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1.  Exercise Training Reduces Central Adiposity and Improves Metabolic Indices in HAART-Treated HIV-Positive Subjects in Rwanda: A Randomized Controlled Trial 
As HAART becomes more accessible in sub-Saharan Africa, metabolic syndromes, body fat redistribution (BFR), and cardiovascular disease may become more prevalent. We conducted a 6-month, randomized controlled trial to test whether cardiorespiratory exercise training (CET), improves metabolic, body composition and cardiorespiratory fitness parameters in HAART-treated HIV+ African subjects with BFR. Six months of CET reduced waist circumference (−7.13 ± 4.4 cm, p < 0.0001), WHR (−0.10 ± 0.1, p < 0.0001), sum skinfold thickness (−6.15 ± 8.2 mm, p < 0.0001) and % body fat mass (−1.5 ± 3.3, p < 0.0001) in HIV+BFR+EXS. Hip circumference was unchanged in non-exercise control groups. CET reduced fasting total cholesterol (−0.03 ± 1.11 mM, p < 0.05), triglycerides (−0.22 ± 0.48 mM, p < 0.05) and glucose levels (−0.21 ± 0.71 mM, p < 0.05) (p < 0.0001). HDL-, LDL-cholesterol and HOMA values were unchanged after CET. Interestingly, HIV+ subjects randomized to non-exercising groups experienced increases in fasting plasma glucose levels, whereas HIV seronegative controls did not (p < 0.001). Predicted VO2 peak increased more in the HIV+BFR+EXS than in all other groups (4.7 ± 3.9 ml/kg/min, p < 0.0001). Exercise training positively modulated body composition and metabolic profiles, and improved cardiorespiratory fitness in HAART-treated HIV+ Africans. These beneficial adaptations imply that exercise training is a safe, inexpensive, practical, and effective treatment for evolving metabolic and cardiovascular syndromes associated with HIV and HAART exposure in resource-limited sub-Saharan countries, where treatment is improving, morbidity and mortality rates are declining, but where minimal resources are available to manage HIV- and HAART-associated cardiovascular and metabolic syndromes.
doi:10.1089/aid.2007.0023
PMCID: PMC3936606  PMID: 18275343
2.  Inappropriately low glycated hemoglobin values and hemolysis in HIV-infected patients 
AIDS Research and Human Retroviruses  2006;22(12):1242-1247.
In order to test the accuracy of glycated hemoglobin (HbA1c) to predict mean glycemia in HIV-infected patients, we recorded consecutive HbA1c measurements from 1238 non-HIV-infected and 112 HIV-infected patients, all devoid of any hemoglobinopathy, in a retrospective, transversal study. Mean fasting glycemia from the six previous weeks (Measured-Gly) and HbA1c-estimated glycemia [HbA1c-Gly, (1.85 x %HbA1c – 4.78) mM] were compared. Mean hemoglobin, red cell volume, serum creatinine, CD4 count, and HIV-viral load from the same period were collected in HIV-infected patients. Although Measured-Gly was not significantly different between non-HIV-infected (6.95 ± 3.23 mM) and HIV-infected patients (6.62 ± 2.42 mM), HbA1c underestimated the mean fasting glycemia by 12.3% in HIV-infected as compared to non-HIV-infected patients (p<0.0001). The difference “Measured-Gly - HbA1c-Gly” was correlated with the red cell volume (p=0.0001) in HIV-infected patients. We then searched for the presence of sub-clinical hemolysis, a cause of both macrocytosis and reduced HbA1c levels, in HIV-infected patients. To this end, we prospectively measured serum haptoglobin in 249 consecutive samples from HIV-infected subjects without any known cause of hemolysis. A very low haptoglobin level, a marker of hemolysis, was frequent and negatively correlated with the red cell volume in these patients. Treatment with nucleoside analogueswas significantly associated with macrocytosis and low haptoglobin. In conclusion, HbA1c could be inappropriately low in HIV-infected patients. Its underestimation of mean fasting glycemia could be due to an antiretroviral-induced sub-clinical hemolysis, but further studies are needed to explore this hypothesis. Self-monitoring of blood glucose should be promoted in diabetic HIV-infected patients.
