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1.
Louise Kuhn Grace M. Aldrovandi Moses Sinkala Chipepo Kankasa Katherine Semrau Prisca Kasonde Mwiya Mwiya Wei-Yann Tsai Donald M. Thea for the Zambia Exclusive Breastfeeding Study 《PloS one》2009,4(6)
Background
We previously reported no benefit of early weaning for HIV-free survival of children born to HIV-infected mothers in intent-to-treat analyses. Since early weaning was poorly accepted, we conducted a secondary analysis to investigate whether beneficial effects may have been hidden.Methods
958 HIV-infected women in Lusaka, Zambia, were randomized to abrupt weaning at 4 months (intervention) or to continued breastfeeding (control). Children were followed to 24 months with regular HIV PCR tests and examinations to determine HIV infection or death. Detailed behavioral data were collected on when all breastfeeding ended. Most participants were recruited before antiretroviral treatment (ART) became available. We compared outcomes among mother-child pairs who weaned earlier or later than intended by study design adjusting for potential confounders.Results
Of infants alive, uninfected and still breastfeeding at 4 months in the intervention group, 16.1% who weaned as instructed acquired HIV or died by 24 months compared to 16.0% who did not comply (p = 0.98). Children of women with less severe disease during pregnancy (not eligible for ART) had worse outcomes if their mothers weaned as instructed (RH = 2.60 95% CI: 1.06–6.36) compared to those who continued breastfeeding. Conversely, children of mothers with more severe disease (eligible for ART but did not receive it) who weaned early had better outcomes (p-value interaction = 0.002). In the control group, weaning before 15 months was associated with 3.94-fold (95% CI: 1.65–9.39) increase in HIV infection or death among infants of mothers with less severe disease.Conclusion
Incomplete adherence did not mask a benefit of early weaning. On the contrary, for women with less severe disease, early weaning was harmful and continued breastfeeding resulted in better outcomes. For women with more advanced disease, ART should be given during pregnancy for maternal health and to reduce transmission, including through breastfeeding.Trial Registration
Clinical trials.gov NCT00310726相似文献2.
Laura Heath Susan Conway Laura Jones Katherine Semrau Kyle Nakamura Jan Walter W. Don Decker Jason Hong Thomas Chen Marintha Heil Moses Sinkala Chipepo Kankasa Donald M. Thea Louise Kuhn James I. Mullins Grace M. Aldrovandi 《PloS one》2010,5(4)
Background
Breast milk transmission of HIV-1 remains a major route of pediatric infection. Defining the characteristics of viral variants to which breastfeeding infants are exposed is important for understanding the genetic bottleneck that occurs in the majority of mother-to-child transmissions. The blood-milk epithelial barrier markedly restricts the quantity of HIV-1 in breast milk, even in the absence of antiretroviral drugs. The basis of this restriction and the genetic relationship between breast milk and blood variants are not well established.Methodology/Principal Findings
We compared 356 HIV-1 subtype C gp160 envelope (env) gene sequences from the plasma and breast milk of 13 breastfeeding women. A trend towards lower viral population diversity and divergence in breast milk was observed, potentially indicative of clonal expansion within the breast. No differences in potential N-linked glycosylation site numbers or in gp160 variable loop amino acid lengths were identified. Genetic compartmentalization was evident in only one out of six subjects in whom contemporaneously obtained samples were studied. However, in samples that were collected 10 or more days apart, six of seven subjects were classified as having compartmentalized viral populations, highlighting the necessity of contemporaneous sampling for genetic compartmentalization studies. We found evidence of CXCR4 co-receptor using viruses in breast milk and blood in nine out of the thirteen subjects, but no evidence of preferential localization of these variants in either tissue.Conclusions/Significance
Despite marked restriction of HIV-1 quantities in milk, our data indicate intermixing of virus between blood and breast milk. Thus, we found no evidence that a restriction in viral genotype diversity in breast milk accounts for the genetic bottleneck observed following transmission. In addition, our results highlight the rapidity of HIV-1 env evolution and the importance of sample timing in analyses of gene flow. 相似文献3.
