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1.  HIV-associated lung cancer: ambiguities and challenges 
AIDS (London, England)  2012;26(8):1031-1033.
PMCID: PMC4243607  PMID: 22552477
HIV; lung cancer; risk
2.  Admixture Analysis of Spontaneous Hepatitis C Virus Clearance in Individuals of African-Descent 
Genes and immunity  2014;15(4):241-246.
Hepatitis C virus (HCV) infects an estimated 3% of the global population with the majority of individuals (75–85%) failing to clear the virus without treatment, leading to chronic liver disease. Individuals of African-descent have lower rates of clearance compared to individuals of European-descent and this is not fully explained by social and environmental factors. This suggests that differences in genetic background may contribute to this difference in clinical outcome following HCV infection. Using 473 individuals and 792,721 SNPs from a genome-wide association study (GWAS), we estimated local African ancestry across the genome. Using admixture mapping and logistic regression we identified two regions of interest associated with spontaneous clearance of HCV (15q24, 20p12). A genome-wide significant variant was identified on chromosome 15 at the imputed SNP, rs55817928 (P=6.18×10−8) between the genes SCAPER and RCN. Each additional copy of the African ancestral C allele is associated with 2.4 times the odds of spontaneous clearance. Conditional analysis using this SNP in the logistic regression model explained one-third of the local ancestry association. Additionally, signals of selection in this area suggest positive selection due to some ancestral pathogen or environmental pressure in African, but not in European populations.
PMCID: PMC4308959  PMID: 24622687
Hepatitis C; Chronic Infection; Admixture; African Ancestry
3.  Human Gut Microbiome and Risk for Colorectal Cancer 
We tested the hypothesis that an altered community of gut microbes is associated with risk of colorectal cancer (CRC) in a study of 47 CRC case subjects and 94 control subjects. 16S rRNA genes in fecal bacterial DNA were amplified by universal primers, sequenced by 454 FLX technology, and aligned for taxonomic classification to microbial genomes using the QIIME pipeline. Taxonomic differences were confirmed with quantitative polymerase chain reaction and adjusted for false discovery rate. All statistical tests were two-sided. From 794217 16S rRNA gene sequences, we found that CRC case subjects had decreased overall microbial community diversity (P = .02). In taxonomy-based analyses, lower relative abundance of Clostridia (68.6% vs 77.8%) and increased carriage of Fusobacterium (multivariable odds ratio [OR] = 4.11; 95% confidence interval [CI] = 1.62 to 10.47) and Porphyromonas (OR = 5.17; 95% CI = 1.75 to 15.25) were found in case subjects compared with control subjects. Because of the potentially modifiable nature of the gut bacteria, our findings may have implications for CRC prevention.
PMCID: PMC3866154  PMID: 24316595
4.  Hepatitis C Viremia and the Risk of Chronic Kidney Disease in HIV-Infected Individuals 
Lucas, Gregory M. | Jing, Yuezhou | Sulkowski, Mark | Abraham, Alison G. | Estrella, Michelle M. | Atta, Mohamed G. | Fine, Derek M. | Klein, Marina B. | Silverberg, Michael J. | Gill, M. John | Moore, Richard D. | Gebo, Kelly A. | Sterling, Timothy R. | Butt, Adeel A. | Kirk, Gregory D. | Benson, Constance A. | Bosch, Ronald J. | Collier, Ann C. | Boswell, Stephen | Grasso, Chris | Mayer, Ken | Hogg, Robert S. | Harrigan, Richard | Montaner, Julio | Cescon, Angela | Brooks, John T. | Buchacz, Kate | Gebo, Kelly A. | Moore, Richard D. | Carey, John T. | Rodriguez, Benigno | Horberg, Michael A. | Silverberg, Michael J. | Horberg, Michael A. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann | Rachlis, Anita R. | Rico, Puerto | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M. John | Deeks, Steven G. | Martin, Jeffrey N. | Patel, Pragna | Brooks, John T. | Saag, Michael S. | Mugavero, Michael J. | Willig, James | Eron, Joseph J. | Napravnik, Sonia | Kitahata, Mari M. | Crane, Heidi M. | Justice, Amy C. | Dubrow, Robert | Fiellin, David | Sterling, Timothy R. | Haas, David | Bebawy, Sally | Turner, Megan | Gange, Stephen J. | Anastos, Kathryn | Moore, Richard D. | Saag, Michael S. | Gange, Stephen J. | Kitahata, Mari M. | McKaig, Rosemary G. | Justice, Amy C. | Freeman, Aimee M. | Moore, Richard D. | Freeman, Aimee M. | Lent, Carol | Kitahata, Mari M. | Van Rompaey, Stephen E. | Crane, Heidi M. | Webster, Eric | Morton, Liz | Simon, Brenda | Gange, Stephen J. | Althoff, Keri N. | Abraham, Alison G. | Lau, Bryan | Zhang, Jinbing | Jing, Jerry | Golub, Elizabeth | Modur, Shari | Hanna, David B. | Rebeiro, Peter | Wong, Cherise | Mendes, Adell
The Journal of Infectious Diseases  2013;208(8):1240-1249.
