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1.  Associations Between Antiretroviral Use and Subclinical Coronary Atherosclerosis 
AIDS (London, England)  2016;30(16):2477-2486.
HIV infection is associated with increased prevalence of subclinical coronary plaque. The extent to which such plaque reflects effects of HIV infection or effects of long-term antiretroviral (ART) use remains unclear and was the goal of this analysis.
Design and Methods
We compared the prevalence and extent of coronary plaque and stenosis between users of specific ART drugs or drug classes using coronary computed tomography (CT) among HIV-infected men in the Multicenter AIDS Cohort Study. To account for time-dependent confounders, including cardiovascular disease (CVD) risk factors and time-varying reasons for using specific treatments, we conducted fully adjusted logistic and linear models with inverse probability of treatment weighting.
There were 618 men who underwent non-contrast coronary CT; 450 also underwent coronary CT angiography. At the time of scanning 81% had undetectable plasma HIV RNA. In fully adjusted models, cumulative use of zidovudine, abacavir, darunavir and protease inhibitors as a drug class were inconsistently associated with specific forms of plaque presence or extent.
Among virally suppressed HIV-infected men with extensive ART exposure, no consistent associations between use of specific ART drugs and both subclinical coronary plaque presence and extent were apparent. Our findings support the hypothesis that, among virally suppressed persons, type of ART used is not in general a major determinant of subclinical coronary plaque risk.
PMCID: PMC5173385  PMID: 27490639
antiretroviral therapy; HIV; subclinical coronary plaque; atherosclerosis; coronary computed tomography (CT); coronary angiography
2.  Spontaneous Clearance of the Hepatitis C Virus Among Men Who Have Sex With Men 
Among men who have sex with men, the probability of and factors associated with spontaneous hepatitis C virus (HCV) clearance differ between sexually and percutaneously acquired infections. Determining the reasons for these differences could be important for HCV vaccine development.
Background. The probability of spontaneous hepatitis C virus (HCV) clearance ranges from 11% to 49%. Our previous cross-sectional study suggests that mode of acquisition explains some of this heterogeneity. We performed this prospective study to determine factors associated with spontaneous HCV clearance among men who have sex with men (MSM).
Methods. A mixture-cure model was used to evaluate the probability of spontaneous HCV clearance among 101 MSM in the Multicenter AIDS Cohort Study with acute HCV infection between 1984 and 2012.
Results. Spontaneous HCV clearance occurred in 46% of MSM (49% in non-injection drug users [IDUs] and 23% in IDUs). In the multivariable analysis, age <30 years (clearance ratio [CR] = 2.43; 95% confidence interval [CI], 1.53–3.87) and being human immunodeficiency virus (HIV) uninfected (CR = 2.97; 95% CI, 1.98–4.46) were independently associated with spontaneous clearance. Among men aged ≥30 years, being HIV uninfected, not having unprotected anal intercourse, older age, and being on highly active antiretroviral therapy were independently associated with higher clearance. The interferon lambda rs12979860 single nucleotide polymorphism (SNP) was not associated with spontaneous clearance among the 88 MSM who were not active IDUs (CR = 0.74; 95% CI, .46–1.21 for CC vs CT/TT genotype).
Conclusions. The high probability of spontaneous HCV clearance together with the lack of an association between the rs12979860 SNP and spontaneous clearance among MSM who do not use injection drugs suggests that the immune mechanisms involved with a successful response to acute HCV differ by mode of virus acquisition. Understanding potential mechanistic differences could be important for HCV vaccine development.
PMCID: PMC4599393  PMID: 26175521
hepatitis C virus; HIV; IL28B; injection drug use; MSM
3.  Data on serologic inflammatory biomarkers assessed using multiplex assays and host characteristics in the Multicenter AIDS Cohort Study (MACS) 
Data in Brief  2016;9:262-270.
This article contains data on the associations between fixed and modifiable host characteristics and twenty-three biomarkers of inflammation and immune activation measured longitudinally in a cohort of 250 HIV-uninfected men from the Multicenter AIDS Cohort Study (1984–2009) after adjusting for age, study site, and blood draw time of day using generalized gamma regression. This article also presents associations between each biomarker and each host characteristic in a sample restricted to 2001–2009. These data are supplemental to our original research article entitled “Host factors associated with serologic inflammatory markers assessed using multiplex assays” (McKay, S. Heather, Bream, H. Jay, Margolick, B. Joseph, Martínez-Maza, Otoniel, Phair, P. John, Rinaldo, R. Charles, Abraham, G. Alison, L.P. Jacobson, 2016) [1].
