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1.  Chlamydia trachomatis infection rates among a cohort of mobile soldiers stationed at Fort Bragg, North Carolina, 2005–2010 
BMC Public Health  2014;14:181.
Background
Fort Bragg, a large Army installation with reported high Chlamydia trachomatis (Ct) infection rates, is characterized by a highly mobile population and a surrounding Ct-endemic community. We assessed the rates of Ct incidence and recurrence among the installation’s active component Army personnel and determined the association of soldier transience, sociodemographic factors, and history of sexually transmitted infection (STI) with these rates.
Methods
A cohort of soldiers stationed at Fort Bragg during 2005 to mid-2010 was followed for incident and recurrent Ct infection using laboratory-confirmed reportable disease data. Linkage to demographic and administrative data permitted multivariate analysis to determine association of covariates with initial or recurrent infection.
Results
Among 67,425 soldiers, 2,198 (3.3%) contracted an incident Ct infection (crude incidence, 21.7 per 1,000 person-years). Among soldiers followed for incident infection, 223 (10.6%, crude incidence 110.8 per 1,000 person-years) contracted a recurrent Ct infection. Being female, of lower rank, under 26 years of age, of non-white race, single, or with a high school diploma or less was significantly associated with incident Ct infection. Having breaks in duty or having deployments during follow-up was associated with a lower infection rate. Among women, having prior deployments was associated with a lower rate of both incident and recurrent infection. Specifically associated with recurrent infection in women was age under 21 years or no education beyond high school.
Conclusions
This analysis reaffirms risk factors for Ct infection determined in other studies. In addition, infection risk was lower for more mobile soldiers and tied to the specific location of their regular duty assignment. The findings support the STI prevention efforts at Fort Bragg and the surrounding community, regardless of how often or for how long soldiers have deployed for military operations.
doi:10.1186/1471-2458-14-181
PMCID: PMC3943576  PMID: 24552420
Chlamydia; Army; Mobility
2.  The Canarypox Virus Vector ALVAC Induces Distinct Cytokine Responses Compared to the Vaccinia Virus-Based Vectors MVA and NYVAC in Rhesus Monkeys 
Journal of Virology  2014;88(3):1809-1814.
Despite the growing use of poxvirus vectors as vaccine candidates for multiple pathogens and cancers, their innate stimulatory properties remain poorly characterized. Here we show that the canarypox virus-based vector ALVAC induced distinct systemic proinflammatory and antiviral cytokine and chemokine levels following the vaccination of rhesus monkeys compared to the vaccinia virus-based vectors MVA and NYVAC. These data suggest that there are substantial biological differences among leading poxvirus vaccine vectors that may influence resultant adaptive immune responses following vaccination.
doi:10.1128/JVI.02386-13
PMCID: PMC3911591  PMID: 24257612
3.  Rare serotype adenoviral vectors for HIV vaccine development 
Human adenoviral vectors are being developed for use in candidate vaccines for HIV-1 and other pathogens. However, this approach suffered a setback when an HIV-1 vaccine using an adenovirus type 5 (Ad5) vector failed to reduce, and might even have increased, the rate of HIV infection in men who were uncircumcised and who had preexisting antibodies specific for Ad5. This increased interest in the evaluation of serologically distinct adenoviral vectors. In this issue of the JCI, Frahm and coworkers report evidence that preexisting cellular immune responses directed toward Ad5 reduce the immunogenicity of antigens expressed in Ad5-vectored vaccines and have cross-reacting potential with non-Ad5 adenoviral vectors. The implications of this observation need to be carefully evaluated in future clinical trials of all serotypes of adenovirus-vectored vaccines.