doi:10.1089/aid.2006.22.1242
PMCID: PMC3893615  PMID: 17209766
Adult; Anti-Retroviral Agents; adverse effects; Blood Glucose; analysis; metabolism; Female; HIV Infections; blood; drug therapy; metabolism; Haptoglobins; analysis; Hemoglobin A, Glycosylated; analysis; metabolism; Hemolysis; drug effects; physiology; Humans; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Retrospective Studies
3.  Does Viral Tropism Play a Role in Heterosexual Transmission of HIV? Findings in the SIV–Rhesus Macaque Model 
AIDS Research and Human Retroviruses  1998;14(Suppl 1):S79-S82.
Substantial effort is being directed toward generating vaccines that can prevent the heterosexual transmission of HIV-1. If “Selection” for specific variants during sexual intercourse occurs, then vaccines should be designed to prevent transmission of these specific viruses. Using the SIV–rhesus macaque model to test the hypothesis that specific HIV genotypes are more efficient at producing infection by sexual transmission, it was possible to demonstrate that the genotypic determinants that permit SIV or SHIV to produce systemic infection differ depending on the route of virus inoculation. This finding supports the conclusion that there is selection for viral genotypes during sexual transmission of HIV. However, the ability of a virus to grow in rhesus macaque monocyte-derived macrophages in vitro does not predict the outcome of intravaginal inoculation with that virus. We did find that after intravenous inoculation all the vaginally transmitting viruses produced plasma antigenemia and high levels of plasma viral RNA. In contrast, although the nontransmitting viruses infect rhesus macaques after intravenous inoculation, the infection that occurs after intravenous inoculation is characterized by a lack of viral antigen in plasma and low levels of plasma viral RNA. On the basis of these results, it is clear that viruses which are adapted to replicate to high levels in vivo are transmitted by vaginal inoculation. This principle may also apply to the transmission of HIV in humans.
PMCID: PMC3401011  PMID: 9581889
4.  Titration of an SIVmac251 Stock by Vaginal Inoculation of Indian and Chinese Origin Rhesus Macaques: Transmission Efficiency, Viral Loads, and Antibody Responses 
AIDS Research and Human Retroviruses  2001;17(15):1455-1466.
The purpose of this study was to determine whether rhesus monkeys of Chinese origin are suitable for studies of mucosal lentivirus transmission by comparing the relative ability of these animals and rhesus macaques of Indian origin to become infected by vaginal (IVAG) inoculation with SIVmac251. In addition, we sought to test the hypothesis that differences in viral load during the first few weeks after inoculation were due to the relative strength of the anti-SIV immune responses in the two populations of rhesus macaques. Significant difference was not observed between the number of Indian and Chinese origin monkeys that were infected after IVAG SIV inoculation in this study. For 8–9 weeks after infection there was considerable overlap in the range of viral loads among the Indian and Chinese animals and the variation among the Indian origin animals was greater than the variation among the Chinese origin monkeys. By 6 weeks postinfection, viral loads in SIV-infected Chinese origin monkeys tended to be at the lower end of the range of viral loads observed in SIV-infected Indian origin monkeys. The strength of the anti-SIV antibody response was also more variable in the Indian origin rhesus macaques, but at 6–8 weeks postinfection, Chinese and Indian origin rhesus macaques had similar titers of anti-SIV antibodies. Microsatellite allele frequencies differed between Chinese and Indian rhesus macaques; however, the majority of alleles present in Indian-origin animals were also found in Chinese macaques. Together these results show that host factors, other than geographic origin, determine the ability of a rhesus macaque to be infected after IVAG SIV exposure and that geographic origin does not predict the viral load of SIV-infected animals during the first 8–9 weeks after IVAG inoculation.
