ellioti) free of SIVcpz infection ?

Simian immunodeficiency virus (SIV) naturally infects two subspecies of chimpanzee: Pan troglodytes troglodytes from Central Africa (SIVcpzPtt) and P. t. schweinfurtii from East Africa (SIVcpzPts), but is absent in P. t. verus from West Africa and appears to be absent in P. t. ellioti inhabiting Nigeria and western Cameroon. One explanation for this pattern is that P. t. troglodytes and P. t schweinfurthii may have acquired SIVcpz after their divergence from P. t. verus and P. t. ellioti. However, all of the subspecies, except P. t. verus, still occasionally exchange migrants making the absence of SIVcpz in P. t. ellioti puzzling. Sampling of P. t. ellioti has been minimal to date, particularly along the banks of the Sanaga River, where its range abuts that of P. t. troglodytes. This study had three objectives. First, we extended the sampling of SIVcpz across the range of chimpanzees north of the Sanaga River to address whether under-sampling might account for the absence of evidence for SIVcpz infection in P. t. ellioti. Second, we investigated how environmental variation is associated with the spread and prevalence of SIVcpz in the two chimpanzee subspecies inhabiting Cameroon since environmental variation has been shown to contribute to their divergence from one another. Finally, we compared the prevalence and distribution of SIVcpz with that of Simian Foamy Virus (SFV) to examine the role of ecology and behavior in shaping the distribution of diseases in wild host populations. The dataset includes previously published results on SIVcpz infection and SFVcpz as well as newly collected data, and represents over 1000 chimpanzee fecal samples from 41 locations across Cameroon. Results revealed that none of the 181 P. t. ellioti fecal samples collected across the range of P. t. ellioti tested positive for SIVcpz. In addition, species distribution models suggest that environmental variation contributes to differences in the distribution and prevalence of SIVcpz and SFVcpz. The ecological niches of these two viruses are largely non-overlapping, although stronger statistical support for this conclusion will require more sampling. Overall this study demonstrates that SIVcpz infection is absent or very rare in P. t. ellioti, despite multiple opportunities for transmission. The reasons for its absence remain unclear, but might be explained by one or more factors, including environmental variation, viral competition, and/or local adaptation—all of which should be explored in greater detail through continued surveillance of this region