doi:10.1172/JCI60988
PMCID: PMC3248308  PMID: 22201675
4.  The Thai Phase III Trial (RV144) Vaccine Regimen Induces T Cell Responses that Preferentially Target Epitopes within the V2 Region of HIV-1 Envelope 
The Thai HIV phase III prime-boost trial (RV144) using ALVAC-HIV® (vCP1521) and AIDSVAX B/E® was, to our knowledge, the first to demonstrate acquisition efficacy. Vaccine-induced, cell-mediated immune responses were assessed. T cell epitope mapping studies using IFN-γ ELISPOT were performed on PBMC from HIV-1 uninfected vaccine (N=61) and placebo (N=10) recipients using HIV-1 Env peptides. Positive responses were measured in 25 (41%) vaccinees and were predominantly CD4+ T cell mediated. Responses were targeted within the HIV Env region, with 15/25 (60%) of vaccinees recognizing peptides derived from the V2 region of HIV-1 Env, which includes the α4β7 integrin binding site. Intracellular cytokine staining confirmed that Env responses predominated (19/30; 63% of vaccine recipients) and were mediated by polyfunctional effector memory CD4+ T cells, with the majority of responders producing both IL-2 and IFN-γ (12/19; 63%). HIV-Env Ab titers were higher in subjects with IL-2 compared to those without IL-2 secreting HIV-Env specific effector memory T cells. Proliferation assays revealed that HIV Ag-specific T cells were CD4+ with the majority (80%) expressing CD107a. HIV-specific T cell lines obtained from vaccine recipients confirmed V2 specificity, polyfunctionality and functional cytolytic capacity. While the RV144 T cell responses were modest in frequency compared to humoral immune responses, the CD4+ T cell response was directed to HIV-1 Env and more particularly the V2 region.
doi:10.4049/jimmunol.1102756
PMCID: PMC3383859  PMID: 22529301
Human; Vaccination; Viral; AIDS; HIV-1; T cells
5.  Gag-Specific Cellular Immunity Determines In Vitro Viral Inhibition and In Vivo Virologic Control following Simian Immunodeficiency Virus Challenges of Vaccinated Rhesus Monkeys 
Journal of Virology  2012;86(18):9583-9589.
A comprehensive vaccine for human immunodeficiency virus type 1 (HIV-1) would block HIV-1 acquisition as well as durably control viral replication in breakthrough infections. Recent studies have demonstrated that Env is required for a vaccine to protect against acquisition of simian immunodeficiency virus (SIV) in vaccinated rhesus monkeys, but the antigen requirements for virologic control remain unclear. Here, we investigate whether CD8+ T lymphocytes from vaccinated rhesus monkeys mediate viral inhibition in vitro and whether these responses predict virologic control following SIV challenge. We observed that CD8+ lymphocytes from 23 vaccinated rhesus monkeys inhibited replication of SIV in vitro. Moreover, the magnitude of inhibition prior to challenge was inversely correlated with set point SIV plasma viral loads after challenge. In addition, CD8 cell-mediated viral inhibition in vaccinated rhesus monkeys correlated significantly with Gag-specific, but not Pol- or Env-specific, CD4+ and CD8+ T lymphocyte responses. These findings demonstrate that in vitro viral inhibition following vaccination largely reflects Gag-specific cellular immune responses and correlates with in vivo virologic control following infection. These data suggest the importance of including Gag in an HIV-1 vaccine in which virologic control is desired.
doi:10.1128/JVI.00996-12
PMCID: PMC3446565  PMID: 22761379
6.  International Seroepidemiology of Adenovirus Serotypes 5, 26, 35, and 48 in Pediatric and Adult Populations 
Vaccine  2011;29(32):5203-5209.
Recombinant adenovirus serotype 5 (rAd5) vaccine vectors for HIV-1 and other pathogens have been shown to be limited by high titers of Ad5 neutralizing antibodies (NAbs) in the developing world. Alternative serotype rAd vectors have therefore been constructed. Here we report Ad5, Ad26, Ad35, and Ad48 NAb titers in 4,381 individuals from North America, South America, sub-Saharan Africa, and Southeast Asia. As expected, Ad5 NAb titers were both frequent and high magnitude in sub-Saharan Africa and Southeast Asia. In contrast, Ad35 NAb titers proved infrequent and low in all regions studied, and Ad48 NAbs were rare in all regions except East Africa. Ad26 NAbs were moderately common in adults in sub-Saharan Africa and Southeast Asia, but Ad26 NAb titers proved markedly lower than Ad5 NAb titers in all regions, and these relatively low Ad26 NAb titers did not detectably suppress the immunogenicity of 4×1010 vp of a rAd26-Gag/Pol/Env/Nef vaccine in rhesus monkeys. These data inform the clinical development of alternative serotype rAd vaccine vectors in the developing world.
doi:10.1016/j.vaccine.2011.05.025
PMCID: PMC3138857  PMID: 21619905
7.  Risk factors for HIV-1 infection in a longitudinal, prospective cohort of adults from the Mbeya Region, Tanzania 
Background
To control the global HIV epidemic targeted interventions to reduce the incidence of HIV infections are urgently needed until an effective HIV vaccine is available. This study describes HIV-1 incidence and associated risk factors in a general population cohort of adults from Mbeya Region, Tanzania, who participated in a vaccine preparedness study.
