Impact of HIV on CD8+ T Cell CD57 Expression Is Distinct from That of CMV and Aging

Background: Chronic antigenic stimulation by cytomegalovirus (CMV) is thought to increase ‘‘immunosenesence’’ of aging, characterized by accumulation of terminally differentiated CD28- CD8+ T cells and increased CD57, a marker of proliferative history. Whether chronic HIV infection causes similar effects is currently unclear. Methods: We compared markers of CD8+ T cell differentiation (e.g., CD28, CD27, CCR7, CD45RA) and CD57 expression on CD28- CD8+ T cells in healthy HIV-uninfected adults with and without CMV infection and in both untreated and antiretroviral therapy (ART)-suppressed HIV-infected adults with asymptomatic CMV infection. Results: Compared to HIV-uninfected adults without CMV (n = 12), those with asymptomatic CMV infection (n = 31) had a higher proportion of CD28-CD8+ T cells expressing CD57 (P = 0.005). Older age was also associated with greater proportions of CD28-CD8+ T cells expressing CD57 (rho: 0.47, P = 0.007). In contrast, untreated HIV-infected CMV+ participants (n = 55) had much lower proportions of CD28- CD8+ cells expressing CD57 than HIV-uninfected CMV+ participants (P,0.0001) and were enriched for less well-differentiated CD28- transitional memory (TTR) CD8+ T cells (P,0.0001). Chronically HIV-infected adults maintaining ART-mediated viral suppression (n = 96) had higher proportions of CD28-CD8+ T cells expressing CD57 than untreated patients (P,0.0001), but continued to have significantly lower levels than HIV-uninfected controls (P = 0.001). Among 45 HIV-infected individuals initiating their first ART regimen, the proportion of CD28-CD8+ T cells expressing CD57 declined (P,0.0001), which correlated with a decline in percent of transitional memory CD8+ T cells, and appeared to be largely explained by a decline in CD28-CD57- CD8+ T cell counts rather than an expansion of CD28-CD57+ CD8+ T cell counts. Conclusions: Unlike CMV and aging, which are associated with terminal differentiation and proliferation of effector memory CD8+ T cells, HIV inhibits this process, expanding less well-differentiated CD28- CD8+ T cells and decreasing the proportion of CD28- CD8+ T cells that express CD57

A Low T Regulatory Cell Response May Contribute to Both Viral Control and Generalized Immune Activation in HIV Controllers

HIV-infected individuals maintaining undetectable viremia in the absence of therapy (HIV controllers) often maintain high HIV-specific T cell responses, which has spurred the development of vaccines eliciting HIV-specific T cell responses. However, controllers also often have abnormally high T cell activation levels, potentially contributing to T cell dysfunction, CD4+ T cell depletion, and non-AIDS morbidity. We hypothesized that a weak T regulatory cell (Treg) response might contribute to the control of viral replication in HIV controllers, but might also contribute to generalized immune activation, contributing to CD4+ T cell loss. To address these hypotheses, we measured frequencies of activated (CD38+ HLA-DR+), regulatory (CD4+CD25+CD127dim), HIV-specific, and CMV-specific T cells among HIV controllers and 3 control populations: HIV-infected individuals with treatment-mediated viral suppression (ART-suppressed), untreated HIV-infected “non-controllers” with high levels of viremia, and HIV-uninfected individuals. Despite abnormally high T cell activation levels, controllers had lower Treg frequencies than HIV-uninfected controls (P = 0.014). Supporting the propensity for an unusually low Treg response to viral infection in HIV controllers, we observed unusually high CMV-specific CD4+ T cell frequencies and a strong correlation between HIV-specific CD4+ T cell responses and generalized CD8+ T cell activation levels in HIV controllers (P≤0.001). These data support a model in which low frequencies of Tregs in HIV controllers may contribute to an effective adaptive immune response, but may also contribute to generalized immune activation, potentially contributing to CD4 depletion

CD56negCD16+NK cells are activated mature NK cells with impaired effector function during HIV-1 infection