PMCID: PMC5024314  PMID: 27668272
4.  Inaccuracy of haemoglobin A1c among HIV-infected men: effects of CD4 cell count, antiretroviral therapies and haematological parameters 
Journal of Antimicrobial Chemotherapy  2014;69(12):3360-3367.
There is limited evidence that among HIV-infected patients haemoglobin A1c (HbA1c) values may not accurately reflect glycaemia. We assessed HbA1c discordance (observed HbA1c − expected HbA1c) and associated factors among HIV-infected participants in the Multicenter AIDS Cohort Study (MACS).
Fasting glucose (FG) and HbA1c were measured at each semi-annual MACS visit since 1999. All HIV-infected and HIV-uninfected men for whom at least one FG and HbA1c pair measurement was available were evaluated. Univariate median regression determined the association between HbA1c and FG by HIV serostatus. The relationship between HbA1c and FG in HIV-uninfected men was used to determine the expected HbA1c. Generalized estimating equations determined factors associated with the Hb1Ac discordance among HIV-infected men. Clinically significant discordance was defined as observed HbA1c − expected HbA1c ≤−0.5%.
Over 13 years, 1500 HIV-uninfected and 1357 HIV-infected men were included, with a median of 11 visits for each participant. At an FG of 125 mg/dL, the median HbA1c among HIV-infected men was 0.21% lower than among HIV-uninfected men and the magnitude of this effect increased with FG >126 mg/dL. Sixty-three percent of HIV-infected men had at least one visit with clinically significant HbA1c discordance, which was independently associated with: low CD4 cell count (<500 cells/mm3); a regimen containing a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor or zidovudine; high mean corpuscular volume; and abnormal corpuscular haemoglobin.
HbA1c underestimates glycaemia in HIV-infected patients and its use in patients with risk factors for HbA1c discordance may lead to under-diagnosis and to under-treatment of established diabetes mellitus.
PMCID: PMC4228777  PMID: 25096078
HbA1c; diabetes; mean corpuscular volume; glycosylated haemoglobin; HIV
5.  Differences in hepatitis C virus (HCV) prevalence and clearance by mode of acquisition among men who have sex with men (MSM) 
Journal of viral hepatitis  2013;21(10):696-705.
To compare the characteristics associated with hepatitis C virus (HCV) antibody (anti-HCV) prevalence and HCV clearance between injection drug using (IDU) and non-IDU men who have sex with men (MSM).
Stored serum and plasma samples were tested for anti-HCV and HCV RNA to determine the HCV status of 6925 MSM at enrollment into the Multicenter AIDS Cohort Study (MACS). Prevalence and clearance ratios (PR and CR) were calculated to determine the characteristics associated with HCV prevalence and clearance. Multivariable analyses were performed using Poisson regression methods with robust variance estimation.
Anti-HCV prevalence was significantly higher among IDU than non-IDU MSM (42.9% vs. 4.0%) while clearance was significantly lower among IDU MSM (11.5% vs. 34.5% among non-IDU MSM). HIV infection, Black race, and older age were independently associated with higher prevalence in both groups while smoking, transfusion history, and syphilis were significantly associated with prevalence only among non-IDU MSM. The rs12979860-C/C genotype was the only characteristic independently associated with HCV clearance in both groups, but the effects of both rs12979860-C/C genotype (CR=4.16 IDUs vs. 1.71 non-IDUs; p=0.03) and HBsAg positivity (CR=5.06 IDUs vs. 1.62 non-IDUs; p=0.03) were significantly larger among IDU MSM. HIV infection was independently associated with lower HCV clearance only among non-IDU MSM (CR=0.59, 95% CI=0.40–0.87).
IDU MSM have higher anti-HCV prevalence and lower HCV clearance than non-IDU MSM. Differences in the factors associated with HCV clearance suggest that the mechanisms driving the response to HCV may differ according to the mode of acquisition.
PMCID: PMC4187219  PMID: 25280229
Hepatitis C; HIV; IFNL4; IL28B; Injection Drug Use; MSM
6.  Long-term predictive value of the Framingham Risk Score for Stroke in HIV-positive vs HIV-negative men 
Neurology  2013;81(24):2094-2102.
