Publications - Infectious Diseases

Increased mortality among publicly insured participants in the HIV Outpatient Study despite HAART treatment.

Sat, 24 Sep 2011 05:00:00 GMT

Increased mortality among publicly insured participants in the HIV Outpatient Study despite HAART treatment. Palella, FJ Jr; Baker, RK; Buchacz, K; Chmiel, JS; Tedaldi, EM; Novak, RM; Durham, MD; Brooks, JT Objective: Understanding mortality differences among HIV-infected patients can focus efforts to improve survival. Design: We evaluated death rates, causes and associated factors among treated patients in the HOPS, a large, prospective, multicenter observational cohort of HIV-infected persons seen at diverse U.S. sites of care. Methods: Among 3754 HOPS participants seen during 1996-2007 with > 6 months of follow-up after initiating HAART and ≥ 75% of time under observation receiving HAART (“substantially treated”), we calculated hazard ratios for death using proportional hazards regression models, death causes and comorbidities. Results: Substantially treated participants, followed a median 4.7 years (IQR, 2.2-8.5), experienced 331 deaths. In multivariable analyses, higher mortality was associated with index CD4 < 200 counts/mm3 (adjusted hazard ratio [aHR], 2.86; 95% CI, 1.95-4.21), older age (aHR, 1.50 per 10 years; 95% CI, 1.33-1.70), log10HIV RNA (aHR, 1.67 per log10; 95% CI, 1.51-1.85), but not race/ethnicity (aHR, 0.99 for blacks vs whites, p=0.92). Mortality was increased among publicly insured (PUB) vs privately insured participants (PRV ) when index CD4 >200 (aHR, 2.03; 95% CI, 1.32-3.14) but not when index CD4 < 200 cells/mm3 (aHR, 1.3, p=0.13). By death cause, PUB had significantly more cardiovascular events and hepatic disorders than PRV. Comorbidities more frequent among PUB vs PRV decedents included cardiovascular disease, renal impairment and chronic hepatitis. Conclusions: Among HAART treated participants with CD4 ≥ 200 cells/mm3, PUB experienced higher death rates than PRV. Non-AIDS death and disease causes predominated among publicly insured decedents, suggesting that treatable comorbidities contributed to survival disparities. Post print version of article may differ from published version. The definitive version is available through Lippincott, Williams & Wilkins at DOI:10.1097/QAD.0b013e32834b3537

A Novel Specificity Protein 1 (SP1)-like Gene Regulating Protein Kinase C-1 (Pkc1)-dependent Cell Wall Integrity and Virulence Factors in Cryptococcus neoformans

Wed, 01 Jun 2011 05:00:00 GMT

A Novel Specificity Protein 1 (SP1)-like Gene Regulating Protein Kinase C-1 (Pkc1)-dependent Cell Wall Integrity and Virulence Factors in Cryptococcus neoformans Adler, Amos; Park, Yoon-Dong; Larsen, Peter; Nagarajan, Vijayaraj; Wollenberg, Kurt; Qiu, Jin; Myers, Timothy G.; Williamson, Peter R. Eukaryotic cells utilize complex signaling systems to detect their environments, responding and adapting as new conditions arise during evolution. The basidiomycete fungus Cryptococcus neoformans is a leading cause of AIDS-related death worldwide and utilizes the calcineurin and protein kinase C-1 (Pkc1) signaling pathways for host adaptation and expression of virulence. In the present studies, a C-terminal zinc finger transcription factor, homologous to both the calcineurin responsive zinc fingers (Crz1) of ascomycetes and to the Pkc1 dependent specificity protein-1 (Sp1) transcription factors of metazoans, was identified and named SP1 because of its greater similarity to the metazoan factors. Structurally, the Cn Sp1 protein was found to have acquired an additional Zn finger motif from that of Crz1 and showed Pkc1 dependent phosphorylation, nuclear localization and whole genome epistatic associations under starvation conditions. Transcriptional targets of Cn Sp1 shared functional similarities with Crz1 factors such as cell wall synthesis, but gained the regulation of processes involved in carbohydrate metabolism including trehalose metabolism and lost others such as the induction of autophagy. In addition, overexpression of Cn Sp1 in a pkc1Δ mutant showed restoration of altered phenotypes involved in virulence including cell wall stability, nitrosative stress and extracellular capsule production. Cn Sp1 was also found to be important for virulence of the fungus using a mouse model. In summary, these data suggest an evolutionary shift in C-terminal Zn finger proteins during fungal evolution, transforming them from calcineurin-dependent to PKC1- dependent transcription factors, helping to shape the role of fungal pathogenesis of Cryptococcus neoformans. This research was originally published in Journal of Biological Chemistry. Amos Adler, Yoon-Dong Park, Peter Larsen, Vijayaraj Nagarajan5, Kurt Wollenberg, Jin Qiu, Timothy G. Myers and Peter R. Williamson. A Novel Specificity Protein 1 (SP1)-like Gene Regulating Protein Kinase C-1 (Pkc1)-dependent Cell Wall Integrity and Virulence Factors in Cryptococcus neoformans. Journal of Biological Chemistry. 2011. 286:20977-20990. © the American Society for Biochemistry and Molecular Biology doi: 10.1074/jbc.M111.230268

Beneficial Effects of a Switch to a Lopinavir/ritonavir-Containing Regimen for Patients with Partial or No Immune Reconstitution with Highly Active Antiretroviral Therapy Despite Complete Viral Suppression

Wed, 01 Jun 2011 05:00:00 GMT

Beneficial Effects of a Switch to a Lopinavir/ritonavir-Containing Regimen for Patients with Partial or No Immune Reconstitution with Highly Active Antiretroviral Therapy Despite Complete Viral Suppression Pitrak, D.L.; Estes, R.; Novak, R.M.; Linnares-Diaz, M.; Tschampa, J.M. The purpose of this study was to determine if switching to an Lopinavir/ritonavir (LPV/r)-containing regimen resulted in greater immune reconstitution in patients with immunologic failure despite complete viral suppression with highly active antiretroviral therapy (HAART). Twenty patients with partial or no immune response to HAART despite viral suppression were enrolled. Ten were randomized to stay on their current regimen and 10 were randomized to LPV/r plus their current NRTI backbone. T cell subsets, ex vivo apoptosis, and the percent of circulating cells with detectable intracellular HIV-1 RNA were measured. The mean increase in CD4+ count at 6 months was 116/mm3 (172–288) for the LPV/r-containing arm versus 32/mm3 (264–296) for continuation regimens ( p=0.03). The number of patients with an increase ≥50 cells/mm3 was also greater in the LPV/r arm (7/9 versus 2/10, p¼0.01). This paralleled a decrease in ex vivo apoptosis of naive CD4þ T cells at 6 months (21.7–11.0% for the LPV/r arm versus 17.3–18.9% for the continuation arm, p=0.04) and memory cells (21.1–14.1% for LPV/r versus 20.2–17.9% for continuation arm, NSS). Switching patients to an LPV/r-containing regimen improved CD4+ counts in patients with prior immunologic failure, and this may be due to an effect of LPV/r on apoptosis. This is a copy of an article published in Aids Research and Human Retroviruses © 2011 [copyright Mary Ann Liebert, Inc.]; Aids Research and Human Retroviruses is available online at: http://www.liebertonline.com.