BACKGROUND: A subset of CD3(neg)CD56(neg)CD16(+) Natural Killer (NK) cells is highly expanded during chronic HIV-1 infection. The role of this subset in HIV-1 pathogenesis remains unclear. The lack of NK cell lineage-specific markers has complicated the study of minor NK cell subpopulations. RESULTS: Using CD7 as an additional NK cell marker, we found that CD3(neg)CD56(neg)CD16(+) cells are a heterogeneous population comprised of CD7(+) NK cells and CD7(neg) non-classical myeloid cells. CD7(+)CD56(neg)CD16(+) NK cells are significantly expanded in HIV-1 infection. CD7(+)CD56(neg)CD16(+) NK cells are mature and express KIRs, the C-type lectin-like receptors NKG2A and NKG2C, and natural cytotoxicity receptors similar to CD7(+)CD56(+)CD16(+) NK cells. CD7(+)CD56(neg) NK cells in healthy donors produced minimal IFNγ following K562 target cell or IL-12 plus IL-18 stimulation; however, they degranulated in response to K562 stimulation similar to CD7(+)CD56(+) NK cells. HIV-1 infection resulted in reduced IFNγ secretion following K562 or cytokine stimulation by both NK cell subsets compared to healthy donors. Decreased granzyme B and perforin expression and increased expression of CD107a in the absence of stimulation, particularly in HIV-1-infected subjects, suggest that CD7(+)CD56(neg)CD16(+) NK cells may have recently engaged target cells. Furthermore, CD7(+)CD56(neg)CD16(+) NK cells have significantly increased expression of CD95, a marker of NK cell activation. CONCLUSIONS: Taken together, CD7(+)CD56(neg)CD16(+) NK cells are activated, mature NK cells that may have recently engaged target cells

Does Educator Training or Experience Affect the Quality of Multiple-Choice Questions?

© 2015 AUR. Rationale and Objectives: Physicians receive little training on proper multiple-choice question (MCQ) writing methods. Well-constructed MCQs follow rules, which ensure that a question tests what it is intended to test. Questions that break these are described as "flawed." We examined whether the prevalence of flawed questions differed significantly between those with or without prior training in question writing and between those with different levels of educator experience. Materials and Methods: We assessed 200 unedited MCQs from a question bank for our senior medical student radiology elective: an equal number of questions (50) were written by faculty with previous training in MCQ writing, other faculty, residents, and medical students. Questions were scored independently by two readers for the presence of 11 distinct flaws described in the literature. Results: Questions written by faculty with MCQ writing training had significantly fewer errors: mean 0.4 errors per question compared to a mean of 1.5-1.7 errors per question for the other groups (P < .001). There were no significant differences in the total number of errors between the untrained faculty, residents, and students (P values .35-.91). Among trained faculty 17/50 questions (34%) were flawed, whereas other faculty wrote 38/50 (76%) flawed questions, residents 37/50 (74%), and students 44/50 (88%). Trained question writers' higher performance was mainly manifest in the reduced frequency of five specific errors. Conclusions: Faculty with training in effective MCQ writing made fewer errors in MCQ construction. Educator experience alone had no effect on the frequency of flaws; faculty without dedicated training, residents, and students performed similarly

Radiology primer: A novel radiology course for undecided medical students

© 2014 American College of Radiology. We developed a new careerdecision-focused course that is novel in several ways: The objectives and activities were focused solely on providing information about the training of and careers of radiologists. As such, it included unique teaching experiences that we intentionally do not include in our general radiology elective for future ordering providers. Our rationale behind these choices is highlighted in Table 3. It was scheduled early in the clinical years (ie, the middle of the third year). Overall, the students were very satisfied with their experience in the Radiology Primer course and felt that they obtained sufficient information to make a career decision. Although we do not expect all institutions to have exactly the same curricular structure or timing flexibility to address these problems in an identical manner, these challenges are common, and a range of similar solutions may be used at various institutions

Does Educator Training or Experience Affect the Quality of Multiple-Choice Questions?

© 2015 AUR. Rationale and Objectives: Physicians receive little training on proper multiple-choice question (MCQ) writing methods. Well-constructed MCQs follow rules, which ensure that a question tests what it is intended to test. Questions that break these are described as "flawed." We examined whether the prevalence of flawed questions differed significantly between those with or without prior training in question writing and between those with different levels of educator experience. Materials and Methods: We assessed 200 unedited MCQs from a question bank for our senior medical student radiology elective: an equal number of questions (50) were written by faculty with previous training in MCQ writing, other faculty, residents, and medical students. Questions were scored independently by two readers for the presence of 11 distinct flaws described in the literature. Results: Questions written by faculty with MCQ writing training had significantly fewer errors: mean 0.4 errors per question compared to a mean of 1.5-1.7 errors per question for the other groups (P < .001). There were no significant differences in the total number of errors between the untrained faculty, residents, and students (P values .35-.91). Among trained faculty 17/50 questions (34%) were flawed, whereas other faculty wrote 38/50 (76%) flawed questions, residents 37/50 (74%), and students 44/50 (88%). Trained question writers' higher performance was mainly manifest in the reduced frequency of five specific errors. Conclusions: Faculty with training in effective MCQ writing made fewer errors in MCQ construction. Educator experience alone had no effect on the frequency of flaws; faculty without dedicated training, residents, and students performed similarly