To test the predictive accuracy of the Framingham Risk Score for Stroke (FRS-S) in HIV-infected (HIV+) vs HIV-uninfected (HIV−) men.
The Multicenter AIDS Cohort Study (MACS) is an ongoing prospective study of HIV+ and HIV− men who have sex with men (MSM) enrolled in 4 US cities. We ascertained all reported stroke events during a recent 15-year timeframe (July 1, 1996 to June 30, 2011) among 3,945 participants (1,776 HIV+ and 2,169 HIV−). For those with strokes, FRS-S were calculated 10 years before the stroke event and assessed according to HIV status.
A total of 114 stroke events occurred, including 57 HIV+ and 37 HIV− participants with first-ever strokes and 19 fatal strokes. The incidence of first-ever stroke was 1.7/1,000 person-years among HIV− and 3.3/1,000 person-years among HIV+ participants. Among those with strokes, HIV+ participants were younger than HIV− participants (median age 51.3 vs 61.8 years, p < 0.0001). For these men with stroke, the average 10-year risk of stroke was higher for HIV− MSM (6.6% [range 3%–26%] vs 4.9% for HIV+ MSM [range 0%–15%], p < 0.04). Traditional risk factors for stroke were similar among the Framingham cohort and the MACS HIV+ and HIV− participants.
FRS-S prediction was systematically different in HIV+ vs HIV− men with stroke events. The FRS-S underestimates the long-term risk of stroke in HIV+ men.
PMCID: PMC3863354  PMID: 24212385
7.  Cardiovascular Disease in HIV Infection 
Current opinion in HIV and AIDS  2011;6(4):266-271.
Purpose of Review
Highly active antiretroviral therapy (HAART) use has markedly reduced AIDS-related mortality and opportunistic illness. With improved survival, cardiovascular disease (CVD) has emerged as an important non-infectious chronic co-morbidity among antiretroviral (ARV)-treated HIV-infected persons.
Recent Findings
HIV infection can impact CVD and co-morbidiities known to increase CVD risk. Untreated HIV can cause proatherogenic elevations in serum lipids. Chronic HIV viremia results in increases in systemic inflammation, hypercoagulation, and reductions in endovascular reactivity, all of which are at least partially reversible with virally suppressive HAART. Chronic T cell activation can also result in adverse vascular effects. Use of some ARV drugs can impact CVD risk by causing pro-atherogenic serum lipid elevations, induction of insulin resistance, increases in visceral adiposity or subcutaneous fat loss. Abacavir use may increase myocardial infarction risk by reducing vascular reactivity and/or increasing platelet activation. Traditional risk factors such as advancing age, smoking, hyperlipidemia, and hypertension remain important predictors of CVD among HAART-treated HIV-infected persons.
HIV in the HAART era is a chronic manageable condition. CVD is an important cause of morbidity among HIV-infected persons. Untreated HIV can increase CVD risk in several ways and these effects are at least partially reversible with successful treatment. Use of specific ARV’s can adversely impact CVD risk but the multiple long-term benefits of chronic HIV suppression and immune reconstitution achievable with potent HAART outweigh the adverse impact upon CVD risks that they may have. Standard CVD screening and risk-reducing interventions should be routinely undertaken for HIV-infected persons.
PMCID: PMC3501268  PMID: 21546831
Cardiovascular disease in HIV infection; Inflammation; hypercoagulation; vascular functioning; Effects of antiretroviral drugs; Hyperlipidemia
8.  A Frailty-Related Phenotype Before HAART Initiation as an Independent Risk Factor for AIDS or Death After HAART Among HIV-Infected Men 
In the general population, frailty, a late stage of the aging process, predicts mortality. We investigated whether manifesting a previously defined frailty-related phenotype (FRP) before initiating highly active antiretroviral therapy (HAART) affects the likelihood of developing clinical AIDS or mortality after HAART initiation.
Among 596 HIV-infected men in the Multicenter AIDS Cohort Study whose date of HAART initiation was known within ±6 months and who had an assessable FRP status within 3 years before HAART, survival analyses were performed to assess the effect of FRP manifestation on clinical AIDS or death after HAART.