doi:10.1089/088922201753197123
PMCID: PMC3401017  PMID: 11679158
5.  Pediatric HIV Type 1 Vaccine Trial Acceptability among Mothers in Kenya 
Vaccination of infants against human immunodeficiency virus type 1 (HIV-1) may prevent mother-to-child HIV-1 transmission. Successful trials and immunization efforts will depend on the willingness of individuals to participate in pediatric vaccine research and acceptance of infant HIV-1 vaccines. In a cross-sectional study, pregnant women presenting to a Nairobi antenatal clinic for routine care were interviewed regarding their attitudes toward participation in research studies and HIV-1 vaccine acceptability for their infants. Among 805 women, 782 (97%) reported they would vaccinate their infant against HIV-1 and 729 (91%) reported willingness to enroll their infant in a research study. However, only 644 (80%) would enroll their infants if HIV-1 testing was required every 3 months and 513 (64%) would agree to HIV-1 vaccine trial participation. Reasons for not wanting to enroll in a pediatric HIV-1 vaccine trial included concerns about side effects (75%), partner objection (34%), and fear of discrimination (10%), HIV-1 acquisition (8%), or false-positive HIV-1 results (5%). The strongest correlate of pediatric vaccine trial participation was maternal willingness to be a vaccine trial participant herself; in univariate and multivariate models this was associated with a 17-fold increased likelihood of participation (HR 17.1; 95% CI 11.7–25; p < 0.001). We conclude from these results that immunizing infants against HIV-1 and participation in pediatric vaccine trials are generally acceptable to women at high risk for HIV-1 infection. It will be important to address barriers identified in this study and to include male partners when mobilizing communities for pediatric HIV-1 vaccine trials and immunization programs.
doi:10.1089/aid.2006.22.491
PMCID: PMC3382079  PMID: 16796522
6.  Breast Milk α-Defensins Are Associated with HIV Type 1 RNA and CC Chemokines in Breast Milk But Not Vertical HIV Type 1 Transmission 
α-Defensins are proteins exhibiting in vitro anti-HIV-1 activity that may protect against mother-to-child transmission of HIV-1 via breast milk. Correlates of α-defensins in breast milk and transmission risk were determined in a cohort of HIV-1-infected pregnant women in Nairobi followed for 12 months postpartum with their infants. Maternal blood was collected antenatally and at delivery for HIV-1 viral load and infant HIV-1 infection status was determined <48 h after birth and at months 1, 3, 6, 9, and 12. Breast milk specimens collected at month 1 were assayed for α-defensins, HIV-1 RNA, subclinical mastitis, and CC and CXC chemokines. We detected α-defensins in breast milk specimens from 108 (42%) of 260 HIV-1-infected women. Women with detectable α-defensins (≥50 pg/ml) had a median concentration of 320 pg/ml and significantly higher mean breast milk HIV-1 RNA levels than women with undetectable α-defensins (2.9 log10 copies/ml versus 2.5 log10 copies/ml, p = 0.003). Increased α-defensins concentrations in breast milk were also associated with subclinical mastitis (Na+/K+ ratio > 1) and increased breast milk chemokine levels. Overall, 40 (15%) infants were HIV-1 uninfected at birth and subsequently acquired HIV-1. There was no significant association between month 1 α-defensins and risk of HIV-1 transmission. In conclusion, α-defensins were associated with breast milk HIV-1 viral load, chemokine levels, and subclinical mastitis, all of which may alter risk of infant HIV-1 acquisition. Despite these associations there was no significant relationship between breast milk α-defensins and mother-to-child transmission, suggesting a complex interplay between breast milk HIV-1, inflammation, and antiinfective factors.
