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21.
Denis R. Chopera Jaclyn K. Mann Philip Mwimanzi Saleha Omarjee Xiaomei T. Kuang Nonkululeko Ndabambi Sarah Goodier Eric Martin Vivek Naranbhai Salim Abdool Karim Quarraisha Abdool Karim Zabrina L. Brumme Thumbi Ndung'u Carolyn Williamson Mark A. Brockman the CAPRISA TRAPS Team 《PloS one》2013,8(8)
Background
Use of antiretroviral-based microbicides for HIV-1 prophylaxis could introduce a transmission barrier that inadvertently facilitates the selection of fitter viral variants among incident infections. To investigate this, we assessed the in vitro function of gag-protease and nef sequences from participants who acquired HIV-1 during the CAPRISA 004 1% tenofovir microbicide gel trial.Methods and Results
We isolated the earliest available gag-protease and nef gene sequences from 83 individuals and examined their in vitro function using recombinant viral replication capacity assays and surface protein downregulation assays, respectively. No major phylogenetic clustering and no significant differences in gag-protease or nef function were observed in participants who received tenofovir gel versus placebo gel prophylaxis.Conclusion
Results indicate that the partial protective effects of 1% tenofovir gel use in the CAPRISA 004 trial were not offset by selection of transmitted/early HIV-1 variants with enhanced Gag-Protease or Nef fitness. 相似文献22.
Vinod B. Patel Grant Theron Laura Lenders Brian Matinyena Cathy Connolly Ravesh Singh Yacoob Coovadia Thumbi Ndung'u Keertan Dheda 《PLoS medicine》2013,10(10)
Background
Tuberculous meningitis (TBM) is difficult to diagnose promptly. The utility of the Xpert MTB/RIF test for the diagnosis of TBM remains unclear, and the effect of host- and sample-related factors on test performance is unknown. This study sought to evaluate the sensitivity and specificity of Xpert MTB/RIF for the diagnosis of TBM.Methods and Findings
235 South-African patients with a meningeal-like illness were categorised as having definite (culture or Amplicor PCR positive), probable (anti-TBM treatment initiated but microbiological confirmation lacking), or non-TBM. Xpert MTB/RIF accuracy was evaluated using 1 ml of uncentrifuged and, when available, 3 ml of centrifuged cerebrospinal fluid (CSF). To evaluate the incremental value of MTB/RIF over a clinically based diagnosis, test accuracy was compared to a clinical score (CS) derived using basic clinical and laboratory information.Of 204 evaluable patients (of whom 87% were HIV-infected), 59 had definite TBM, 64 probable TBM, and 81 non-TBM. Overall sensitivity and specificity (95% CI) were 62% (48%–75%) and 95% (87%–99%), respectively. The sensitivity of Xpert MTB/RIF was significantly better than that of smear microscopy (62% versus 12%; p = 0.001) and significantly better than that of the CS (62% versus 30%; p = 0.001; C statistic 85% [79%–92%]). Xpert MTB/RIF sensitivity was higher when centrifuged versus uncentrifuged samples were used (82% [62%–94%] versus 47% [31%–61%]; p = 0.004). The combination of CS and Xpert MTB/RIF (Xpert MTB/RIF performed if CS<8) performed as well as Xpert MTB/RIF alone but with a ∼10% reduction in test usage. This overall pattern of results remained unchanged when the definite and probable TBM groups were combined. Xpert MTB/RIF was not useful in identifying TBM among HIV-uninfected individuals, although the sample was small. There was no evidence of PCR inhibition, and the limit of detection was ∼80 colony forming units per millilitre. Study limitations included a predominantly HIV-infected cohort and the limited number of culture-positive CSF samples.Conclusions
Xpert MTB/RIF may be a good rule-in test for the diagnosis of TBM in HIV-infected individuals from a tuberculosis-endemic setting, particularly when a centrifuged CSF pellet is used. Further studies are required to confirm these findings in different settings. Please see later in the article for the Editors'' Summary 相似文献23.
Wright JK Novitsky V Brockman MA Brumme ZL Brumme CJ Carlson JM Heckerman D Wang B Losina E Leshwedi M van der Stok M Maphumulo L Mkhwanazi N Chonco F Goulder PJ Essex M Walker BD Ndung'u T 《Journal of virology》2011,85(8):3996-4006
HLA class I-mediated selection of immune escape mutations in functionally important Gag epitopes may partly explain slower disease progression in HIV-1-infected individuals with protective HLA alleles. To investigate the impact of Gag function on disease progression, the replication capacities of viruses encoding Gag-protease from 60 individuals in early HIV-1 subtype C infection were assayed in an HIV-1-inducible green fluorescent protein reporter cell line and were correlated with subsequent disease progression. Replication capacities did not correlate with viral load set points (P = 0.37) but were significantly lower in individuals with below-median viral load set points (P = 0.03), and there was a trend of correlation between lower replication capacities and lower rates of CD4 decline (P = 0.09). Overall, the proportion of host HLA-specific Gag polymorphisms in or adjacent to epitopes was negatively associated with replication capacities (P = 0.04), but host HLA-B-specific polymorphisms were associated with higher viral load set points (P = 0.01). Further, polymorphisms associated with host-specific protective HLA alleles were linked with higher viral load set points (P = 0.03). These data suggest that transmission or early HLA-driven selection of Gag polymorphisms results in reduced early cytotoxic T-lymphocyte (CTL) responses and higher viral load set points. In support of the former, 46% of individuals with nonprotective alleles harbored a Gag polymorphism exclusively associated with a protective HLA allele, indicating a high rate of their transmission in sub-Saharan Africa. Overall, HIV disease progression is likely to be affected by the ability to mount effective Gag CTL responses as well as the replication capacity of the transmitted virus. 相似文献
24.