In men free of AIDS before HAART, AIDS or death after HAART occurred in 13/36 (36%) men who exhibited the FRP before HAART but only in 69/436 (16%) men who did not (hazard ratio = 2.6; 95% confidence interval = 1.4–4.6; p < .01). After adjusting for age, ethnicity, education, nadir CD4+ T-cell count, peak HIV viral load, and hemoglobin in the 3 years before HAART, having the FRP at >25% of visits in the 3 years before HAART significantly predicted AIDS or death (adjusted hazard ratio = 3.8; 95% confidence interval = 1.9–7.9; p < .01). Results were unchanged when the analysis was restricted to the 335 AIDS-free men who were HAART responders, to the 124 men who had AIDS at HAART initiation, or to the subsets of men for whom indices of liver and kidney function could be taken into account.
Having a persistent frailty-like phenotype before HAART initiation predicted a worse prognosis after HAART, independent of known risk factors.
PMCID: PMC3156632  PMID: 21719610
HIV; Aging; Frailty; HAART response; Survival analysis
9.  Association between human immunodeficiency virus (HIV) infection and stiffness of the common carotid artery 
Background and purpose
Human immunodeficiency virus (HIV)-infected persons taking highly active antiretroviral therapy (HAART) may have an increased risk for cardiovascular-related events, although the underlying mechanism remains unclear. We tested the hypothesis that carotid arterial stiffness was higher among persons taking HAART compared to HAART-naïve and HIV-uninfected persons.
Between 2004 and 2006, we performed high resolution B-mode ultrasound on 2,789 HIV-infected and HIV-uninfected participants of the Women’s Interagency HIV Study (WIHS; 1865 women) and the Multicenter AIDS Cohort Study (MACS; 924 men) and determined carotid arterial distensibility, a direct measure of carotid arterial stiffness. We used generalized estimating equations to evaluate the association between distensibility and HIV infection, CD4+ cell count, and exposure to HAART adjusted for demographic, behavioral, and clinical characteristics.
In multivariable analysis, distensibility was 4.3% lower (95% confidence interval (CI): -7.4% to -1.1%) among HIV-infected versus uninfected participants. Among HIV-infected participants with fewer than 200 CD4+ cells, distensibility was 10.5% lower (95% CI: -14.5% to -6.2%) than that among HIV-uninfected participants, and this effect did not differ significantly by cohort or race. Concurrent HAART use was independently associated with lower distensibility among MACS participants but not among WIHS participants.
Our finding that advanced HIV-related immunosuppression was associated with increased carotid arterial stiffness independent from the effects of traditional atherosclerosis risk factors suggests that the etiologic mechanism underlying reports of an increased cardiovascular disease risk among HIV-infected individuals might involve HIV-related immunosuppression leading to vascular dysfunction and arterial stiffening.
PMCID: PMC2972735  PMID: 20798374
atherosclerosis; cardiovascular disease; carotid arteries; HIV; epidemiology
10.  In Vitro Susceptibility of Pseudomonas aeruginosa to Carbenicillin and the Combination of Carbenicillin and Gentamicin 
Applied Microbiology  1969;18(3):303-306.
One hundred and eleven strains of Pseudomonas aeruginosa isolated from clinical material were studied for susceptibility to carbenicillin. Of the strains, 80% were inhibited by 125 μg/ml or more. The combination of carbenicillin and gentamicin was shown to have inhibitory and bactericidal synergistic effect on 15 of 16 strains of P. aeruginosa tested. There was poor correlation between the single-disc sensitivity method and the tube dilution method.
PMCID: PMC377973  PMID: 4984762
11.  The Relationship Between Antibody to R7V and Progression of HIV Type 1 Infection 
The presence of antibody to R7V (anti-R7VAb), a seven-amino acid sequence derived from β2-microglobulin incorporated into HIV-1 virions from the surface of infected cells, has been proposed as an early marker of nonprogressive HIV-1 infection. The present study was undertaken because no prospective studies have tested this hypothesis. Stored samples collected prospectively from 361 HIV-1 seroconverting men in the Multicenter AIDS Cohort Study (0.44–1.53 years after seroconversion) were assayed for the presence or absence of anti-R7VAb, using a standardized ELISA. Using Cox proportional hazards models, crude and adjusted relative hazards (RH) were determined for the following outcomes: (a) clinically defined AIDS, (b) clinically defined AIDS or CD4 T cell count of <200 cells/μl, and (c) death. A total of 143 (39.6%) men had early anti-R7VAb and 218 (60.4%) did not; 192 (53.2%) developed AIDS. At the visit tested, men with anti-R7VAb had significantly lower CD4 T cell counts and higher plasma HIV-1 viral loads than those without antibody. After adjustment for CD4 T cell count, HIV-1 viral load, CCR5 polymorphism, and use of combined antiretroviral therapy, the presence of anti-R7VAb was associated with a higher risk of progression for all outcomes, but not significantly so. Absence of anti-R7VAb was significantly associated with expression of HLA-B*5701 and -B*2705, two alleles associated with slower progression of HIV-1 disease. The early presence of anti-R7VAb in HIV-1 seroconverters was not associated with slower progression of HIV-1 disease.