Methods
We conducted a closed prospective cohort study with six-monthly follow-up from 2002–2006, enrolling adults from the general population. HIV-1 incidence and risk factors for HIV-1 acquisition were analysed using Cox regression.
Results
We observed 2,578 sero-negative participants for a mean period of 3.06 PY (7,471 PY in total). Overall HIV-1 incidence was 1.35 per 100 PY (95% confidence interval [CI]=1.10-1.64/100 PY). The highest overall HIV-1 incidence was found in females from Itende village (1.55 per 100 PY, 95%CI=0.99-2.30/100 PY), the highest age-specific incidence was observed in semi-urban males aged 30-34 years (2.75 per 100 PY, 95%CI=0.75-7.04). HIV-1 acquisition was independently associated with female gender (hazard ratio [HR]=1.64, 95%CI=1.05-2.57), younger age at enrolment (age 18-19 vs. 35-39: HR=0.29, 95%CI=0.11-0.75), alcohol consumption (almost daily vs. none: HR 2.01, 95%CI=1.00-4.07), education level (secondary school vs. none: HR 0.39, 95%CI=0.17-0.89) and number of lifetime sex partners (more than five vs. one: HR 2.22, 95%CI=1.13-4.36).
Conclusions
A high incidence of HIV was observed in this cohort, and incident infection was strongly associated with young age, alcohol consumption, low school education level and number of sex partners. Targeted interventions are needed to address the elevated risk associated with these factors.
doi:10.1097/QAI.0b013e3182118fa3
PMCID: PMC3139808  PMID: 21297483
HIV-1; incidence; risk factors; cohort study; Tanzania; Africa
8.  Defining epitope coverage requirements for T cell-based HIV vaccines: Theoretical considerations and practical applications 
Background
HIV vaccine development must address the genetic diversity and plasticity of the virus that permits the presentation of diverse genetic forms to the immune system and subsequent escape from immune pressure. Assessment of potential HIV strain coverage by candidate T cell-based vaccines (whether natural sequence or computationally optimized products) is now a critical component in interpreting candidate vaccine suitability.
Methods
We have utilized an N-mer identity algorithm to represent T cell epitopes and explore potential coverage of the global HIV pandemic using natural sequences derived from candidate HIV vaccines. Breadth (the number of T cell epitopes generated) and depth (the variant coverage within a T cell epitope) analyses have been incorporated into the model to explore vaccine coverage requirements in terms of the number of discrete T cell epitopes generated.
Results
We show that when multiple epitope generation by a vaccine product is considered a far more nuanced appraisal of the potential HIV strain coverage of the vaccine product emerges. By considering epitope breadth and depth several important observations were made: (1) epitope breadth requirements to reach particular levels of vaccine coverage, even for natural sequence-based vaccine products is not necessarily an intractable problem for the immune system; (2) increasing the valency (number of T cell epitope variants present) of vaccine products dramatically decreases the epitope requirements to reach particular coverage levels for any epidemic; (3) considering multiple-hit models (more than one exact epitope match with an incoming HIV strain) places a significantly higher requirement upon epitope breadth in order to reach a given level of coverage, to the point where low valency natural sequence based products would not practically be able to generate sufficient epitopes.
Conclusions
When HIV vaccine sequences are compared against datasets of potential incoming viruses important metrics such as the minimum epitope count required to reach a desired level of coverage can be easily calculated. We propose that such analyses can be applied early in the planning stages and during the execution phase of a vaccine trial to explore theoretical and empirical suitability of a vaccine product to a particular epidemic setting.
doi:10.1186/1479-5876-9-212
PMCID: PMC3284408  PMID: 22152192
9.  RecDraw: A Software Package for the Representation of HIV-1 Recombinant Structures 
AIDS Research and Human Retroviruses  2010;26(12):1317-1321.
