Quentin Eichbaum

PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression

Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.

The collectins in innate immunity

The collectins are proteins with collagen tails and globular lectin domains that appear to play an important role in mammalian first line host defense. Recent insights have clarified the structural basis of ligand recognition, the interactions of collectins with complement cascades, and the association with disease susceptibility.

Induction of Robust Cellular and Humoral Virus-Specific Adaptive Immune Responses in Human Immunodeficiency Virus-Infected Humanized BLT Mice

ABSTRACT The generation of humanized BLT mice by the cotransplantation of human fetal thymus and liver tissues and CD34+ fetal liver cells into nonobese diabetic/severe combined immunodeficiency mice allows for the long-term reconstitution of a functional human immune system, with human T cells, B cells, dendritic cells, and monocytes/macrophages repopulating mouse tissues. Here, we show that humanized BLT mice sustained high-level disseminated human immunodeficiency virus (HIV) infection, resulting in CD4+ T-cell depletion and generalized immune activation. Following infection, HIV-specific humoral responses were present in all mice by 3 months, and HIV-specific CD4+ and CD8+ T-cell responses were detected in the majority of mice tested after 9 weeks of infection. Despite robust HIV-specific responses, however, viral loads remained elevated in infected BLT mice, raising the possibility that these responses are dysfunctional. The increased T-cell expression of the negative costimulator PD-1 recently has been postulated to contribute to T-cell dysfunction in chronic HIV infection. As seen in human infection, both CD4+ and CD8+ T cells demonstrated increased PD-1 expression in HIV-infected BLT mice, and PD-1 levels in these cells correlated positively with viral load and inversely with CD4+ cell levels. The ability of humanized BLT mice to generate both cellular and humoral immune responses to HIV will allow the further investigation of human HIV-specific immune responses in vivo and suggests that these mice are able to provide a platform to assess candidate HIV vaccines and other immunotherapeutic strategies.

A three-item scale for the early prediction of stroke recovery

BACKGROUND Accurate assessment of prognosis in the first hours of stroke is desirable for best patient management. We aimed to assess whether the extent of ischaemic brain injury on magnetic reasonance diffusion-weighted imaging (MR DWI) could provide additional prognostic information to clinical factors. METHODS In a three-phase study we studied 66 patients from a North American teaching hospital who had: MR DWI within 36 h of stroke onset; the National Institutes of Health Stroke Scale (NIHSS) score measured at the time of scanning; and the Barthel Index measured no later than 3 months after stroke. We used logistic regression to derive a predictive model for good recovery. This logistic regression model was applied to an independent series of 63 patients from an Australian teaching hospital, and we then developed a three-item scale for the early prediction of stroke recovery. FINDINGS Combined measurements of the NIHSS score (p=0.01), time in hours from stroke onset to MR DWI (p=0.02), and the volume of ischaemic brain tissue on MR DWI (p=0.04) gave the best prediction of stroke recovery. The model was externally validated on the Australian sample with 0.77 sensitivity and 0.88 specificity. Three likelihood levels for stroke recovery-low (0-2), medium (3-4), and high (5-7)-were identified on the three-item scale. INTERPRETATION The combination of clinical and MR DWI factors provided better prediction of stroke recovery than any factor alone, shortly after admission to hospital. This information was incorporated into a three-item scale for clinical use.

Marked Epitope- and Allele-Specific Differences in Rates of Mutation in Human Immunodeficiency Type 1 (HIV-1) Gag, Pol, and Nef Cytotoxic T-Lymphocyte Epitopes in Acute/Early HIV-1 Infection

ABSTRACT During acute human immunodeficiency virus type 1 (HIV-1) infection, early host cellular immune responses drive viral evolution. The rates and extent of these mutations, however, remain incompletely characterized. In a cohort of 98 individuals newly infected with HIV-1 subtype B, we longitudinally characterized the rates and extent of HLA-mediated escape and reversion in Gag, Pol, and Nef using a rational definition of HLA-attributable mutation based on the analysis of a large independent subtype B data set. We demonstrate rapid and dramatic HIV evolution in response to immune pressures that in general reflect established cytotoxic T-lymphocyte (CTL) response hierarchies in early infection. On a population level, HLA-driven evolution was observed in ∼80% of published CTL epitopes. Five of the 10 most rapidly evolving epitopes were restricted by protective HLA alleles (HLA-B*13/B*51/B*57/B*5801; P = 0.01), supporting the importance of a strong early CTL response in HIV control. Consistent with known fitness costs of escape, B*57-associated mutations in Gag were among the most rapidly reverting positions upon transmission to non-B*57-expressing individuals, whereas many other HLA-associated polymorphisms displayed slow or negligible reversion. Overall, an estimated minimum of 30% of observed substitutions in Gag/Pol and 60% in Nef were attributable to HLA-associated escape and reversion events. Results underscore the dominant role of immune pressures in driving early within-host HIV evolution. Dramatic differences in escape and reversion rates across codons, genes, and HLA restrictions are observed, highlighting the complexity of viral adaptation to the host immune response.

