Browsing by Author "Williamson, Carolyn"

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    Detectable HIV-1 in semen in individuals with very low blood viral loads
    (BioMed Central, 2020-03-05) Kariuki, Samuel Mundia; Selhorst, Philippe; Norman, Jennifer; Cohen, Karen; Rebe, Kevin; Williamson, Carolyn; Dorfman, Jeffrey R
    Background: Several reports indicate that a portion (5–10%) of men living with HIV-1 intermittently shed HIV-1 RNA into seminal plasma while on long term effective antiretroviral therapy (ART). This is highly suggestive of an HIV-1 reservoir in the male genital tract. However, the status of this reservoir in men living with HIV-1 who are not under treatment is underexplored and has implications for understanding the origins and evolution of the reservoir. Finding: Forty-three HIV-1 positive, antiretroviral therapy naïve study participants attending a men’s health clinic were studied. Semen viral loads and blood viral loads were generally correlated, with semen viral loads generally detected in individuals with blood viral loads > 10,000 cp/ml. However, we found 1 individual with undetectable viral loads (<20cp/ml) and 2 individuals with very low blood viral load (97 and 333cp/ml), but with detectable HIV-1 in semen (485–1157 copies/ semen sample). Blood viral loads in the first individual were undetectable when tested three times over the prior 5 years. Conclusions: Semen HIV-1 viral loads are usually related to blood viral loads, as we confirm. Nonetheless, this was not true in a substantial minority of individuals suggesting unexpectedly high levels of replication in the male genital tract in a few individuals, despite otherwise effective immune control. This may reflect establishment of a local reservoir of HIV-1 populations.
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    Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models
    (BioMed Central, 2013-12-02) Lacerda, Miguel; Moore, Penny L.; Ngandu, Nobubelo K.; Seaman, Michael; Gray, Elin S.; Murrell, Ben; Krishnamoorthy, Mohan; Nonyane, Molati; Madiga, Maphuti; Wibmer, Constantinos K.; Sheward, Daniel; Bailer, Robert T.; Gao, Hongmei; Greene, Kelli M.; Karim, Salim S. A.; Mascola, John R.; Korber, Bette T. M.; Montefiori, David C.; Morris, Lynn; Williamson, Carolyn; Seoighe, Cathal; the CAVD-NSDP Consortium
    Background Identification of the epitopes targeted by antibodies that can neutralize diverse HIV-1 strains can provide important clues for the design of a preventative vaccine. Methods We have developed a computational approach that can identify key amino acids within the HIV-1 envelope glycoprotein that influence sensitivity to broadly cross-neutralizing antibodies. Given a sequence alignment and neutralization titers for a panel of viruses, the method works by fitting a phylogenetic model that allows the amino acid frequencies at each site to depend on neutralization sensitivities. Sites at which viral evolution influences neutralization sensitivity were identified using Bayes factors (BFs) to compare the fit of this model to that of a null model in which sequences evolved independently of antibody sensitivity. Conformational epitopes were identified with a Metropolis algorithm that searched for a cluster of sites with large Bayes factors on the tertiary structure of the viral envelope. Results We applied our method to ID50 neutralization data generated from seven HIV-1 subtype C serum samples with neutralization breadth that had been tested against a multi-clade panel of 225 pseudoviruses for which envelope sequences were also available. For each sample, between two and four sites were identified that were strongly associated with neutralization sensitivity (2ln(BF) > 6), a subset of which were experimentally confirmed using site-directed mutagenesis. Conclusions Our results provide strong support for the use of evolutionary models applied to cross-sectional viral neutralization data to identify the epitopes of serum antibodies that confer neutralization breadth.
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    Intra- and inter-clade cross-reactivity by HIV-1 gag specific T-cells reveals exclusive and commonly targeted regions : implications for current vaccine trials
    (Public Library of Science, 2011-10-12) Zembe, Lycias; Burgers, Wendy A.; Jaspan, Heather B.; Bekker, Linda-Gail; Bredell, Helba; Stevens, Gwynneth; Gilmour, Jill; Cox, Josephine H.; Fast, Patricia; Hayes, Peter; Vardas, Eftyhia; Williamson, Carolyn; Gray, Clive M.
    ENGLISH ABSTRACT: The genetic diversity of HIV-1 across the globe is a major challenge for developing an HIV vaccine. To facilitate immunogen design, it is important to characterize clusters of commonly targeted T-cell epitopes across different HIV clades. To address this, we examined 39 HIV-1 clade C infected individuals for IFN-c Gag-specific T-cell responses using five sets of overlapping peptides, two sets matching clade C vaccine candidates derived from strains from South Africa and China, and three peptide sets corresponding to consensus clades A, B, and D sequences. The magnitude and breadth of T-cell responses against the two clade C peptide sets did not differ, however clade C peptides were preferentially recognized compared to the other peptide sets. A total of 84 peptides were recognized, of which 19 were exclusively from clade C, 8 exclusively from clade B, one peptide each from A and D and 17 were commonly recognized by clade A, B, C and D. The entropy of the exclusively recognized peptides was significantly higher than that of commonly recognized peptides (p = 0.0128) and the median peptide processing scores were significantly higher for the peptide variants recognized versus those not recognized (p = 0.0001). Consistent with these results, the predicted Major Histocompatibility Complex Class I IC50 values were significantly lower for the recognized peptide variants compared to those not recognized in the ELISPOT assay (p,0.0001), suggesting that peptide variation between clades, resulting in lack of cross-clade recognition, has been shaped by host immune selection pressure. Overall, our study shows that clade C infected individuals recognize clade C peptides with greater frequency and higher magnitude than other clades, and that a selection of highly conserved epitope regions within Gag are commonly recognized and give rise to cross-clade reactivities.