Abstract
The crucial role of recombination in HIV-1 biology is being increasingly recognized. In vitro studies have shown that up to 30 strand-transfer events may occur per viral replication cycle. Thus, recombination may surpass mutation as a major mechanism driving HIV-1 evolution. Currently, recombinant strains comprise 37% of the full-genome HIV-1 sequence database, including sequences representing 47 Circulating Recombinant Forms (CRFs) and more than 250 different Unique Recombinant Forms (URFs). Mapping of recombination breakpoints helps establish relationships among strains that are related by descent, such as CRF07_BC and CRF08_BC in China, and sheds light on their origin and epidemic spread. Additionally, unrelated recombinants sharing common breakpoints may reflect recombination hotspots within the viral genome. Here we present a software tool, RecDraw, for the graphical representation and efficient comparison of recombinant HIV-1 structures and breakpoints. RecDraw is a platform-flexible, Java stand-alone application available through http://www.hivresearch.org/research.php?ServiceID = 5&SubServiceID = 6.
doi:10.1089/aid.2010.0127
PMCID: PMC3012000  PMID: 20961275
10.  Human Immunodeficiency Virus Type 1 Infection Is Associated with Increased NK Cell Polyfunctionality and Higher Levels of KIR3DL1+ NK Cells in Ugandans Carrying the HLA-B Bw4 Motif ▿  
Journal of Virology  2011;85(10):4802-4811.
Natural killer (NK) cells are important innate effector cells controlled by an array of activating and inhibitory receptors. Some alleles of the inhibitory killer-cell immunoglobulin-like receptor KIR3DL1 in combination with its HLA class I ligand Bw4 have been genetically associated with slower HIV-1 disease progression. Here, we observed that the presence of HLA-B Bw4 was associated with elevated frequencies of KIR3DL1+ CD56dim NK cells in chronically HIV-1-infected individuals from the rural district of Kayunga, Uganda. In contrast, levels of KIR2DL1+ CD56dim NK cells were decreased, and levels of KIR2DL3+ CD56dim NK cells were unchanged in infected subjects carrying their respective HLA-C ligands. Furthermore, the size of the KIR3DL1+ NK cell subset correlated directly with viral load, and this effect occurred only in HLA-B Bw4+ patients, suggesting that these cells expand in response to viral replication but may have relatively poor antiviral capacity. In contrast, no association with viral load was present for KIR2DL1+ and KIR2DL3+ NK cells. Interestingly, chronic HIV-1 infection was associated with an increased polyfunctional response in the NK cell compartment, and, upon further investigation, KIR3DL1+ CD56dim NK cells exhibited a significantly increased functional response in the patients carrying HLA-B Bw4. These results indicate that chronic HIV-1 infection is associated with increased NK cell polyfunctionality and elevated levels of KIR3DL1+ NK cells in Ugandans carrying the HLA-B Bw4 motif.
doi:10.1128/JVI.00111-11
PMCID: PMC3126187  PMID: 21411516
11.  HIV Vaccines - Lessons learned and the way forward 
Current opinion in HIV and AIDS  2010;5(5):428-434.
Purpose of Review
An effective HIV vaccine is a global health priority. We describe lessons learned from four HIV vaccine trials that failed to demonstrate efficacy and one that showed modest protection as a pathway forward.
Recent findings
The Merck Ad5 phase IIb T-cell vaccine failed to show efficacy and might have increased the risk of HIV acquisition in MSM. While VaxGen gp120 alone was not efficacious in groups at high risk for HIV-1 infection, the RV144 ALVAC prime and gp120 boost regimen showed 31% efficacy in low incidence heterosexuals. All trials demonstrated the limitations of available laboratory and animal models to both assess relevant vaccine-induced immune responses and to predict clinical trial outcome. Analysis of innate and adaptive responses induced in RV 144 will guide future trial design.