Background. The role of active hepatitis C virus (HCV) replication in chronic kidney disease (CKD) risk has not been clarified.
Methods. We compared CKD incidence in a large cohort of HIV-infected subjects who were HCV seronegative, HCV viremic (detectable HCV RNA), or HCV aviremic (HCV seropositive, undetectable HCV RNA). Stages 3 and 5 CKD were defined according to standard criteria. Progressive CKD was defined as a sustained 25% glomerular filtration rate (GFR) decrease from baseline to a GFR < 60 mL/min/1.73 m2. We used Cox models to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
Results. A total of 52 602 HCV seronegative, 9508 HCV viremic, and 913 HCV aviremic subjects were included. Compared with HCV seronegative subjects, HCV viremic subjects were at increased risk for stage 3 CKD (adjusted HR 1.36 [95% CI, 1.26, 1.46]), stage 5 CKD (1.95 [1.64, 2.31]), and progressive CKD (1.31 [1.19, 1.44]), while HCV aviremic subjects were also at increased risk for stage 3 CKD (1.19 [0.98, 1.45]), stage 5 CKD (1.69 [1.07, 2.65]), and progressive CKD (1.31 [1.02, 1.68]).
Conclusions. Compared with HIV-infected subjects who were HCV seronegative, both HCV viremic and HCV aviremic individuals were at increased risk for moderate and advanced CKD.
PMCID: PMC3778973  PMID: 23904290
HIV; hepatitis C virus; chronic kidney disease; hepatitis C RNA; cohort study; glomerular filtration rate; injection drug use
5.  Lack of recall response to Tax in ATL and HAM/TSP patients but not in asymptomatic carriers of human T-cell leukemia virus type 1 
Journal of clinical immunology  2013;33(7):1223-1239.
Purpose & methods
The immunopathogenic mechanisms responsible for debilitating neurodegenerative and oncologic diseases associated with human T-cell leukemia virus type 1 (HTLV-1) are not fully understood. In this respect, a patient cohort from HTLV-1 endemic region that included seronegative controls (controls), asymptomatic carriers (ACs), and patients with adult T-cell leukemia (ATL) or HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) was analyzed for CD8+ T cells polyfunctionality in response to the viral antigen Tax.
Compared to ACs, ATL and HAM/TSP patients had lower frequency and polyfunctionality of CTLs in response to Tax suggesting dysfunction of CD8+ T cells in these individuals. As an underlying mechanism, programmed death-1 (PD-1) receptor was found to be highly unregulated in Tax-responsive as well as total CD8+ T cells from ATL and HAM/TSP but not from ACs and directly correlated with the lack of polyfunctionality in these individuals. Further, PD-1 expression showed a direct whereas MIP-1α expression had an indirect correlation with the proviral load providing new insights about the immunopathogenesis of HTLV-associated diseases. Additionally, we identified key cytokine signatures defining the immune activation status of clinical samples by the luminex assay.
Collectively, our findings suggest that reconstitution of fully functional CTLs, stimulation of MIP-1α expression, and/or blockade of the PD-1 pathway are potential approaches for immunotherapy and therapeutic vaccine against HTLV-mediated diseases.
PMCID: PMC3784618  PMID: 23888327
Chronic viral infections; Cytotoxic T cell; CD4+ T cell; CD8+ T cell; Human T-cell leukemia virus type 1; HTLV-associated myelopathy/tropical spastic paraparesis; Tax
6.  An Altered Maturation and Adhesion Phenotype of Dendritic Cells in Diseased Individuals Compared to Asymptomatic Carriers of Human T Cell Leukemia Virus Type 1 
AIDS Research and Human Retroviruses  2013;29(9):1273-1285.