Kyle J. Nakamura Johannes S. Gach Laura Jones Katherine Semrau Jan Walter Frederic Bibollet-Ruche Julie M. Decker Laura Heath William D. Decker Moses Sinkala Chipepo Kankasa Donald Thea James Mullins Louise Kuhn Michael B. Zwick Grace M. Aldrovandi 《PloS one》2010,5(3)
Human antibody 4E10 targets the highly conserved membrane-proximal external region (MPER) of the HIV-1 transmembrane glycoprotein, gp41, and has extraordinarily broad neutralizing activity. It is considered by many to be a prototype for vaccine development. In this study, we describe four subjects infected with viruses carrying rare MPER polymorphisms associated with resistance to 4E10 neutralization. In one case resistant virus carrying a W680G substitution was transmitted from mother to infant. We used site-directed mutagenesis to demonstrate that the W680G substitution is necessary for conferring the 4E10-resistant phenotype, but that it is not sufficient to transfer the phenotype to a 4E10-sensitive Env. Our third subject carried Envs with a W680R substitution causing variable resistance to 4E10, indicating that residues outside the MPER are required to confer the phenotype. A fourth subject possessed a F673L substitution previously associated with 4E10 resistance. For all three subjects with W680 polymorphisms, we observed additional residues in the MPER that co-varied with position 680 and preserved charged distributions across this region. Our data provide important caveats for vaccine development targeting the MPER. Naturally occurring Env variants described in our study also represent unique tools for probing the structure-function of HIV-1 envelope. 相似文献
4.
Infectious molecular clone of a recently transmitted pediatric human immunodeficiency virus clade C isolate from Africa: evidence of intraclade recombination 下载免费PDF全文
Grisson RD Chenine AL Yeh LY He J Wood C Bhat GJ Xu W Kankasa C Ruprecht RM 《Journal of virology》2004,78(24):14066-14069
Although human immunodeficiency virus type 1 (HIV-1) clade C continues to dominate the pandemic, only two infectious clade C proviral DNA clones have been described (N. Mochizuki, N. Otsuka, K. Matsuo, T. Shiino, A. Kojima, T. Kurata, K. Sakai, N. Yamamoto, S. Isomura, T. N. Dhole, Y. Takebe, M. Matsuda, and M. Tatsumi, AIDS Res. Hum. Retrovir. 15:1321-1324, 1999; T. Ndung'u, B. Renjifo, and M. Essex, J. Virol. 75:4964-4972, 2001). We have generated an infectious molecular clone of a pediatric clade C strain, HIV1084i, which was isolated from a Zambian infant infected either intrapartum or through breastfeeding. HIV1084i is an R5, non-syncytium-inducing isolate that bears all known clade C signatures; gag, pol, and env consistently mapped within clade C. Interestingly, gag resembled Asian isolates, whereas pol and env resembled African isolates, indicating that HIV1084i probably arose from an intraclade recombination. As a recently transmitted clade C strain, HIV1084i will be a useful vaccine development tool. 相似文献
5.
Nagadenahalli B. Siddappa Ruijiang Song Victor G. Kramer Agnès-Laurence Chenine Vijayakumar Velu Helena Ong Robert A. Rasmussen Ricky D. Grisson Charles Wood Hong Zhang Chipeppo Kankasa Rama Rao Amara James G. Else Francis J. Novembre David C. Montefiori Ruth M. Ruprecht 《Journal of virology》2009,83(3):1422-1432
Human immunodeficiency virus clade C (HIV-C) accounts for >56% of all HIV infections worldwide. To investigate vaccine safety and efficacy in nonhuman primates, a pathogenic, R5-tropic, neutralization-sensitive simian-human immunodeficiency virus (SHIV) carrying HIV-C env would be desirable. We have constructed SHIV-2873Ni, an R5-tropic SHIV carrying a primary pediatric HIV-C env gene isolated from a 2-month-old Zambian infant, who died within 1 year of birth. SHIV-2873Ni was constructed using SHIV-1157ipd3N4 (R. J. Song, A. L. Chenine, R. A. Rasmussen, C. R. Ruprecht, S. Mirshahidi, R. D. Grisson, W. Xu, J. B. Whitney, L. M. Goins, H. Ong, P. L. Li, E. Shai-Kobiler, T. Wang, C. M. McCann, H. Zhang, C. Wood, C. Kankasa, W. E. Secor, H. M. McClure, E. Strobert, J. G. Else, and R. M. Ruprecht. J. Virol. 80:8729-8738, 2006) as the backbone, since the latter contains additional NF-κB sites in the long terminal repeats to enhance viral replicative capacity. The parental virus, SHIV-2873Ni, was serially passaged through five rhesus monkeys (RMs); SHIV-2873Nip, the resulting passaged virus, was reisolated from the fourth recipient about 1 year postinoculation. SHIV-2873Nip was replication competent in RM peripheral blood mononuclear cells of all random donors tested and was exclusively R5 tropic, and its env gene clustered with HIV-C by phylogenetic analysis; its high sensitivity to neutralization led to classification as a tier 1 virus. Indian-origin RMs were inoculated by different mucosal routes, resulting in high peak viral RNA loads. Signs of virus-induced disease include depletion of gut CD4+ T lymphocytes, loss of memory T cells in blood, and thrombocytopenia that resulted