Identification of an Evolutionarily Conserved Transcriptional Signature of CD8 Memory Differentiation That Is Shared by T and B Cells

After Ag encounter, naive lymphocytes differentiate into populations of memory cells that share a common set of functions including faster response to Ag re-exposure and the ability to self-renew. However, memory lymphocytes in different lymphocyte lineages are functionally and phenotypically diverse. It is not known whether discrete populations of T and B cells use similar transcriptional programs during differentiation into the memory state. We used cross-species genomic analysis to examine the pattern of genes up-regulated during the differentiation of naive lymphocytes into memory cells in multiple populations of human CD4, CD8, and B cell lymphocytes as well as two mouse models of memory development. We identified and validated a signature of genes that was up-regulated in memory cells compared with naive cells in both human and mouse CD8 memory differentiation, suggesting marked evolutionary conservation of this transcriptional program. Surprisingly, this conserved CD8 differentiation signature was also up-regulated during memory differentiation in CD4 and B cell lineages. To validate the biologic significance of this signature, we showed that alterations in this signature of genes could distinguish between functional and exhausted CD8 T cells from a mouse model of chronic viral infection. Finally, we generated genome-wide microarray data from tetramer-sorted human T cells and showed profound differences in this differentiation signature between T cells specific for HIV and those specific for influenza. Thus, our data suggest that in addition to lineage-specific differentiation programs, T and B lymphocytes use a common transcriptional program during memory development that is disrupted in chronic viral infection.

The problem with competencies in global health education.

The demand for global health educational opportunities among students and trainees in high-income countries (HICs) has led to a proliferation of available global health programs. In keeping with the drive towards competency-based medical education, many of these programs have been defining their own global health competencies. Developing such competencies presents several unique challenges, including (1) a failure to take sufficient account of local contexts coupled with a lack of inclusiveness in developing these competencies, (2) the disjunction between the learning approaches of “individualism” in HICs and the relative “collectivism” of most host countries, and (3) shortcomings associated with assessing competencies in resource-limited settings. To meet these challenges, the author recommends reenvisioning the approach to competencies in global health using fresh metaphors, innovative modes of assessment, and the creation of more appropriate competency domains.

Global networks, alliances and consortia in global health education-the case for south-to-south partnerships.

As President’s Emergency Plan for AIDS Relief (PEPFAR) delegates its operations on the African continent to local providers, close attention should be given to appropriate capacity building and strengthening of health care systems by nurturing partnerships between institutions on the subcontinent. Health infrastructures originally crafted for treating HIV will also need to be expanded to cope with the coming wave of chronic diseases. Given the alarming discrepancy between the small health workforce and the burden of disease, such workforce capacity will likely only be achievable through sharing partnerships—or “networks, alliances and consortia” as suggested in a recent article in The Lancet (2010). Medical schools, as the training ground of the emerging workforce, will be at the forefront of this change. How global donors allocate funding to emerging medical and nursing schools will be crucial to the ultimate success of a sustainable health workforce development. A 2011 publication identified 168 medical schools in Africa. With scores of new medical schools likely to open in Africa over the next decade (by some estimates, more than 100 schools), the need for sharing of ideas, faculty, and resources will become more pressing. Compatible with current global financial exigencies, donor nations should consider making available smaller grants to complement the current strategy of awarding multimillion dollar funding to a few schools. This is where the Medical Education Partnership Initiative (MEPI) should have a decisive role to play. MEPI was established by PEPFAR in partnership with the National Institutes of Health Fogarty International Center to strengthen health care systems in Africa by training an additional 140,000 new health care workers through

Building learning communities: evolution of the colleges at Vanderbilt University School of Medicine.

133 million in grants to established African schools of medicine and nursing over a 5-year period (2010–2014). The strategy by which MEPI decided to disburse this funding has been perplexing. MEPI funds were largely awarded to just 11 medical schools –mostly well-established schools rather than to new schools. (The University of Botswana was an exception, a new school that did garner MEPI support.) These were competitive awards and a number of variables went into the complex decision-making process. Nonetheless, we believe that a broader distribution of funds to more African medical schools would have been more equitable and ultimately also have achieved a wider range of sustainable goals in terms of health-care strengthening and capacity building. Smaller awards to more medical schools could serve a vital role in developing novel medical school curricula, context-appropriate competencies, and training programs. Such an MEPI funding strategy might also have been better aligned with the proposals of the recent landmark report in The Lancet (2010) by a panel of distinguished global health

Challenges and opportunities for new medical schools in Africa

Learning communities, which are an emerging trend in medical education, create a foundation for professional and academic development through the establishment of longitudinal relationships between students and faculty. In this article, the authors describe the robust learning community system at Vanderbilt University School of Medicine, which encompasses wellness, career planning, professional development, and academics. The Vanderbilt Advisory Colleges Program introduced in 2006 initially focused on two goals: promoting wellness and providing career advising. In the 2011–2012 academic year, the focus of the colleges expanded to incorporate an enhanced level of personal career advising and an academic component. In the four-year College Colloquium course, faculty selected as college mentors teach the medical humanities and lead sessions dedicated to student professional development in the areas of leadership, research, and service-learning. This academic and professional development program builds on the existing strengths of the colleges and has transformed the colleges into learning communities. The authors reflect on lessons learned and discuss future plans. They report that internal data and data from the Association of American Medical Colleges Medical School Graduation Questionnaire support consistently high and increasing satisfaction among Vanderbilt medical students, across the metrics of personal counseling, faculty mentoring, and career planning.