Ajoge HO Gordon ML de Oliveira T Green TN Ibrahim S Shittu OS Olonitola SO Ahmad AA Ndung'u T 《PloS one》2011,6(3):e17865
HIV-1 CRF02_AG and subtype G (HIV-1G) account for most HIV infections in Nigeria, but their evolutionary trends have not been well documented. To better elucidate the dynamics of the epidemic in Nigeria we characterised the gag and env genes of North-Central Nigerian HIV-1 isolates from pregnant women. Of 28 samples sequenced in both genes, the predominant clades were CRF02_AG (39%) and HIV-1G (32%). Higher predicted proportion of CXCR4-tropic (X4) HIV-1G isolates was noted compared to CRF02_AG (p = 0.007, Fisher''s exact test). Phylogenetic and Bayesian analysis conducted on our sequences and all the dated available Nigerian sequences on the Los Alamos data base showed that CRF02_AG and HIV-1G entered into Nigeria through multiple entries, with presence of HIV-1G dating back to early 1980s. This study underlines the genetic complexity of the HIV-1 epidemic in Nigeria, possible subtype-specific differences in co-receptor usage, and the evolutionary trends of the predominant HIV-1 strains in Nigeria, which may have implications for the design of biomedical interventions and better understanding of the epidemic. 相似文献
25.
Huang KH Goedhals D Carlson JM Brockman MA Mishra S Brumme ZL Hickling S Tang CS Miura T Seebregts C Heckerman D Ndung'u T Walker B Klenerman P Steyn D Goulder P Phillips R;Bloemfontein-Oxford Collaborative Group van Vuuren C Frater J 《PloS one》2011,6(4):e19018
We lack the understanding of why HIV-infected individuals in South Africa
progress to AIDS. We hypothesised that in end-stage disease there is a shifting
dynamic between T cell imposed immunity and viral immune escape, which, through
both compensatory and reverting viral mutations, results in increased viral
fitness, elevated plasma viral loads and disease progression. We explored how T
cell responses, viral adaptation and viral fitness inter-relate in South African
cohorts recruited from Bloemfontein, the Free State
(n = 278) and Durban, KwaZulu-Natal
(n = 775). Immune responses were measured by
γ-interferon ELISPOT assays. HLA-associated viral polymorphisms were
determined using phylogenetically corrected techniques, and viral replication
capacity (VRC) was measured by comparing the growth rate of gag-protease
recombinant viruses against recombinant NL4-3 viruses. We report that in
advanced disease (CD4 counts <100 cells/µl), T cell responses narrow,
with a relative decline in Gag-directed responses (p<0.0001). This is
associated with preserved selection pressure at specific viral amino acids
(e.g., the T242N polymorphism within the HLA-B*57/5801 restricted TW10
epitope), but with reversion at other sites (e.g., the T186S polymorphism within
the HLA-B*8101 restricted TL9 epitope), most notably in Gag and suggestive
of “immune relaxation”. The median VRC from patients with CD4 counts
<100 cells/µl was higher than from patients with CD4 counts ≥500
cells/µl (91.15% versus 85.19%,
p = 0.0004), potentially explaining the rise in viral load
associated with disease progression. Mutations at HIV Gag T186S and T242N
reduced VRC, however, in advanced disease only the T242N mutants demonstrated
increasing VRC, and were associated with compensatory mutations
(p = 0.013). These data provide novel insights into the
mechanisms of HIV disease progression in South Africa. Restoration of fitness
correlates with loss of viral control in late disease, with evidence for both
preserved and relaxed selection pressure across the HIV genome. Interventions
that maintain viral fitness costs could potentially slow progression. 相似文献
26.