The immunopathogenic mechanisms underlying human T cell leukemia virus type 1 (HTLV-1)-mediated diseases such as adult T cell leukemia (ATL) and HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are not clearly understood. As critical effectors of antiviral immune response, dendritic cells (DCs) are implicated to play an important role in determining the outcome of HTLV-1 infection. However, a complete understanding of their role in any disease pathogenesis requires extensive assessment of the phenotypic and functional state of DCs. To enable this, we developed a polychromatic antibody cocktail comprising key phenotypic and functional markers of DCs and applied it in a patient cohort from the HTLV-1 endemic region, Jamaica, consisted of seronegative controls, asymptomatic carriers (ACs), ATL, and HAM/TSP patients. This ex vivo analyses included two major subsets of blood DCs, myeloid and plasmacytoid (mDCs and pDCs, respectively). The comparative analyses of results demonstrated a decreased pDC frequency in both ATL and HAM/TSP patients as compared to ACs and seronegative controls. Similarly, CD86 expression on both mDCs and pDCs was significantly higher in HAM/TSP (but not ATL) patients compared to ACs. Interestingly, HLA-DR expression was significantly lower on pDCs of patients as compared to carriers; however, for mDCs, only the HAM/TSP group had significantly lower expression of HLA-DR. Unlike HAM/TSP individuals, ATL individuals had higher HLA-ABC expression on mDCs compared to ACs. Finally, both mDCs and pDCs of HAM/TSP patients had significantly higher expression of the programmed death ligand 1 (PD-L1) compared to ACs. Overall, this study suggests that DCs exhibit a differential phenotypic and functional profile between patients (ATL and HAM/TSP) and carriers of HTLV-1 and could provide an important tool for understanding HTLV-1 immunopathogenesis during infection and disease.
PMCID: PMC3749709  PMID: 23750452
7.  Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1 
Nature genetics  2007;39(6):733-740.
Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection.
PMCID: PMC4135476  PMID: 17496894
8.  The microbiota and human health: Beyond exploration 
European journal of clinical investigation  2013;43(7):10.1111/eci.12100.
PMCID: PMC3874368  PMID: 23611431
9.  Assessment of the human fecal microbiota: II. Reproducibility and associations of 16S rRNA pyrosequences 
We conducted a pilot study of reproducibility and associations of microbial diversity and composition in fecal microbial DNA.
Methods and results
Participants (25 men, 26 women, ages 17–65 years) provided questionnaire data and multiple samples of one stool collected with two Polymedco and two Sarstedt devices pre-loaded with RNAlater. 16S rRNA genes in each fecal DNA aliquot were amplified, sequenced (Roche/454 Life Sciences), and assigned to taxa. Devices were compared for ease of use and reproducibility [intraclass correlation coefficient (ICC)] between duplicate aliquots on diversity and taxonomic assignment. Associations were tested by linear regression. Both collection devices were easy to use. Both alpha diversity (Shannon index) and beta diversity (UniFrac) were higher between than within duplicates (P≤10−8) and did not differ significantly by device (P≥0.62). Reproducibility was good (ICC ≥0.77) for alpha diversity and taxonomic assignment to the most abundant phyla, Firmicutes and Bacteroidetes (71.5% and 25.0% of sequences, respectively), but reproducibility was low (ICC≤0.48) for less abundant taxa. Alpha diversity was lower with non-antibiotic prescription medication (P=0.02), younger age (P=0.03) and marginally with higher body mass index (P=0.08).
With sampling from various parts of a stool, both devices provided good reproducibility on overall microbial diversity and classification for the major phyla, but not for minor phyla. Implementation of these methods should provide insights on how broad microbial parameters, but not necessarily rare microbes, affect risk for various conditions.
PMCID: PMC3369017  PMID: 22385292
Microbiome; alpha diversity; beta diversity; bacterial phylogenetics; medications; body mass index
10.  A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A 
Human Molecular Genetics  2013;22(9):1903-1910.
Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions.
Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979–1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity.
A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect.
Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.