PMCID: PMC2933163  PMID: 20415637
12.  Examination of disease based selection, demographic history and population structure in European Y chromosome haplogroup I 
Journal of human genetics  2010;55(9):613-620.
We attempted to refine the understanding of an association of Y-chromosomal haplogroup I (hg-I) with enhanced AIDS progression that had been previously reported. First, we compared the progression phenotype between hg-I and its phylogenetically closest haplogroup J (hg-J). Then, we took a candidate gene approach resequencing DDX3Y, a crucial autoimmunity gene, in hg-I and other common European Y- chromosome haplogroups looking for functional variants. We extended the genetic analyses to CD24L4 and compared and contrasted the roles of disease based selection, demographic history, and population structure shaping the contemporary genetic landscape of hg-I chromosomes. Our results confirmed and refined the AIDS progression signal to hg-I, though no gene variant was identified that can explain the disease association. Molecular evolutionary and genetic analyses of the examined loci suggested a unique evolutionary history in hg-I, probably shaped by complex interactions of selection, demographic history, and high geographical differentiation leading to the formation of distinct hg-I subhaplogroups that today are associated with HIV/AIDS onset. Clearly, further studies on Y chromosome candidate loci sequencing to discover functional variants and discern the roles of evolutionary factors are warranted.
PMCID: PMC2945452  PMID: 20574427
AIDS progression; CD24L4; DDX3Y; population growth; population structure; selection; Y chromosome
13.  Association of Y chromosome haplogroup I with HIV progression, and HAART outcome 
Human genetics  2009;125(3):281-294.
The host genetic basis of differential outcomes in HIV infection, progression, viral load set point and highly active retroviral therapy (HAART) responses was examined for the common Y haplogroups in European Americans and African Americans. Accelerated progression to acquired immune deficiency syndrome (AIDS) and related death in European Americans among Y chromosome haplogroup I (Y-I) subjects was discovered. Additionally, Y-I haplogroup subjects on HAART took a longer time to HIV-1 viral suppression and were more likely to fail HAART. Both the accelerated progression and longer time to viral suppression results observed in haplogroup Y-I were significant after false-discovery-rate corrections. A higher frequency of AIDS-defining illnesses was also observed in haplogroup Y-I. These effects were independent of the previously identified autosomal AIDS restriction genes. When the Y-I haplogroup subjects were further subdivided into six I subhaplogroups, no one subhaplogroup accounted for the effects on HIV progression, viral load or HAART response. Adjustment of the analyses for population stratification found significant and concordant haplogroup Y-I results. The Y chromosome haplogroup analyses of HIV infection and progression in African Americans were not significant. Our results suggest that one or more loci on the Y chromosome found on haplogroup Y-I have an effect on AIDS progression and treatment responses in European Americans.
PMCID: PMC2885350  PMID: 19169712
14.  Relationship between a frailty-related phenotype and progressive deterioration of the immune system in HIV-infected men 
Immunological similarities have been noted between HIV-infected individuals and older HIV-negative adults. Immunologic alterations with aging have been noted in frailty in older adults, a clinical syndrome of high risk for mortality and other adverse outcomes. Using a frailty-related phenotype (FRP), we investigated in the Multicenter AIDS Cohort Study (MACS) whether progressive deterioration of the immune system among HIV positive individuals independently predicts onset of FRP.
FRP was evaluated semiannually in 1,046 HIV-infected men from 1994–2005. CD4 T-cell count and plasma viral load were evaluated as predictors of FRP by logistic regression (GEE), adjusting for age, ethnicity, educational level, AIDS status, and treatment era (pre-HAART (1994–1995) and HAART (1996–1999 and 2000–2005)).
Adjusted prevalences of FRP remained low for CD4 T-cell counts >400 cells/mm3 and increased exponentially and significantly for lower counts. Results were unaffected by treatment era. After 1996, CD4 cell T-count, but not plasma viral load, was independently associated with FRP.