Philippa C. Matthews Jennifer Listgarten Jonathan M. Carlson Rebecca Payne Kuan-Hsiang Gary Huang John Frater Dominique Goedhals Dewald Steyn Cloete van Vuuren Paolo Paioni Pieter Jooste Anthony Ogwu Roger Shapiro Zenele Mncube Thumbi Ndung'u Bruce D. Walker David Heckerman Philip J. R. Goulder 《PloS one》2012,7(10)
Background
HLA class I genotype is a major determinant of the outcome of HIV infection, and the impact of certain alleles on HIV disease outcome is well studied. Recent studies have demonstrated that certain HLA class I alleles that are in linkage disequilibrium, such as HLA-A*74 and HLA-B*57, appear to function co-operatively to result in greater immune control of HIV than mediated by either single allele alone. We here investigate the extent to which HLA alleles - irrespective of linkage disequilibrium - function co-operatively.Methodology/Principal Findings
We here refined a computational approach to the analysis of >2000 subjects infected with C-clade HIV first to discern the individual effect of each allele on disease control, and second to identify pairs of alleles that mediate ‘co-operative additive’ effects, either to improve disease suppression or to contribute to immunological failure. We identified six pairs of HLA class I alleles that have a co-operative additive effect in mediating HIV disease control and four hazardous pairs of alleles that, occurring together, are predictive of worse disease outcomes (q<0.05 in each case). We developed a novel ‘sharing score’ to quantify the breadth of CD8+ T cell responses made by pairs of HLA alleles across the HIV proteome, and used this to demonstrate that successful viraemic suppression correlates with breadth of unique CD8+ T cell responses (p = 0.03).Conclusions/Significance
These results identify co-operative effects between HLA Class I alleles in the control of HIV-1 in an extended Southern African cohort, and underline complementarity and breadth of the CD8+ T cell targeting as one potential mechanism for this effect. 相似文献27.
28.
Co-Infection with Mycobacterium tuberculosis Impairs HIV-Specific CD8+ and CD4+ T Cell Functionality
Shivan Chetty Pamla Govender Jennifer Zupkosky Mona Pillay Musie Ghebremichael Mahomed-Yunus S. Moosa Thumbi Ndung’u Filippos Porichis Victoria O. Kasprowicz 《PloS one》2015,10(3)
The ability of antigen-specific T cells to simultaneously produce multiple cytokines is thought to correlate with the functional capacity and efficacy of T cells. These ‘polyfunctional’ T cells have been associated with control of HIV. We aimed to assess the impact of co-infection with Mycobacterium tuberculosis (MTB) on HIV-specific CD8+ and CD4+ T cell function. We assessed T cell functionality in 34 South African adults by investigating the IFN-y, IL-2, TNF-α, IL-21 and IL-17 cytokine secretion capacity, using polychromatic flow cytometry, following HIV Gag-specific stimulation of peripheral blood mononuclear cells. We show that MTB is associated with lower HIV-specific T cell function in co-infected as compared to HIV mono-infected individuals. This decline in function was greatest in co-infection with active Tuberculosis (TB) compared to co-infection with latent MTB (LTBI), suggesting that mycobacterial load may contribute to this loss of function. The described impact of MTB on HIV-specific T cell function may be a mechanism for increased HIV disease progression in co-infected subjects as functionally impaired T cells may be less able to control HIV. 相似文献
29.
30.
M. Kariuki Njenga Leonard Njagi S. Mwangi Thumbi Samuel Kahariri Jane Githinji Eunice Omondi Amy Baden Mbabu Murithi Janusz Paweska Peter M. Ithondeka Kisa J. Ngeiywa Baptiste Dungu Meritxell Donadeu Peninah M. Munyua 《PLoS neglected tropical diseases》2015,9(3)
BackgroundAlthough livestock vaccination is effective in preventing Rift Valley fever (RVF) epidemics, there are concerns about safety and effectiveness of the only commercially available RVF Smithburn vaccine. We conducted a randomized controlled field trial to evaluate the immunogenicity and safety of the new RVF Clone 13 vaccine, recently registered in South Africa.MethodsIn a blinded randomized controlled field trial, 404 animals (85 cattle, 168 sheep, and 151 goats) in three farms in Kenya were divided into three groups. Group A included males and non-pregnant females that were randomized and assigned to two groups; one vaccinated with RVF Clone 13 and the other given placebo. Groups B included animals in 1st half of pregnancy, and group C animals in 2nd half of pregnancy, which were also randomized and either vaccinated and given placebo. Animals were monitored for one year and virus antibodies titers assessed on days 14, 28, 56, 183 and 365.ResultsIn vaccinated goats (N = 72), 72% developed anti-RVF virus IgM antibodies and 97% neutralizing IgG antibodies. In vaccinated sheep (N = 77), 84% developed IgM and 91% neutralizing IgG antibodies. Vaccinated cattle (N = 42) did not develop IgM antibodies but 67% developed neutralizing IgG antibodies. At day 14 post-vaccination, the odds of being seropositive for IgG in the vaccine group was 3.6 (95% CI, 1.5 – 9.2) in cattle, 90.0 (95% CI, 25.1 – 579.2) in goats, and 40.0 (95% CI, 16.5 – 110.5) in sheep. Abortion was observed in one vaccinated goat but histopathologic analysis did not indicate RVF virus infection. There was no evidence of teratogenicity in vaccinated or placebo animals.ConclusionsThe results suggest RVF Clone 13 vaccine is safe to use and has high (>90%) immunogenicity in sheep and goats but moderate (> 65%) immunogenicity in cattle. 相似文献