PMCID: PMC3613165  PMID: 23372042
11.  Trends and Disparities in Antiretroviral Therapy Initiation and Virologic Suppression Among Newly Treatment-Eligible HIV-Infected Individuals in North America, 2001–2009 
Hanna, David B. | Buchacz, Kate | Gebo, Kelly A. | Hessol, Nancy A. | Horberg, Michael A. | Jacobson, Lisa P. | Kirk, Gregory D. | Kitahata, Mari M. | Korthuis, P. Todd | Moore, Richard D. | Napravnik, Sonia | Patel, Pragna | Silverberg, Michael J. | Sterling, Timothy R. | Willig, James H. | Lau, Bryan | Althoff, Keri N. | Crane, Heidi M. | Collier, Ann C. | Samji, Hasina | Thorne, Jennifer E. | Gill, M. John | Klein, Marina B. | Martin, Jeffrey N. | Rodriguez, Benigno | Rourke, Sean B. | Gange, Stephen J. | Benson, A. | Bosch, Ronald J. | Collier, Ann C. | Boswell, Stephen | Grasso, Chris | Mayer, Ken | Hogg, Robert S. | Harrigan, Richard | Montaner, Julio | Cescon, Angela | Brooks, John T. | Buchacz, Kate | Gebo, Kelly A. | Moore, Richard D. | Rodriguez, Benigno | Horberg, Michael A. | Silverberg, Michael J. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann | Rachlis, Anita R. | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M. John | Deeks, Steven G. | Martin, Jeffrey N. | Saag, Michael S. | Mugavero, Michael J. | Willig, James | Eron, Joseph J. | Napravnik, Sonia | Kitahata, Mari M. | Crane, Heidi M. | Justice, Amy C. | Dubrow, Robert | Fiellin, David | Sterling, Timothy R. | Haas, David | Bebawy, Sally | Turner, Megan | Gange, Stephen J. | Anastos, Kathryn | Moore, Richard D. | Saag, Michael S. | Gange, Stephen J. | Kitahata, Mari M. | McKaig, Rosemary G. | Justice, Amy C. | Freeman, Aimee M. | Moore, Richard D. | Freeman, Aimee M. | Lent, Carol | Platt, Aaron | Kitahata, Mari M. | Van Rompaey, Stephen E. | Crane, Heidi M. | Webster, Eric | Morton, Liz | Simon, Brenda | Gange, Stephen J. | Abraham, Alison G. | Lau, Bryan | Althoff, Keri N. | Zhang, Jinbing | Jing, Jerry | Golub, Elizabeth | Modur, Shari | Hanna, David B. | Rebeiro, Peter | Wong, Cherise | Mendes, Adell
In the last decade, timely initiation of antiretroviral therapy and resulting virologic suppression have greatly improved in North America concurrent with the development of better tolerated and more potent regimens, but significant barriers to treatment uptake remain.
Background. Since the mid-1990s, effective antiretroviral therapy (ART) regimens have improved in potency, tolerability, ease of use, and class diversity. We sought to examine trends in treatment initiation and resulting human immunodeficiency virus (HIV) virologic suppression in North America between 2001 and 2009, and demographic and geographic disparities in these outcomes.
Methods. We analyzed data on HIV-infected individuals newly clinically eligible for ART (ie, first reported CD4+ count <350 cells/µL or AIDS-defining illness, based on treatment guidelines during the study period) from 17 North American AIDS Cohort Collaboration on Research and Design cohorts. Outcomes included timely ART initiation (within 6 months of eligibility) and virologic suppression (≤500 copies/mL, within 1 year). We examined time trends and considered differences by geographic location, age, sex, transmission risk, race/ethnicity, CD4+ count, and viral load, and documented psychosocial barriers to ART initiation, including non–injection drug abuse, alcohol abuse, and mental illness.
Results. Among 10 692 HIV-infected individuals, the cumulative incidence of 6-month ART initiation increased from 51% in 2001 to 72% in 2009 (Ptrend < .001). The cumulative incidence of 1-year virologic suppression increased from 55% to 81%, and among ART initiators, from 84% to 93% (both Ptrend < .001). A greater number of psychosocial barriers were associated with decreased ART initiation, but not virologic suppression once ART was initiated. We found significant heterogeneity by state or province of residence (P < .001).
Conclusions. In the last decade, timely ART initiation and virologic suppression have greatly improved in North America concurrent with the development of better-tolerated and more potent regimens, but significant barriers to treatment uptake remain, both at the individual level and systemwide.
PMCID: PMC3657490  PMID: 23315317
antiretroviral therapy; healthcare disparities; HIV; time factors; viral load
13.  Invasive cervical cancer risk among HIV-infected women: A North American multi-cohort collaboration prospective study 
HIV infection and low CD4+ T-cell count are associated with an increased risk of persistent oncogenic HPV infection – the major risk factor for cervical cancer. Few reported prospective cohort studies have characterized the incidence of invasive cervical cancer (ICC) in HIV-infected women.
Data were obtained from HIV-infected and -uninfected female participants in the NA-ACCORD with no history of ICC at enrollment. Participants were followed from study entry or January, 1996 through ICC, loss-to follow-up or December, 2010. The relationship of HIV infection and CD4+ T-cell count with risk of ICC was assessed using age-adjusted Poisson regression models and standardized incidence ratios (SIR). All cases were confirmed by cancer registry records and/or pathology reports. Cervical cytology screening history was assessed through medical record abstraction.