doi:10.1089/aid.2006.0125
PMCID: PMC3382116  PMID: 17331027
7.  Human Leukocyte Antigen (HLA) B*18 and Protection against Mother-to-Child HIV Type 1 Transmission 
Human leukocyte antigen (HLA) molecules regulate the cellular immune system and may be determinants of infant susceptibility to human immunodeficiency virus type 1 (HIV-1) infection. Molecular HLA typing for class I alleles was performed on infants followed in a Kenyan perinatal cohort. Early HIV-1 infection status was defined as infection occurring at birth or month 1, while late infection via breast milk was defined as first detection of HIV-1 after 1 month of age. Likelihood ratio tests based on a proportional hazards model adjusting for maternal CD4 T cell count and HIV-1 viral load at 32 weeks of gestation were used to test associations between infant allelic variation and incident HIV-1 infection. Among 433 infants, 76 (18%) were HIV-1 infected during 12 months of follow-up. HLA B*18 was associated with a significantly lower risk of early HIV-1 transmission [relative risk (RR) = 0.26; 95% confidence interval (CI) 0.04–0.82], and none of the 24 breastfeeding infants expressing HLA B*18 who were uninfected at month 1 acquired HIV-1 late via breast milk. We observed a trend toward increased early HIV-1 acquisition for infants presenting HLA A*29 (RR = 2.0; 95% CI 1.0–3.8) and increased late HIV-1 acquisition via breast milk for both Cw*07 and Cw*08 (RR = 4.0; 95% CI 1.0–17.8 and RR = 7.2; 95% CI 1.2–37.3, respectively). HLA B*18 may protect breast-feeding infants against both early and late HIV-1 acquisition, a finding that could have implications for the design and monitoring of HIV-1 vaccines targeting cellular immune responses against HIV-1.
doi:10.1089/0889222041524616
PMCID: PMC3380108  PMID: 15307911
8.  Comparison of the Effects of Pathogenic Simian Human Immunodeficiency Virus Strains SHIV-89.6P and SHIV-KU2 in Cynomolgus Macaques 
Factors explaining why human immunodeficiency virus (HIV) enhances the risk of reactivated tuberculosis (TB) are poorly understood. Unfortunately, experimental models of HIV-induced reactivated TB are lacking. We examined whether cynomolgus macaques, which accurately model latent TB in humans, could be used to model pathogenesis of HIV infection in the lungs and associated lymph nodes. These experiments precede studies modeling the effects of HIV infection on latent TB. We infected two groups of macaques with chimeric simian–human immunodeficiency viruses (SHIV-89.6P and SHIV-KU2) and followed viral titers and immunologic parameters including lymphocytes numbers and phenotype in the blood, bronchoalveolar lavage cells, and lymph nodes over the course of infection. Tissues from the lungs, liver, kidney, spleen, and lymph nodes were similarly examined at necropsy. Both strains produced dramatic CD4+ T cell depletion. Plasma titers were not different between viruses, but we found more SHIV-89.6P in the lungs. Both viruses induced similar patterns of cell activation markers. SHIV-89.6P induced more IFN-γ expression than SHIV-KU2. These results indicate SHIV-89.6P and SHIV-KU2 infect cynomolgus macaques and may be used to accurately model effects of HIV infection on latent TB.
doi:10.1089/aid.2007.0238
PMCID: PMC3311977  PMID: 18366326
9.  Lack of indinavir-associated nephrological complications in HIV-infected adults (predominantly women) with high indinavir plasma concentration in Abidjan, Côte d'Ivoire 
Objective
To report the tolerance of indinavir combined with ritonavir (IDV/r 800/100mg) twice daily (bid) in sub-Saharan African HIV-infected adults.
Design
Prospective cohort study.
Methods
HAART-naïves patients started zidovudine plus lamivudine plus IDV/r 800/100mg bid. Follow-up included: standardised documentation of morbidity; CD4+ cell count, creatininemia, plasma HIV-1 RNA, and IDV minimal plasma concentration (Cmin) measurements at month-1 (M1), M3 and M6.
Results
70 HIV-1 infected adults (68 women, median CD4 235/mm3) started HAART. At M6, 63% had undetectable viral load, and the median gain in CD4 since baseline was +128/mm3. During the first six months, 21 patients experimented 23 treatment modifications (reduction to IDV/r 400/100mg bid: n=11; switch for efavirenz: n=11; zidovudine replaced by stavudine: n=1), including 22 for digestive intolerance and one for severe anaemia. At M1, M3 and M6, 67, 59 and 48 patients were still receiving IDV/r 800/100 mg bid, of whom 70%, 72% and 60% had IDV Cmin above 5 ng/mL, respectively. In these patients, at M1, M3 and M6, the mean (± SD) IDV Cmin, were 3431 ± 3835ng/ml, 2288 ± 2116ng/ml and 1543 ± 2398ng/ml, respectively. There was no renal insufficiency of any grade, and no symptom of urinary stones.