Summary
Future HIV vaccine trials should define the RV 144 immune responses relevant to protection, improve durability and level of protection, and assess efficacy in diverse risk groups. New strategies examining heterologous vector prime boost, universal inserts, replicating vectors, and novel protein/adjuvant immunogens should be explored to induce both T-cell and antibody responses. HIV vaccine development requires innovative ideas and a sustained long-term commitment of scientists, governments, and the community.
doi:10.1097/COH.0b013e32833d17ac
PMCID: PMC2990218  PMID: 20978385
HIV; vaccine; Thailand; clinical trial; efficacy
12.  Cell Type-Specific Proteasomal Processing of HIV-1 Gag-p24 Results in an Altered Epitope Repertoire▿  
Journal of Virology  2010;85(4):1541-1553.
Proteasomes are critical for the processing of antigens for presentation through the major histocompatibility complex (MHC) class I pathway. HIV-1 Gag protein is a component of several experimental HIV-1 vaccines. Therefore, understanding the processing of HIV-1 Gag protein and the resulting epitope repertoire is essential. Purified proteasomes from mature dendritic cells (DC) and activated CD4+ T cells from the same volunteer were used to cleave full-length Gag-p24 protein, and the resulting peptide fragments were identified by mass spectrometry. Distinct proteasomal degradation patterns and peptide fragments were unique to either mature DC or activated CD4+ T cells. Almost half of the peptides generated were cell type specific. Two additional differences were observed in the peptides identified from the two cell types. These were in the HLA-B35-Px epitope and the HLA-B27-KK10 epitope. These epitopes have been linked to HIV-1 disease progression. Our results suggest that the source of generation of precursor MHC class I epitopes may be a critical factor for the induction of relevant epitope-specific cytotoxic T cells.
doi:10.1128/JVI.01790-10
PMCID: PMC3028885  PMID: 21106750
13.  Distinct Circulating Recombinant HIV-1 Strains Among Injecting Drug Users and Sex Workers in Afghanistan 
Abstract
Little information is available regarding a circulating HIV genotype among high-risk groups in Afghanistan; we describe HIV genotypes among injecting drug users (IDUs) and sex workers (SWs) in four Afghan cities. Participants completed behavioral questionnaires and HIV testing. Western blot–confirmed specimens had peripheral mononuclear blood cells isolated for genotyping. Analysis of recombinants was done by bootscanning and manual sequence alignment. The single SW sample harbored a CRF01_AE strain. Of 10 IDUs available for analysis, all were CRF35_AD and from Hirat. Analyzed subregions (gag p17 and env C1-C5) revealed close homology between the Hirat specimens. Three distinct subclusters comprising two or three strains were identified, whereas two other strains were generally equidistant from previously identified Kabul strains. Results suggest that the nascent HIV epidemic among IDUs in Hirat is largely, if not entirely, subtype CRF35_AD, and the close homology suggests recent infection; harm reduction should be supported to avert further transmission.
doi:10.1089/aid.2009.0226
PMCID: PMC2933162  PMID: 20438383
14.  Host determinants of HIV-1 control in African Americans 
The Journal of infectious diseases  2010;201(8):1141-1149.
We performed a whole-genome association study on HIV-1 viral load setpoint in an African American cohort (n=515), and an intronic SNP in the HLA-B gene showed one of the strongest associations. Using a subset of patients, we show that this SNP reflects the effect of the HLA-B*5703 allele, which shows a genome-wide significant association with HIV-1 VL setpoint (p=5.6×10−10). These analyses therefore confirm a member of the HLA-B*57 group of alleles as the most important common variant influencing viral load variation in African Americans, consistent with what is observed in individuals of European ancestry in which the most important common variant is HLA-B*5701.
doi:10.1086/651382
PMCID: PMC2838940  PMID: 20205591
HIV; viral load setpoint; host genetics; association study; HLA
15.  Immunological and Virological Events in Early HIV Infection Predict Subsequent Rate of Progression 
The Journal of infectious diseases  2010;201(2):272-284.
Background
Variability in HIV disease progression cannot fully be predicted by CD4 T-cell counts or viral load. Because central memory T cells (TCM) play a critical role in the pathogenesis of SIV disease, we hypothesized that quantifying these cells in early HIV-infection could provide prognostic information.
