Publications

Background. Millions of people are infected with hepatitis C virus (HCV) worldwide and 30% spontaneously clear the infection. Reasons for HCV clearance without antiviral treatment are not well understood. Methods. Blood was collected for DNA analysis from patients with chronic HCV infection or evidence of spontaneous clearance. To overcome anticipated limitations of small sample size, primary analyses consisted of a candidate gene analysis of 12 preselected genes based on known association with host immunologic response to HCV infection. To further reduce the impact of multiple testing on power, a single likelihood ratio test was conducted for each gene using all associated SNPs assayed on the Illumina Quad 610/660W chip. Step-down permutation methods were used to adjust for multiple testing in all analyses. Results. Ninety-five and 62 patients with HCV chronic infection or spontaneous clearance, respectively, were included for analysis. HLA-DQB1 (p = 1.76⁎10(-5)) and IL-6 (p = 0.0007) genes were significantly associated with spontaneous HCV clearance. IL-28B was not significantly associated with spontaneous clearance (p = 0.17). Conclusion. Our whole-gene analytic strategy identified a previously unreported association of IL-6 with spontaneous clearance of HCV infection. We also confirmed the finding that HLA-DQB1 is associated with spontaneous resolution of HCV infection.

Identifying host immune determinants governing HIV transcription, latency and infectivity in vivo is critical to developing an HIV cure. Based on our recent finding that the host factor p21 regulates HIV transcription during antiretroviral therapy (ART), and published data demonstrating that the human carbohydrate-binding immunomodulatory protein galectin-9 regulates p21, we hypothesized that galectin-9 modulates HIV transcription. We report that the administration of a recombinant, stable form of galectin-9 (rGal-9) potently reverses HIV latency in vitro in the J-Lat HIV latency model. Furthermore, rGal-9 reverses HIV latency ex vivo in primary CD4+ T cells from HIV-infected, ART-suppressed individuals (p = 0.002), more potently than vorinostat (p = 0.02). rGal-9 co-administration with the latency reversal agent "JQ1", a bromodomain inhibitor, exhibits synergistic activity (p<0.05). rGal-9 signals through N-linked oligosaccharides and O-linked hexasaccharides on the T cell surface, modulating the gene expression levels of key transcription initiation, promoter proximal-pausing, and chromatin remodeling factors that regulate HIV latency. Beyond latent viral reactivation, rGal-9 induces robust expression of the host antiviral deaminase APOBEC3G in vitro and ex vivo (FDR<0.006) and significantly reduces infectivity of progeny virus, decreasing the probability that the HIV reservoir will be replenished when latency is reversed therapeutically. Lastly, endogenous levels of soluble galectin-9 in the plasma of 72 HIV-infected ART-suppressed individuals were associated with levels of HIV RNA in CD4+ T cells (p<0.02) and with the quantity and binding avidity of circulating anti-HIV antibodies (p<0.009), suggesting a role of galectin-9 in regulating HIV transcription and viral production in vivo during therapy. Our data suggest that galectin-9 and the host glycosylation machinery should be explored as foundations for novel HIV cure strategies.

PURPOSE

Whole-genome sequencing (WGS) can be used as a powerful diagnostic tool as well as for screening, but it may lead to anxiety, unnecessary testing, and overtreatment. Current guidelines suggest reporting clinically actionable secondary findings when diagnostic testing is performed. We examined preferences for receiving WGS results.

METHODS

A US nationally representative survey (n = 410 adults) was used to rank preferences for who decides (an expert panel, your doctor, you) which WGS results are reported. We estimated the value of information about variants with varying levels of clinical usefulness by using willingness to pay contingent valuation questions.

RESULTS

The results were as follows: 43% preferred to decide themselves what information is included in the WGS report. 38% (95% confidence interval (CI): 33-43%) would not pay for actionable variants, and 3% (95% CI: 1-5%) would pay more than $1,000. 55% (95% CI: 50-60%) would not pay for variants for which medical treatment is currently unclear, and 7% (95% CI: 5-9%) would pay more than $400.

CONCLUSION

Most people prefer to decide what WGS results are reported. Despite valuing actionable information more, some respondents perceive that genetic information could negatively impact them. Preference heterogeneity for WGS information should be considered in the development of policies, particularly to integrate patient preferences with personalized medicine and shared decision making.Genet Med 18 12, 1295-1302.

Despite more than 25 documented outbreaks of Ebola since 1976, our understanding of the disease is limited, in particular the social, political, ecological, and economic forces that promote (or limit) its spread. In the following study, we seek to provide new ways of understanding the 2013-2016 Ebola pandemic. We use the term, 'pandemic,' instead of 'epidemic,' so as not to elide the global forces that shape every localized outbreak of infectious disease. By situating life histories via a biosocial approach, the forces promoting or retarding Ebola transmission come into sharper focus. We conclude that biomedical and culturalist claims of causality have helped obscure the role of human rights failings (colonial legacies, structural adjustment, exploitative mining companies, enabled civil war, rural poverty, and the near absence of quality health care, to name but a few) in the genesis of the 2013-16 pandemic. From early 20th century smallpox and influenza outbreaks to 21st century Ebola, transnational relations of inequality continue to be embodied as viral disease in West Africa, resulting in the preventable deaths of hundreds of thousands of people.

OBJECTIVE

To examine how the time from HIV testing to care referral and from referral to care linkage influenced time to care engagement for newly diagnosed HIV-infected adolescents.

METHODS

We evaluated the Care Initiative, a care linkage and engagement program for HIV-infected adolescents in 15 US clinics. We analyzed client-level factors, provider type, and intervals from HIV testing to care referral and from referral to care linkage as predictors of care engagement. Engagement was defined as a second HIV-related medical visit within 16 weeks of initial HIV-related medical visit (linkage).

RESULTS

At 32 months, 2143 youth had been referred. Of these, 866 were linked to care through the Care Initiative within 42 days and thus eligible for study inclusion. Of the linked youth, 90.8% were ultimately engaged in care. Time from HIV testing to referral (eg, ≤7 days versus >365 days) was associated with engagement [adjusted odds ratio = 2.91; 95% confidence interval (CI): 1.43 to 5.94] and shorter time to engagement (adjusted hazard ratio = 1.41; 95% CI: 1.11 to 1.79). Individuals with shorter care referral to linkage intervals (eg, ≤7 days versus 22-42 days) engaged in care faster (adjusted hazard ratio = 2.90; 95% CI: 2.34 to 3.60) and more successfully (adjusted odds ratio = 2.01; 95% CI: 1.04 to 3.89).

CONCLUSIONS

These data address a critical piece of the care continuum and can offer suggestions of where and with whom to intervene to best achieve the care engagement goals outlined in the US National HIV/AIDS Strategy. These results may also inform programs and policies that set concrete milestones and strategies for optimal care linkage timing for newly diagnosed adolescents.