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Chirenje Z.M.,University of Zimbabwe | Masse B.R.,Fred Hutchinson Cancer Research Center | Maslankowski L.A.,University of Pennsylvania | Ramjee G.,Medical Research Council of South Africa | And 5 more authors.
Journal of the International AIDS Society | Year: 2012

Background: The majority of new HIV infections are acquired through heterosexual transmission. There is urgent need for prevention methods to compliment behavior change and condom use. Topical microbicide represent a potential strategy for reduction of HIV transmission in women. Methods: Monthly Colposcopy evaluations were performed during pelvic examinations among 299 women enrolled in the Phase 2 portion of HPTN 035 study at four sites (1 in USA, 3 in Southern Africa). This was a phase 2/2b, multisite, randomized, and controlled clinical trial with four arms: BufferGel, 0.5% PRO2000 Gel, placebo gel and no gel. At two of the sites, pelvic examinations were conducted by the use of naked eye without colposcopy. Results: A colposcopy finding of any kind was detected in 48% of participants at baseline compared to 40% at 3 months (p=0.04). The lower rates were also observed in vaginal discharge (22% at baseline, 16% at 3 months, p=0.06), erythema (15% at baseline, 8% at 3 months, p=0.004). The trend towards significance at p=0.05 disappear when utilizing stringent statistical significance levels. A pelvic finding of any kind was detected in 71% of colposcopy participants compared to 41% of participants who had naked eye examination only conducted at two sites that performed both colposcopy and naked eye without colposcopy. Use of colposcopy yielded significantly higher rates of participants with deep epithelial disruption, erythema and ecchymosis.We observed no cases of incident Chlamydia, Gonorrhea, or Syphilis during the three month follow up. There were 2 cases of incident HIV during 3-month study period neither of which was associated with any abnormal colposcopy evaluation findings. Conclusion: No safety signals were observed in the 4 study arms, allowing seamless transition from phase 2 to 2b. Colposcopy utility in microbicide clinical trials has minimal value given high rates of background noise findings of no relevant clinical significance. Copyright: © 2012 Piloya T et al; licensee International AIDS Society.

Xu G.J.,Harvard University | Xu G.J.,Harvard Massachusetts Institute of Technology Division of Health Sciences and Technology | Xu G.J.,Howard Hughes Medical Institute | Kula T.,Howard Hughes Medical Institute | And 21 more authors.
Science | Year: 2015

The human virome plays important roles in health and immunity. However, current methods for detecting viral infections and antiviral responses have limited throughput and coverage. Here, we present VirScan, a high-throughput method to comprehensively analyze antiviral antibodies using immunoprecipitation and massively parallel DNA sequencing of a bacteriophage library displaying proteome-wide peptides from all human viruses. We assayed over 108 antibody-peptide interactions in 569 humans across four continents, nearly doubling the number of previously established viral epitopes. We detected antibodies to an average of 10 viral species per person and 84 species in at least two individuals. Although rates of specific virus exposure were heterogeneous across populations, antibody responses targeted strongly conserved "public epitopes" for each virus, suggesting that they may elicit highly similar antibodies. VirScan is a powerful approach for studying interactions between the virome and the immune system.

Kasprowicz V.O.,Harvard University | Kasprowicz V.O.,KwaZulu Natal Research Institute for Tuberculosis and HIV K RITH | Kasprowicz V.O.,Doris Duke Medical Research Institute | Halliday J.S.,University of Oxford | And 3 more authors.
Biomarkers in Medicine | Year: 2012

IFN-γ release by antigen-specific T cells can be used to track immune responses to infections and vaccines. In recent years, there have been substantial advances in the techniques available to measure IFN-γ release and a generation of such assays are now available for clinical use, as well as in a research setting. Interferon release leads to subsequent release of interferon-responsive chemokines such as MIG and IP-10, thus amplifying the original signal. A number of investigators have assessed whether measurement of these chemokines might provide a sensitive platform for detection of infection and antigen-specific T-cell responses. In this article, we assess the potential of these new approaches. We have termed the new antigen-specific T-cell assays monokine-amplified IFN-γ release assays (MIGRAs). Overall, it seems likely that improvements in the detection threshold could be made by analysis of antigen-triggered chemokines and potentially of other molecules in the future, although whether MIGRAs will provide additional clinical utility still remains to be determined. © 2012 Future Medicine Ltd.

Mitchell J.E.,Massachusetts Institute of Technology | Mitchell J.E.,Doris Duke Medical Research Institute | Chetty S.,Doris Duke Medical Research Institute | Govender P.,Doris Duke Medical Research Institute | And 11 more authors.
PLoS ONE | Year: 2012

Monitoring of latent Mycobacterium tuberculosis infection may prevent disease. We tested an ESAT-6 and CFP-10-specific IFN-γ Elispot assay (RD1-Elispot) on 163 HIV-infected individuals living in a TB-endemic setting. An RD1-Elispot was performed every 3 months for a period of 3-21 months. 62% of RD1-Elispot negative individuals were positive by cultured Elispot. Fluctuations in T cell response were observed with rates of change ranging from -150 to +153 spot-forming cells (SFC)/200,000 PBMC in a 3-month period. To validate these responses we used an RD1-specific real time quantitative PCR assay for monokine-induced by IFN-γ (MIG) and IFN-γ inducible protein-10 (IP10) (MIG: r = 0.6527, p = 0.0114; IP-10: r = 0.6967, p = 0.0056; IP-10+MIG: r = 0.7055, p = 0.0048). During follow-up 30 individuals were placed on ARVs and 4 progressed to active TB. Fluctuations in SFC did not correlate with CD4 count, viral load, treatment initiation, or progression to active TB. The RD1-Elispot appears to have limited value in this setting. © 2012 Mitchell et al.

Gurdasani D.,Wellcome Trust Sanger Institute | Gurdasani D.,University of Cambridge | Iles L.,Wellcome Trust Sanger Institute | Iles L.,University of Cambridge | And 15 more authors.
AIDS | Year: 2014

The study of individuals at opposite ends of the HIV clinical spectrum can provide invaluable insights into HIV biology. Heterogeneity in criteria used to define these individuals can introduce inconsistencies in results from research and make it difficult to identify biological mechanisms underlying these phenotypes. In this systematic review, we formally quantified the heterogeneity in definitions used for terms referring to extreme phenotypes in the literature, and identified common definitions and components used to describe these phenotypes. We assessed 714 definitions of HIV extreme phenotypes in 501 eligible studies published between 1 January 2000 and 15 March 2012, and identified substantial variation among these. This heterogeneity in definitions may represent important differences in biological endophenotypes and clinical progression profiles of individuals selected by these, suggesting the need for harmonized definitions. In this context, we were able to identify common components in existing definitions that may provide a framework for developing consensus definitions for these phenotypes in HIV infection. © 2014 Wolters Kluwer Health.

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