CD4 T-cell count predicted the development of a frailty-related phenotype among HIV infected men, independent of HAART use. This suggests that compromise of the immune system in HIV-infected individuals contributes to the systemic physiologic dysfunction of frailty.
PMCID: PMC2699396  PMID: 19194312
HIV; aging; frailty; CD4 T-cell count; Highly active antiretroviral therapy; prospective population-based cohort
15.  Detection of HIV-1 p24 Gag in plasma by a nanoparticle-based bio-barcode-amplification method 
Detection of HIV-1 in patients is limited by the sensitivity and selectivity of available tests. The nanotechnology-based bio-barcode-amplification method offers an innovative approach to detect specific HIV-1 antigens from diverse HIV-1 subtypes. We evaluated the efficacy of this protein-detection method in detecting HIV-1 in men enrolled in the Chicago component of the Multicenter AIDS Cohort Study (MACS).
The method relies on magnetic microparticles with antibodies that specifically bind the HIV-1 p24 Gag protein and nanoparticles that are encoded with DNA and antibodies that can sandwich the target protein captured by the microparticle-bound antibodies. The aggregate sandwich structures are magnetically separated from solution, and treated to remove the conjugated barcode DNA. The DNA barcodes (hundreds per target) were identified by a nanoparticle-based detection method that does not rely on PCR.
Of 112 plasma samples from HIV-1-infected subjects, 111 were positive for HIV-1 p24 Gag protein (range: 0.11–71.5 ng/ml of plasma) by the bio-barcode-amplification method. HIV-1 p24 Gag protein was detected in only 23 out of 112 men by the conventional ELISA. A total of 34 uninfected subjects were negative by both tests. Thus, the specificity of the bio-barcode-amplification method was 100% and the sensitivity 99%. The bio-barcode-amplification method detected HIV-1 p24 Gag protein in plasma from all study subjects with less than 200 CD4+ T cells/μl of plasma (100%) and 19 out of 20 (95%) HIV-1-infected men who had less than 50 copies/ml of plasma of HIV-1 RNA. In a separate group of 60 diverse international isolates, representative of clades A, B, C and D and circulating recombinant forms CRF01_AE and CRF02_AG, the bio-barcode-amplification method identified the presence of virus correctly.
The bio-barcode-amplification method was superior to the conventional ELISA assay for the detection of HIV-1 p24 Gag protein in plasma with a breadth of coverage for diverse HIV-1 subtypes. Because the bio-barcode-amplification method does not require enzymatic amplification, this method could be translated into a robust point-of-care test.
PMCID: PMC2821699  PMID: 18510425
bio-barcode-amplification method; HIV-1; major core protein of HIV-1 (p24 Gag)
16.  Emergence and Persistence of CXCR4-Tropic HIV-1 in a Population of Men from the Multicenter AIDS Cohort Study 
The Journal of infectious diseases  2008;198(8):1104-1112.
We examined the emergence of CXCR4 (i.e., X4) tropism in 67 male human immunodeficiency virus type 1 (HIV-1) seroconverters from the Multicenter AIDS Cohort Study (MACS) who were selected to reflect the full spectrum of rates of HIV-1 disease progression. A mean of 10 serial samples per donor were evaluated by a laboratory-validated, commercially available assay to determine phenotypic coreceptor use. A total of 52% of men had dual- or mixed-tropic HIV-1 detected at 1 or more of the time points tested. Use of X4 by HIV-1 was detected more frequently among men who developed AIDS (defined as a CD4+ T cell count of < 200 cells/μL and/or an AIDS-defining illness)≤11 years after seroconversion than among those who did not (P = .005), as well as among men who exhibited a total T cell count decline (i.e., a CD3+ inflection point), compared with those who did not (P = .03). For men in whom both X4 virus and an inflection point were detected, emergence of X4 virus preceded the inflection point by a median of 0.83 years. The median CD4+ T cell count at first detection of X4 viruses before the onset of AIDS was 475 cells/μL. We conclude that HIV-1 variants that used X4 frequently emerged at high CD4+ T cell counts and may contribute to the decrease in T cell numbers during late HIV-1 infection.
PMCID: PMC2753263  PMID: 18783316
17.  Fidelity of SNP Array Genotyping Using Epstein Barr Virus-Transformed B-Lymphocyte Cell Lines: Implications for Genome-Wide Association Studies 
PLoS ONE  2009;4(9):e6915.