in fatal cerebral hemorrhage. SHIV-2873Nip is a highly replication-competent, mucosally transmissible, pathogenic R5-tropic virus that will be useful to study viral pathogenesis and to assess the efficacy of immunogens targeting HIV-C Env.Currently, 33 million people are living with human immunodeficiency virus (HIV)/AIDS (www.unaids.org), and the majority of them live in sub-Saharan Africa and South and Southeast Asia, including China and India, where HIV subtype C (HIV-C) circulates in >90% of the HIV-infected population (UNAIDS) (50). This distribution makes HIV-C the most prevalent subtype in the global pandemic, accounting for >56% of all HIV infections worldwide (www.unaids.org). Globally, HIV is one of the leading causes of childhood morbidity and mortality. Children account for 20% of all HIV-related deaths, 7% of individuals living with HIV, and 16% of new infections annually (reviewed in references 26, 29, and 38). In sub-Saharan Africa, HIV-C is responsible for approximately 50% of all infections, and a significant number of infections are in infants and children. HIV transmission from infected mothers to their infants is the primary mode of infection in children and can occur in utero, intrapartum, or postnatally through breast milk. The use of antiretroviral drugs has successfully reduced the rate of HIV infection in infants in the developed world to approximately 1%; nevertheless, such regimens have only recently become available in many of the developing nations where mother-to-child transmission of HIV is most significant (reviewed in references 26 and 38).Simian-human immunodeficiency viruses (SHIVs) are chimeric viruses that contain HIV envelope genes in the simian immunodeficiency virus (SIV) backbone. They have been used in a wide range of studies investigating lentiviral pathogenesis, antiviral immunity, virus-host interactions, mucosal transmission, and vaccine and drug efficacy (20). However, the majority of current SHIV strains utilize envelope genes derived from HIV clade B strains, which represent fewer than 10% of all global infections. Therefore, the available SHIV chimeras do not reflect the genetic diversity of the HIV epidemic, which is dominated by non-B clades, especially by HIV-C. Only a few studies have focused on developing anti-clade C Env vaccines (25, 27, 44, 49), with one efficacy study in primate models (44). To investigate lentiviral pathogenesis as well as anti-HIV-C vaccine safety and efficacy in nonhuman primate models, a pathogenic, CCR5-restricted, clade C SHIV (SHIV-C) would be very useful.Previously, we have generated an R5-tropic SHIV-C, SHIV-1157i (6, 51), which carries env from a 6-month-old Zambian infant born to an HIV-positive mother. During prospective long-term follow-up, this infant turned out to be a long-term nonprogressor who has remained asymptomatic at 8 years of age (61). The rhesus monkey (RM)-adapted strain, SHIV-1157ip, was pathogenic and has caused AIDS in several monkeys thus far, but with a relatively low rate of disease progression. AIDS developed in RMs between 127 and 300 weeks postinoculation (17a). A late virus was reisolated and engineered to contain extra NF-κB sites in the long terminal repeats (LTRs) (51); follow-up times for monkeys infected with this late form are not yet sufficient to assess development to AIDS, although signs of disease have developed. A possible explanation is that the env gene used to construct the original SHIV-1157i is an important determinant of the disease progression rate. The fact that the env gene was derived from a long-term nonprogressor may be linked to the relatively slow disease progression we observed in RMs infected with SHIV carrying the corresponding env gene.We sought to test whether constructing an R5-tropic SHIV with an env gene derived from a rapid progressor would give rise to a more virulent R5-tropic SHIV-C. Although HIV- or SIV-infected individuals with either typical rates of disease progression or long-term nonprogression have been studied extensively, few reports were focused on the virologic and immunologic characteristics of patients with rapid disease progression (9, 22). Patients who progress to AIDS within 1 to 2 years from the time of infection have been identified among infants and adults (7, 13, 34, 35, 46), with a higher frequency in infant populations. These patients demonstrate rapid loss of CD4+ T cells and lack potent cellular and humoral immune responses.Here we report the construction of SHIV-2873Ni, a chimera that carries env of an R5-tropic HIV-C strain isolated from a rapid progressor, a 2-month-old Zambian baby who died of AIDS-related disease within 1 year of birth. SHIV-2873Ni was serially passaged through five RMs; SHIV-2873Nip, the passaged virus, was reisolated and characterized from the fourth recipient about 1 year postinoculation when signs of disease were manifest. The RM-adapted virus caused T-cell depletion within a few months postinoculation. 相似文献
6.