A total of 13,690 HIV-infected and 12,021 HIV-uninfected women contributed 66,249 and 70,815 person-years (pys) of observation, respectively. Incident ICC was diagnosed in 17 HIV-infected and 4 HIV-uninfected women (incidence rate of 26 and 6 per 100,000 pys, respectively). HIV-infected women with baseline CD4+ T-cells of ≥ 350, 200–349 and <200 cells/uL had a 2.3-times, 3.0-times and 7.7-times increase in ICC incidence, respectively, compared with HIV-uninfected women (Ptrend =0.001). Of the 17 HIV-infected cases, medical records for the 5 years prior to diagnosis showed that 6 had no documented screening, 5 had screening with low grade or normal results, and 6 had high-grade results.
This study found elevated incidence of ICC in HIV-infected compared to -uninfected women, and these rates increased with immunosuppression.
PMCID: PMC3633634  PMID: 23254153
Human papilloma virus; HIV-infection; Invasive Cervical Cancer; Immunosuppression
14.  Feasibility of self-collection of fecal specimens by randomly sampled women for health-related studies of the gut microbiome 
BMC Research Notes  2014;7:204.
The field of microbiome research is growing rapidly. We developed a method for self-collection of fecal specimens that can be used in population-based studies of the gut microbiome. We conducted a pilot study to test the feasibility of our methods among a random sample of healthy, postmenopausal women who are members of Kaiser Permanente Colorado (KPCO). We aimed to collect questionnaire data, fecal and urine specimens from 60 women, aged 55–69, who recently had a normal screening mammogram. We designed the study such that all questionnaire data and specimens could be collected at home.
We mailed an invitation packet, consent form and opt-out postcard to 300 women, then recruited by telephone women who did not opt-out. Verbally consented women were mailed an enrollment package including a risk factor questionnaire, link to an online diet questionnaire, specimen collection kit, and instructions for collecting stool and urine. Specimens were shipped overnight to the biorepository. Of the 300 women mailed an invitation packet, 58 (19%) returned the opt-out postcard. Up to 3 attempts were made to telephone the remaining women, of whom 130 (43%) could not be contacted, 23 (8%) refused, and 12 (4%) were ineligible. Enrollment packages were mailed to 77 women, of whom 59 returned the risk factor questionnaire and specimens. We found no statistically significant differences between enrolled women and those who refused participation or could not be contacted.
We demonstrated that a representative sample of women can be successfully recruited for a gut microbiome study; however, significant personal contact and carefully timed follow-up from the study personnel are required. The methods employed by our study could successfully be applied to analytic studies of a wide range of clinical conditions that have been postulated to be influenced by the gut microbial population.
PMCID: PMC3974920  PMID: 24690120
Study design; Microbiome; Breast cancer
15.  Impact of highly effective antiretroviral therapy on the risk for Hodgkin lymphoma among people with human immunodeficiency virus infection 
Current opinion in oncology  2012;24(5):531-536.
Purpose of review
To estimate the impact of highly effective antiretroviral therapy (ART) on the incidence and prognosis of Hodgkin lymphoma among people with human immunodeficiency virus infection or AIDS (PWHA).
Recent findings
Age-adjusted incidence of Hodgkin lymphoma in PWHA is unchanged and is still five-fold to fifteen-fold higher than in the general population. Aging of the PWHA population with ART may account for increasing numbers of Hodgkin lymphoma cases. CD4 cell count has a complex relationship to Hodgkin lymphoma risk in PWHA. Depending on the time of measurement, Hodgkin lymphoma risk is highest with 50–249 CD4cells/µl, and falling CD4 count on ART may be a harbinger of Hodgkin lymphoma onset. HIV load appears irrelevant to Hodgkin lymphoma. For obscure reasons, Hodgkin lymphoma risk may be elevated soon after starting ART, but the risk is probably modestly reduced with 6 or more months on ART. For PWHA who develop Hodgkin lymphoma, ART and ABVD chemotherapy can be administered safely, with one recent study demonstrating equivalent outcomes for HIV-positive and HIV-negative Hodgkin lymphoma patients.
Vigilance for Hodgkin lymphoma is needed for immune-deficient PWHA, including those on ART. ART with opportunistic infection prophylaxis enables the delivery of effective chemotherapy for Hodgkin lymphoma, leading to a good prognosis.