Methods
We measured expression of CD45RO, CCR5, CCR7, CD27, and CD28 to enumerate naïve and memory subsets in samples from recently-infected individuals. We also quantified proliferation, CD127 expression, and cell-associated viral load. Disease progression was compared across subgroups defined by these measurements, using Kaplan-Meier survival curves and multivariate Cox proportional hazards regression.
Results
466 subjects contributed 101 events. The proportion or absolute count of TCM did not correlate with disease progression, defined as the time to AIDS or death. However, significant associations were observed for: proliferation within CD4 or CD8 T cells, loss of naïve or CD127+ CD8 T cells, and CD4 cell-associated proviral load.
Conclusion
Our results demonstrate that the extent of the immunopathogenesis established early in HIV infection predicts the course of future disease. Since antiretroviral drug treatment reverses such defects in part, our study provides mechanistic clues to why early use of antiretrovirals may prove beneficial.
doi:10.1086/649430
PMCID: PMC2939466  PMID: 20001854
Central memory; immune activation; cell associated viral load; disease progression; survival
16.  Quality Monitoring of HIV-1-Infected and Uninfected Peripheral Blood Mononuclear Cell Samples in a Resource-Limited Setting▿  
Human immunodeficiency virus type 1 (HIV-1) vaccine and natural history studies are critically dependent on the ability to isolate, cryopreserve, and thaw peripheral blood mononuclear cell (PBMC) samples with a high level of quality and reproducibility. Here we characterize the yield, viability, phenotype, and function of PBMC from HIV-1-infected and uninfected Ugandans and describe measures to ascertain reproducibility and sample quality at the sites that perform cryopreservation. We have developed a comprehensive internal quality control program to monitor processing, including components of method validation. Quality indicators for real-time performance assessment included the time from venipuncture to cryopreservation, time for PBMC processing, yield of PBMC from whole blood, and viability of the PBMC before cryopreservation. Immune phenotype analysis indicated lowered B-cell frequencies following processing and cryopreservation for both HIV-1-infected and uninfected subjects (P < 0.007), but all other major lymphocyte subsets were unchanged. Long-term cryopreservation did not impact function, as unstimulated specimens exhibited low background and all specimens responded to staphylococcal enterotoxin B (SEB) by gamma interferon and interleukin-2 production, as measured by intracellular cytokine staining. Samples stored for more than 3 years did not decay with regard to yield or viability, regardless of HIV-1 infection status. These results demonstrate that it is possible to achieve the high level of quality necessary for vaccine trials and natural history studies in a resource-limited setting and provide strategies for laboratories to monitor PBMC processing performance.
doi:10.1128/CVI.00492-09
PMCID: PMC2884426  PMID: 20200187
17.  Design and evaluation of multi-gene, multi-clade HIV-1 MVA vaccines 
Vaccine  2009;27(42):5885-5895.
Recombinant modified vaccinia virus Ankara (rMVA) expressing HIV-1 genes are promising vaccine candidates. Toward the goal of conducting clinical trials with one or a cocktail of recombinant viruses, four rMVAs expressing env and gag-pol genes from primary HIV-1 isolates representing predominant subtypes from Kenya, Tanzania, Uganda, and Thailand (A, C, D, and CRF01_AE, respectively) were constructed. Efficient expression, processing, and function of Env and Gag were demonstrated. All inserted genes were shown to be genetically stable after repeated passage in cell culture. Strong HIV-specific cellular and humoral immune responses were elicited in mice immunized with each individual vaccine candidate. The MVA/CMDR vaccine candidate expressing CRF01_AE genes has elicited HIV-specific T-cell responses in two independent Phase I clinical trials. Further testing of the other rMVA is warranted.
doi:10.1016/j.vaccine.2009.07.039
PMCID: PMC2743792  PMID: 19654066
MVA; HIV vaccine; immune response
18.  Impact of pulmonary tuberculosis on survival of HIV-infected adults: a prospective epidemiologic study in Uganda 
AIDS (London, England)  2000;14(9):1219-1228.
Background
Retrospective cohort studies of tuberculosis suggest that active tuberculosis accelerates the progression of HIV infection. The validity of these findings has been questioned because of their retrospective design, diverse study populations, variable compliance with anti-tuberculous therapy and use of anti-retroviral medication. To assess the impact of tuberculosis on survival in HIV infection we performed a prospective study among HIV-infected Ugandan adults with and without tuberculosis.