As availability of primary cells can be limited for genetic studies of human disease, lymphoblastoid cell lines (LCL) are common sources of genomic DNA. LCL are created in a transformation process that entails in vitro infection of human B-lymphocytes with the Epstein-Barr Virus (EBV).
Methodology/Principal Findings
To test for genotypic errors potentially induced by the Epstein-Barr Virus transformation process, we compared single nucleotide polymorphism (SNP) genotype calls in peripheral blood mononuclear cells (PBMC) and LCL from the same individuals. The average mismatch rate across 19 comparisons was 0.12% for SNPs with a population call rate of at least 95%, and 0.03% at SNPs with a call rate of at least 99%. Mismatch rates were not correlated across genotype subarrays run on all sample pairs.
Genotypic discrepancies found in PBMC and LCL pairs were not significantly different than control pairs, and were not correlated across subarrays. These results suggest that mismatch rates are minimal with stringent quality control, and that most genotypic discrepancies are due to technical artifacts rather than the EBV transformation process. Thus, LCL likely constitute a reliable DNA source for host genotype analysis.
PMCID: PMC2731852  PMID: 19730697
18.  Sexual activity and Kaposi’s sarcoma among HIV-1 and HHV-8 coinfected men 
Annals of epidemiology  2008;18(7):517-521.
There is notable heterogeneity in the progression to Kaposi’s Sarcoma (KS) among men coinfected with HIV-1 and HHV-8; additional determinants of KS likely exist. Here, we explore sexual activity as a proxy for a sexually transmitted determinant beyond HIV-1 and HHV-8.
The association between sexual activity and incident KS was estimated using data from 1,354 HIV-1 and HHV-8 coinfected homosexual men followed for up to 10 years in the Multicenter AIDS Cohort Study.
As expected, white race, low CD4 cell count and acquiring HHV-8 after HIV-1 infection increased, while smoking decreased, the hazard of KS. The unadjusted hazard of KS among those with high sexual activity was 0.68 relative to the hazard of those with low sexual activity (95% confidence interval [CI]: 0.49, 0.93), and was somewhat muted after adjustment for characteristics measured at study entry (i.e. race, smoking, CD4 cell count, infection order, history of sexual activity, and sexually transmitted diseases). However, adjustment for time-varying covariates, particularly CD4 cell count, resulted in a nullification of the association (adjusted hazard ratio = 1.06; 95% CI: 0.77, 1.48).
Once HIV-1 and HHV-8 coinfection is established in homosexual men, progression to KS does not appear to be due to a third pathogen transmitted by sexual activity.
PMCID: PMC2587441  PMID: 18504143
HIV-1; HHV-8; Kaposi’s sarcoma; sexual activity
19.  Cellular Immune Response to Cytomegalovirus Infection After Renal Transplantation 
Infection and Immunity  1978;22(1):176-180.
A prospective study of 15 patients who received renal transplants defined the effect of renal transplantation on the cellular immune response to cytomegalovirus infection. Of 15 patients, 14 developed cytomegalovirus infection, usually in the first 2 months after transplantation, and all infections were accompanied by a normal humoral immune response. After the initiation of immunosuppressive therapy and transplantation, there was a general depression of lymphocyte transformation, as reflected in the response to phytohemagglutinin, accompanied by a specific defect in cellular immunity, as indicated by lymphocyte transformation to cytomegalovirus antigen. Eleven patients had cellular immunity to cytomegalovirus before transplantation, and all of these became negative in the first month after transplantation. In subsequent months, only 6 of the 14 study patients with cytomegalovirus infection developed specific cellular immune responses to cytomegalovirus. This occurred most often in patients who had severe febrile illnesses in association with infection. The specific cellular immune response which developed in the posttransplant period did not persist in three of the patients. This study demonstrates the dissociation of the humoral and cellular immune response to cytomegalovirus infection in renal transplant patients and indicates the importance of the loss of cellular immunity in the appearance of infection. Previously infected patients lost their cell-mediated immunity and had reactivation infections despite the presence of serum antibody.