PMCID: PMC3604881  PMID: 22729154
acquired immunodeficiency syndrome; antiretroviral therapy; cancer chemotherapy; CD4 count; Hodgkin lymphoma; human immunodeficiency virus
16.  LILRB2 Interaction with HLA Class I Correlates with Control of HIV-1 Infection 
PLoS Genetics  2014;10(3):e1004196.
Natural progression of HIV-1 infection depends on genetic variation in the human major histocompatibility complex (MHC) class I locus, and the CD8+ T cell response is thought to be a primary mechanism of this effect. However, polymorphism within the MHC may also alter innate immune activity against human immunodeficiency virus type 1 (HIV-1) by changing interactions of human leukocyte antigen (HLA) class I molecules with leukocyte immunoglobulin-like receptors (LILR), a group of immunoregulatory receptors mainly expressed on myelomonocytic cells including dendritic cells (DCs). We used previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals (N = 5126) to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Our analyses in persons of European descent, the largest ethnic group examined, show that the effect of HLA-B alleles on HIV-1 control correlates with the binding strength between corresponding HLA-B allotypes and LILRB2 (p = 10−2). Moreover, overall binding strength of LILRB2 to classical HLA class I allotypes, defined by the HLA-A/B/C genotypes in each patient, positively associates with viral replication in the absence of therapy in patients of both European (p = 10−11–10−9) and African (p = 10−5–10−3) descent. This effect appears to be driven by variations in LILRB2 binding affinities to HLA-B and is independent of individual class I allelic effects that are not related to the LILRB2 function. Correspondingly, in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs. Thus, we propose an impact of LILRB2 on HIV-1 disease outcomes through altered regulation of DCs by LILRB2-HLA engagement.
Author Summary
Leukocyte immunoglobulin-like receptors B1 and B2 (LILRB1 and LILRB2) bind HLA class I allotypes with variable affinities. Here, we show that the binding strength of LILRB2 to HLA class I positively associates with level of viremia in a large cohort of untreated HIV-1-infected patients. This effect appears to be driven by HLA-B polymorphism and demonstrates independence from class I allelic effects on viral load. Our in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of dendritic cells (DCs). Thus, we propose an impact of LILRB2 on HIV-1 immune control through altered regulation of DCs by LILRB2-HLA engagement.
PMCID: PMC3945438  PMID: 24603468
17.  Proportions of Kaposi Sarcoma, Selected Non-Hodgkin Lymphomas, and Cervical Cancer in the United States Occurring in Persons With AIDS, 1980–2007 
Given the higher risk of AIDS-defining malignancies that include Kaposi sarcoma (KS), certain non-Hodgkin lymphomas (NHLs), and cervical cancer in persons with human immunodeficiency virus (HIV) infection, the HIV epidemic has likely contributed to the overall numbers of these cancers in the United States.
To quantify the proportions of KS, AIDS-defining NHLs, and cervical cancer in the United States that occurred among persons with AIDS from 1980 to 2007.
Design, Setting, and Participants
The HIV/AIDS Cancer Match Study (1980–2007) linked data from 16 US HIV/AIDS and cancer registries to identify cases with and without AIDS for KS, AIDS-defining NHLs (ie, diffuse large B-cell lymphoma [DLBCL], Burkitt lymphoma [BL], and central nervous system [CNS] lymphoma), and cervical cancer. Using linked data, we derived cancer rates for persons with and without AIDS. To estimate national counts, the rates were applied to national AIDS surveillance and US Census data.
Main Outcome Measure
Proportion of AIDS-defining malignancies in the United States occurring in persons with AIDS.
In the United States, an estimated 79.0% (95% confidence interval [CI], 78.6%–79.4%) of 85 922 KS cases, 5.5% (95% CI, 5.3%–5.6%) of 383 095 DLBCL cases, 19.4% (95% CI, 17.8%–21.1%) of 17 780 BL cases, 26.2% (95% CI, 25.2%–27.1%) of 28 259 CNS lymphoma cases, and 0.41% (95% CI, 0.36%–0.46%) of 386 166 cervical cancer cases occurred among persons with AIDS during 1980–2007. The proportion of KS and AIDS-defining NHLs in persons with AIDS peaked in the early 1990s (1990–1995: KS, 89.0% [95%CI, 88.6%–89.3%]; DLBCL, 9.5% [95%CI, 9.2%–9.8%]; BL, 27.4% [95% CI, 25.0%–29.7%]; and CNS lymphoma, 47.2% [95% CI, 45.7%–48.7%]; all P<.001 [compared with 1980–1989]) and then declined (2001–2007: KS, 67.0% [95% CI, 64.5%–69.4%]; DLBCL, 4.3% [95% CI, 3.9%–4.6%]; BL, 20.8% [95% CI, 17.2%–24.3%]; and CNS lymphoma, 12.3% [95% CI, 10.1%–14.4%]; all P<.001 [compared with 1990–1995]). The proportion of cervical cancers in persons with AIDS increased overtime (1980–1989: 0.11% [95% CI, 0.08%–0.13%]; 2001–2007: 0.69% [95% CI, 0.49%–0.89%]; P<.001).