Methods
In a prospective cohort study, 230 patients with HIV-associated tuberculosis and 442 HIV-infected subjects without tuberculosis were followed for a mean duration of 19 months for survival. To assess changes in viral load over 1 year, 20 pairs of tuberculosis cases and controls were selected and matched according to baseline CD4 lymphocyte count, age, sex and tuberculin skin test status.
Results
During the follow-up period, 63 out of of 230 tuberculosis cases (28%) died compared with 85 out of 442 controls (19%), with a crude risk ratio of 1.4 [95% confidence interval (CI), 1.07–1.87]. Most deaths occurred in patients with CD4 lymphocyte counts < 200 × 106 cells/l at baseline (n = 99) and occurred with similar frequency in the tuberculosis cases (46%) and the controls (44%). When the CD4 lymphocyte count was > 200 × 106 /l, however, the relative risk of death in HIV-associated tuberculosis was 2.1 (95% CI, 1.27–3.62) compared with subjects without tuberculosis. For subjects with a CD4 lymphocyte count > 200 × 106/l, the 1-year survival proportion was slightly lower in the cases than in the controls (0.91 versus 0.96), but by 2 years the survival proportion was significantly lower in the cases than in the controls (0.84 versus 0.91; P < 0.02; log-rank test). For subjects with a CD4 lymphocyte count of 200 × 106 cells/l or fewer, the survival proportion at 1 year for the controls was lower than cases (0.59 versus 0.64), but this difference was not statistically significant (P = 0.53; logrank test). After adjusting for age, sex, tuberculin skin test status, CD4 lymphocyte count, and history of HIV-related infections, the overall relative hazard for death associated with tuberculosis was 1.81 (95% CI, 1.24–2.65). In a nested Cox regression model, the relative hazard for death was 3.0 (95% CI, 1.62–5.63) for subjects with CD4 lymphocyte counts > 200 × 106/l and 1.5 (95% CI, 0.99–2.40) for subjects with a CD4 lymphocyte count of 200 × 106/l or fewer.
Conclusion
The findings from this prospective study indicate that active tuberculosis exerts its greatest effect on survival in the early stages of HIV infection, when there is a reserve capacity of the host immune response. These observations provide a theoretical basis for the treatment of latent tuberculous infection in HIV-infected persons.
PMCID: PMC2869086  PMID: 10894287
HIV-1; tuberculosis; survival; Africa; prospective cohort study
21.  Reference Ranges for the Clinical Laboratory Derived from a Rural Population in Kericho, Kenya 
PLoS ONE  2008;3(10):e3327.
The conduct of Phase I/II HIV vaccine trials internationally necessitates the development of region-specific clinical reference ranges for trial enrolment and participant monitoring. A population based cohort of adults in Kericho, Kenya, a potential vaccine trial site, allowed development of clinical laboratory reference ranges. Lymphocyte immunophenotyping was performed on 1293 HIV seronegative study participants. Hematology and clinical chemistry were performed on up to 1541 cohort enrollees. The ratio of males to females was 1.9∶1. Means, medians and 95% reference ranges were calculated and compared with those from other nations. The median CD4+ T cell count for the group was 810 cells/µl. There were significant gender differences for both red and white blood cell parameters. Kenyan subjects had lower median hemoglobin concentrations (9.5 g/dL; range 6.7–11.1) and neutrophil counts (1850 cells/µl; range 914–4715) compared to North Americans. Kenyan clinical chemistry reference ranges were comparable to those from the USA, with the exception of the upper limits for bilirubin and blood urea nitrogen, which were 2.3-fold higher and 1.5-fold lower, respectively. This study is the first to assess clinical reference ranges for a highland community in Kenya and highlights the need to define clinical laboratory ranges from the national community not only for clinical research but also care and treatment.
doi:10.1371/journal.pone.0003327
PMCID: PMC2553265  PMID: 18833329
22.  Large-Scale Human Immunodeficiency Virus Rapid Test Evaluation in a Low-Prevalence Ugandan Blood Bank Population▿  
Journal of Clinical Microbiology  2007;45(10):3281-3285.