PMCID: PMC422133  PMID: 215541
20.  Surveillance of Gentamicin-Resistant Gram-Negative Bacilli in a General Hospital 
Aerobic gram-negative bacilli isolated from clinical specimens from 1 January to 31 December 1976 were tested for gentamicin and tobramycin resistance by standardized disk testing. For Pseudomonas isolates, gentamicin resistance was 17.1% and tobramycin resistance was 2.8%. For other gram-negative bacilli, gentamicin resistance was 5.5% and tobramycin resistance was 5.4%. Seventy-four patients from whom gentamicin-resistant organisms were isolated from 1 January to 30 June 1976 were studied prospectively. These patients were elderly, had serious underlying diseases, and had received prior antibiotic therapy. Eleven patients carried gentamicin-resistant organisms at the time of transfer to our hospital from community hospitals or nursing homes. Of the 82 isolates from these 74 patients, 52 were from the urine. Pseudomonas was found most frequently (32 isolates), followed by Klebsiella (15 isolates), Enterobacter (10 isolates), Serratia (10 isolates), and Proteus (9 isolates). Only 3 of 32 Pseudomonas isolates caused symptomatic infection, while 16 of 50 other gram-negative bacilli were responsible for symptomatic infection. Although amikacin was the most active drug against gentamicin-resistant gram-negative bacilli and had not been used in our hospital at the time of this study, 25% of Pseudomonas and 18% of all gram-negative bacilli showed resistance to this aminoglycoside.
PMCID: PMC352363  PMID: 677859
21.  Nosocomial Infection with Gentamicin-Carbenicillin-Resistant Pseudomonas aeruginosa 
Pseudomonas aeruginosa resistant to both gentamicin and carbenicillin was isolated with increasing frequency at the Cincinnati Veterans Administration Hospital during the period 1971 to 1974. A comparison of patients from whom P. aeruginosa was isolated during this period failed to reveal any significant clinical differences between the patients colonized or infected with resistant organisms and those colonized or infected with susceptible organisms. Overt clinical infection attributable to either organism was rare. The antibiotic-resistant organisms were isolated most frequently from urine. Isolation of the antibiotic-resistant organisms was more frequent from patients who had previously received gentamicin.
PMCID: PMC429805  PMID: 825033
22.  Virulence in Rats of Gentamicin-Carbenicillin-Resistant Pseudomonas 
Strains of Pseudomonas aeruginosa, with resistance to gentamicin and carbenicillin which is R factor mediated, showed no alteration in virulence as tested by intraperitoneal injection of rats.
PMCID: PMC429385  PMID: 811161
23.  Evaluation of the Efficacy of Minocycline Therapy for Staphylococcal Soft-Tissue Infection 
Ten patients with soft-tissue infections due to Staphylococcus aureus were treated with minocycline, a semisynthetic tetracycline with potent in vitro antistaphylococcal effects. Serum concentrations averaged three to five times the concentration of minocycline required to inhibit growth of S. aureus in vitro. Clearing of the infecting organism was slow (less than 50% of lesions were sterile on day 10 of therapy), but clinical improvement was noted in 8 of 10 patients.
PMCID: PMC444691  PMID: 15825304
24.  Cell-Mediated Immunity in Humans During Viral Infection: Dermal Hypersensitivity and In Vitro Lymphocyte Proliferation During Mild Viral Respiratory Infections 
Infection and Immunity  1974;10(4):757-761.
In vitro lymphocyte proliferation in response to phytohemagglutinin and streptokinase-streptodornase and delayed dermal hypersensitivity to several antigens were assessed in patients with mild viral upper respiratory infections. The response to phytohemagglutinin in 18 patients was not diminished during the viral infection. Deoxyribonucleic acid synthesis induced by streptokinase-streptodornase remained unaffected by the viral illness in five patients, and skin test reactivity was not depressed during the viral infection. Thus, it appeared that localized viral upper respiratory infections were not associated with suppression of systemic cell-mediated immunity.
PMCID: PMC423018  PMID: 4372179
25.  Cell-Mediated Immunity in Humans During Viral Infection I. Effect of Rubella on Dermal Hypersensitivity, Phytohemagglutinin Response, and T Lymphocyte Numbers 
Infection and Immunity  1974;10(1):212-215.
Phytohemagglutinin-induced lymphocyte deoxyribonucleic acid synthesis, dermal hypersensitivity, and peripheral blood thymus-derived lymphocyte numbers were assessed in nine men with experimentally induced rubella infection. Five of these men and two additional volunteers received treatment with tilorone dihydrochloride, an antiviral drug. Response to phytohemagglutinin was not changed during rubella; T lymphocyte numbers in peripheral blood were not influenced by the viral illness. However, dermal hypersensitivity was markedly impaired in all volunteers during the height of the illness. Tilorone alone, or with rubella, had no effect on any of the parameters studied.
PMCID: PMC414979  PMID: 4546284

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