In the United States, the estimated proportions of AIDS-defining malignancies that occurred among persons with AIDS were substantial, particularly for KS and some NHLs. Except for cervical cancer, the proportions of AIDS-defining malignancies occurring among persons with AIDS peaked in the mid-1990s and then declined.
PMCID: PMC3909038  PMID: 21486978
18.  Relationship between Plasmodium falciparum malaria prevalence, genetic diversity and endemic Burkitt lymphoma in Malawi 
Scientific Reports  2014;4:3741.
Endemic Burkitt lymphoma (eBL) has been linked to Plasmodium falciparum (Pf) malaria infection, but the contribution of infection with multiple Pf genotypes is uncertain. We studied 303 eBL (cases) and 274 non eBL-related cancers (controls) in Malawi using a sensitive and specific molecular-barcode array of 24 independently segregating Pf single nucleotide polymorphisms. Cases had a higher Pf malaria prevalence than controls (64.7% versus 45.3%; odds ratio [OR] 2.1, 95% confidence interval (CI): 1.5 to 3.1). Cases and controls were similar in terms of Pf density (4.9 versus 4.5 log copies, p = 0.28) and having ≥3 non-clonal calls (OR 2.7, 95% CI: 0.7-9.9, P = 0.14). However, cases were more likely to have a higher Pf genetic diversity score (153.9 versus 133.1, p = 0.036), which measures a combination of clonal and non-clonal calls, than controls. Further work is needed to evaluate the possible role of Pf genetic diversity in the pathogenesis of endemic BL.
PMCID: PMC3894552  PMID: 24434689
19.  Prevalence of Toscana and Sicilian Phlebovirus Antibodies in Classic Kaposi Sarcoma Case Patients and Control Subjects in Sicily 
The Journal of Infectious Diseases  2011;204(9):1423-1426.
To assess whether arthropod bites promote Kaposi sarcoma (KS), we determined the seroprevalence of Sicilian (SFSV) and Toscana (TOSV) phlebovirus antibodies in 30 patients with classic KS and 100 controls in Sicily. Nine (6.9%) subjects, all controls, were positive for SFSV, whereas 41 (31.5%) were positive for TOSV. Seroprevalence with immunoglobulin (Ig) M or IgG against either virus was significantly higher in controls (43% vs 13.3% in case patients; P < .01). Adjusted for age, IgG seroprevalence was significantly lower in KS patients compared to controls (adjusted odds ratio, 0.22; 95% confidence interval, .07–.72). Low phlebovirus seroprevalence in patients with KS may reflect incapacity to produce robust, persistent antibody responses, and suggests that arthropod bites do not promote KS.
PMCID: PMC3182312  PMID: 21900487
22.  The association between cancer and amyotrophic lateral sclerosis 
Cancer causes & control : CCC  2012;24(1):55-60.
Increasing evidence suggests that some neurodegenerative disorders, such as Parkinson’s disease, are inversely related to cancer. Few epidemiologic studies have examined the relationship between cancer and amyotrophic lateral sclerosis (ALS), another major neurodegenerative disease. This study addresses that gap.
Using data from 16 population-based cancer registries of the Surveillance, Epidemiology, and End Results (SEER) Program of the U.S. National Cancer Institute and death certificates, we followed 2.7 million cancer survivors who were diagnosed between 1973 and 2007, and who survived at least 1 year following cancer diagnosis. The standardized mortality ratio (SMR) of observed to expected ALS deaths in cancer survivors was calculated.
A total of 1,216 ALS deaths were reported among 1 year survivors of cancer over 16.6 million person-years of follow-up. ALS mortality was not significantly associated with the incidence of total cancers [SMR = 1.00 (95 % confidence interval (CI), 0.95–1.06)]. There was, however, a significantly elevated risk of ALS death among survivors of melanoma [SMR = 1.49 (95 % (CI), 1.17–1.85)] and of tongue cancer [SMR = 2.57 (95 % CI, 1.41–4.32)], and a significantly reduced ALS death risk among prostate cancer survivors [SMR = 0.86 (95 % CI, 0.76–0.96)].