The use of rapid tests for human immunodeficiency virus (HIV) has become standard in HIV testing algorithms employed in resource-limited settings. We report an extensive HIV rapid test validation study conducted among Ugandan blood bank donors at low risk for HIV infection. The operational characteristics of four readily available commercial HIV rapid test kits were first determined with 940 donor samples and were used to select a serial testing algorithm. Uni-Gold Recombigen HIV was used as the screening test, followed by HIV-1/2 STAT-PAK for reactive samples. OraQuick HIV-1 testing was performed if the first two test results were discordant. This algorithm was then tested with 5,252 blood donor samples, and the results were compared to those of enzyme immunoassays (EIAs) and Western blotting. The unadjusted algorithm sensitivity and specificity were 98.6 and 99.9%, respectively. The adjusted sensitivity and specificity were 100 and 99.96%, respectively. This HIV testing algorithm is a suitable alternative to EIAs and Western blotting for Ugandan blood donors.
doi:10.1128/JCM.00894-07
PMCID: PMC2045340  PMID: 17699650
23.  Assessment of the Kinetics of Treponema pallidum Dissemination into Blood and Tissues in Experimental Syphilis by Real-Time Quantitative PCR▿  
Infection and Immunity  2007;75(6):2954-2958.
Little is known about the size and kinetics of treponemal burdens in blood and tissues during acquired or experimental syphilitic infection. We used real-time quantitative PCR to measure Treponema pallidum DNA levels in rabbits infected intratesticularly with the prototype Nichols strain. At the outset, we performed a series of in vitro blood spiking experiments to determine the effect of blood processing procedures on the distribution of treponemes in various blood components. T. pallidum DNA levels in plasma and whole blood were approximately 10-fold higher than those in serum and more than 200-fold greater than those in peripheral blood mononuclear cells (PBMCs). Ten rabbits were inoculated intratesticularly with doses of treponemes ranging from 4 × 107 to 2 × 108 organisms. In five rabbits, T. pallidum DNA levels were measured sequentially in serum, plasma, whole blood, and PBMCs until sacrifice at peak orchitis, at which time brain, kidney, liver, spleen, and testicles were harvested; blood and organs were also harvested at orchitis from the other five rabbits. T. pallidum DNA was detected in plasma within 24 h postinfection. Treponeme levels in whole blood and blood components increased significantly with the development of peak orchitis. Overall, levels in serum and PBMCs were lower than those in plasma and whole blood; this disparity was particularly marked at early time points. Significantly greater numbers of spirochetes were found in the spleen than in liver, kidney, or brain tissue at the time of sacrifice. Our findings highlight the remarkable capacity of T. pallidum to disseminate from the site of infection to blood and tissues, and they identify the spleen as a prime target for treponemal invasion.
doi:10.1128/IAI.00090-07
PMCID: PMC1932886  PMID: 17438037
24.  Sensitivity of the Multispot HIV-1/HIV-2 Rapid Test Using Samples from Human Immunodeficiency Virus Type 1-Positive Individuals with Various Levels of Exposure to Highly Active Antiretroviral Therapy 
Journal of Clinical Microbiology  2006;44(5):1831-1833.
The Multispot HIV-1/HIV-2 rapid test detects human immunodeficiency virus type 1 (HIV-1) gp41 antibodies, which can wane over time in some HIV-1-infected populations, resulting in false-negative screening results. Multispot sensitivity was 100% using 248 sera from one such population, and it correctly identified serostatus in individuals who previously tested false negative with rapid testing.
doi:10.1128/JCM.44.5.1831-1833.2006
PMCID: PMC1479184  PMID: 16672414
25.  Use of Rapid and Conventional Testing Technologies for Human Immunodeficiency Virus Type 1 Serologic Screening in a Rural Kenyan Reference Laboratory 
Journal of Clinical Microbiology  2004;42(8):3850-3852.
We report a prospective comparison of human immunodeficiency virus type 1 testing by enzyme immunoassay and Western blot with four rapid tests of 486 subjects performed in rural Kenya. Rapid test sensitivity was 100%. Specificity ranged from 99.1 to 100%. Combined use of two Food and Drug Administration-approved rapid tests yielded a single false-positive result.
doi:10.1128/JCM.42.8.3850-3852.2004
PMCID: PMC497567  PMID: 15297547

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