Neutralization-Sensitive R5-Tropic Simian-Human Immunodeficiency Virus SHIV-2873Nip,Which Carries env Isolated from an Infant with a Recent HIV Clade C Infection 下载免费PDF全文
Nagadenahalli B. Siddappa Ruijiang Song Victor G. Kramer Agnès-Laurence Chenine Vijayakumar Velu Helena Ong Robert A. Rasmussen Ricky D. Grisson Charles Wood Hong Zhang Chipeppo Kankasa Rama Rao Amara James G. Else Francis J. Novembre David C. Montefiori Ruth M. Ruprecht 《Journal of virology》2009,83(16):8297
7.
Ashok A. Kumar Catherine Chunda-Liyoka Jonathan W. Hennek Hamakwa Mantina S. Y. Ryan Lee Matthew R. Patton Pauline Sambo Silvester Sinyangwe Chipepo Kankasa Chifumbe Chintu Carlo Brugnara Thomas P. Stossel George M. Whitesides 《PloS one》2014,9(12)
Although simple and low-cost interventions for sickle cell disease (SCD) exist in many developing countries, child mortality associated with SCD remains high, in part, because of the lack of access to diagnostic tests for SCD. A density-based test using aqueous multiphase systems (SCD-AMPS) is a candidate for a low-cost, point-of-care diagnostic for SCD. In this paper, the field evaluation of SCD-AMPS in a large (n = 505) case-control study in Zambia is described. Of the two variations of the SCD-AMPS used, the best system (SCD-AMPS-2) demonstrated a sensitivity of 86% (82–90%) and a specificity of 60% (53–67%). Subsequent analysis identified potential sources of false positives that include clotting, variation between batches of SCD-AMPS, and shipping conditions. Importantly, SCD-AMPS-2 was 84% (62–94%) sensitive in detecting SCD in children between 6 months and 1 year old. In addition to an evaluation of performance, an assessment of end-user operability was done with health workers in rural clinics in Zambia. These health workers rated the SCD-AMPS tests to be as simple to use as lateral flow tests for malaria and HIV. 相似文献
8.
Pankaj Kumar Nithal Y. Kuwa Veenu Minhas Clemence Marimo Danielle M. Shea Chipepo Kankasa Charles Wood 《PloS one》2013,8(8)
Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent for Kaposi Sarcoma (KS), the most common cancer diagnosed in HIV- infected patients. The role of neutralizing antibodies in KS pathogenesis and in KSHV infected individuals is not clearly understood. The goal of this study was to investigate and compare the prevalence and titers of neutralizing antibodies in plasma samples from KS patients and KSHV infected asymptomatic individuals from Zambia, a KS endemic region in sub-Saharan Africa. Plasma samples (N = 267) consisting of KS patients (group 1) and asymptomatic individuals (group 2) were collected from Lusaka, Zambia. A flow cytometry based quantitative neutralization assay utilizing recombinant KSHV expressing GFP was used to detect KSHV neutralizing antibodies. Our results show that the overall prevalence of neutralizing antibodies in KS patients (group 1) was 66.7% which was significantly higher than the prevalence of 6.5% present in KSHV infected asymptomatic individuals (group 2). Total antibody titers as well as neutralizing antibodies titers were found to be significantly higher among KS patients. It is likely that higher neutralizing antibodies prevalence and titers in KS patients result from higher levels of antigenic stimulation over time. This study is first to compare prevalence and titers of neutralizing antibodies in participants with and without disease from a KSHV endemic region. 相似文献
9.
Louise Kuhn Moses Sinkala Chipepo Kankasa Katherine Semrau Prisca Kasonde Nancy Scott Mwiya Mwiya Cheswa Vwalika Jan Walter Wei-Yann Tsai Grace M. Aldrovandi Donald M. Thea 《PloS one》2007,2(12)