Cancer at certain sites may be related to risk of ALS death. Possible biologic factors linking ALS to these cancers are discussed. Future studies should attempt to confirm these associations using incident ALS outcomes. Establishing relationships between cancer and neurodegenerative diseases, such as ALS, opens new opportunities for understanding related pathophysiologic and therapeutic possibilities for these diseases.
PMCID: PMC3529829  PMID: 23090035
Amyotrophic lateral sclerosis; Neoplasms; Melanoma; Tongue neoplasms; Prostatic neoplasms
23.  Closing the Gap: Increases in Life Expectancy among Treated HIV-Positive Individuals in the United States and Canada 
PLoS ONE  2013;8(12):e81355.
Combination antiretroviral therapy (ART) has significantly increased survival among HIV-positive adults in the United States (U.S.) and Canada, but gains in life expectancy for this region have not been well characterized. We aim to estimate temporal changes in life expectancy among HIV-positive adults on ART from 2000–2007 in the U.S. and Canada.
Participants were from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), aged ≥20 years and on ART. Mortality rates were calculated using participants' person-time from January 1, 2000 or ART initiation until death, loss to follow-up, or administrative censoring December 31, 2007. Life expectancy at age 20, defined as the average number of additional years that a person of a specific age will live, provided the current age-specific mortality rates remain constant, was estimated using abridged life tables.
The crude mortality rate was 19.8/1,000 person-years, among 22,937 individuals contributing 82,022 person-years and 1,622 deaths. Life expectancy increased from 36.1 [standard error (SE) 0.5] to 51.4 [SE 0.5] years from 2000–2002 to 2006–2007. Men and women had comparable life expectancies in all periods except the last (2006–2007). Life expectancy was lower for individuals with a history of injection drug use, non-whites, and in patients with baseline CD4 counts <350 cells/mm3.
A 20-year-old HIV-positive adult on ART in the U.S. or Canada is expected to live into their early 70 s, a life expectancy approaching that of the general population. Differences by sex, race, HIV transmission risk group, and CD4 count remain.
PMCID: PMC3867319  PMID: 24367482
24.  Free Light Chains and the Risk of AIDS-Defining Opportunistic Infections in HIV-Infected Individuals 
Circulating κ and λ free light chains are associated with elevated risk of AIDS in human immunodeficiency virus (HIV)–infected individuals. Therefore, polyclonal B-cell dysfunction may play an important role in HIV-related immune suppression and predispose to clinical AIDS events.
Background. The relevance of B-cell dysfunction for progression to AIDS among human immunodeficiency virus (HIV)–infected individuals has not been clearly defined. We evaluated the association between circulating κ and λ free light chains (FLCs), which are markers of B-cell dysfunction, and risk of developing an AIDS-defining opportunistic infection in HIV-infected men.
Methods. The study included 252 case patients with clinical AIDS and 252 HIV-infected controls from the Multicenter Hemophilia Cohort Study I. Case patients were matched to controls on birth date, specimen type, blood sample collection date, and CD4 cell count. Levels of κ and λ FLCs were measured in serum or plasma collected 0–2.5 years before selection. Elevated FLC levels (κ or λ, above the upper limit of normal) were classified as polyclonal (normal κ-λ ratio) or monoclonal (abnormally skewed κ-λ ratio). We used conditional logistic regression to estimate odds ratios (ORs) for AIDS.
Results. FLC levels were higher in case patients than in controls, for κ (median, 4.03 vs 2.98 mg/dL) and λ (3.77 vs 2.42 mg/dL) FLCs. Compared with normal levels, above-normal FLC levels were associated with AIDS (OR, 3.13 [95% confidence interval (CI), 1.78–5.49] for κ and 3.47 [2.31–5.20] for λ FLCs), and the association with AIDS was strengthened with increasing κ and λ FLC levels (P trends < .0001). Polyclonal FLC elevation was associated with a 4-fold increase in the risk of AIDS (OR, 3.85; 95% CI, 1.97–7.54), but monoclonal FLC elevation was not associated with AIDS.
Conclusions. Circulating FLCs are associated with elevated risk of AIDS in HIV-infected individuals. Polyclonal B-cell dysfunction may contribute to HIV-related immune suppression and predispose to clinical AIDS events.
PMCID: PMC3478141  PMID: 22893577

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