Conclusion
The IDV/r 800/100mg bid containing regimen led to high IDV Cmin, and high rate of digestive intolerance. There was a surprising lack of nephrological side-effects during the 6 months of follow-up, supporting the hypothesis that nephrological tolerance of IDV might be higher in sub-Saharan African individuals than in American or European ones.
doi:10.1089/aid.2006.0038
PMCID: PMC3219609  PMID: 17263634
Adults - sub-Saharan Africa; Ritonavir - Indinavir - toxicity; Adult; Cohort Studies; Cote d'Ivoire; Female; Follow-Up Studies; HIV Infections; blood; drug therapy; virology; HIV Protease Inhibitors; adverse effects; blood; therapeutic use; HIV-1; isolation & purification; HIV-2; isolation & purification; Humans; Indinavir; adverse effects; blood; therapeutic use; Male; RNA, Viral; blood; Retrospective Studies; Time Factors; Treatment Outcome; Viral Load
10.  Factors Associated with Poor Immunologic Response to Virologic Suppression by Highly Active Antiretroviral Therapy in HIV-Infected Women 
Virologic response to highly active antiretroviral therapy (HAART) typically results in a substantial rise in CD4 cell counts. We investigated factors associated with poor CD4 response among HIV-infected women followed at 6-monthly intervals in the Women’s Interagency HIV Study. Women with nadir CD4 counts <350 cells/mm3 who achieved at least 6 months of plasma HIV RNA < 400 copies/ml were studied. Demographic, clinical, and treatment factors were compared between immunologic nonresponders, defined as the lower quartile of CD4 count change after two visits with virologic suppression (<56 cell/mm3; n = 38), and the remaining group of responders (n = 115). Immunologic nonresponders had lower baseline HIV RNA levels and higher CD4 counts, more frequently used HAART 6 months prior to achieving consistent viral suppression, and more commonly had HIV RNA levels >80 but <400 copies/mL at both suppressive visits (21 vs. 7.8%, p = 0.024). In multivariate analysis, higher CD4 count and lower HIV RNA level at the last presuppressive visit were associated with immune nonresponse. We conclude that higher baseline CD4 count and lower HIV RNA level were associated with poor immunologic response to HAART in women with virologic suppression for at least 6 months. Persistent low level viremia may also contribute.
doi:10.1089/aid.2006.22.222
PMCID: PMC3126664  PMID: 16545008
11.  HSV-2 infection increases HIV DNA detection in vaginal tissue of mice expressing human CD4 and CCR5 
AIDS research and human retroviruses  2009;25(11):1157-1164.
The goal of this study was to develop an in vivo murine model that can be used to study the influence of HSV-2 on HIV infection. Mice expressing transgenes for human CD4, CCR5 and Cyclin T1 were infected intra-vaginally with HSV-2 and 3-7 days later infected with HIV. HIV DNA was detected by real time PCR. The frequency of detection of HIV DNA was significantly higher (65%) in vaginal tissue of HSV-2-infected mice compared to mock-infected mice (35%) when HIV was given 3 days after HSV-2. HSV-2 infected mice also had significantly higher levels of HIV DNA in vaginal tissue. HIV DNA was not detected in vaginal tissue of mice lacking human CD4. Longer periods (5 or 7 days) between infection with HSV-2 and HIV did not increase the frequency of detection or the amount of HIV DNA detected. HIV DNA was also detected in lymph nodes from some of the mice that were infected intra-vaginally with HSV-2 and HIV. Flow cytometric and mRNA analysis of human CD4 in vaginal tissue suggested that HSV-2 infection increased the number of T cells expressing human CD4 in vaginal tissue. This study provides evidence that HIV infection of cells occurs in the vagina of mice expressing human CD4, CCR5 and Cyclin T1 and that HSV-2 infection increases HIV infection. These findings demonstrate that this model can be used to study the mechanisms responsible for increased susceptibility to HIV in HSV-2-infected persons and for testing preventative treatments.
doi:10.1089/aid.2009.0035
PMCID: PMC2826840  PMID: 19886831
12.  The Dead Cell: A Potent Escort for HIV-1 Trans-Infection 
AIDS research and human retroviruses  2009;25(11):1123-1128.
HIV-1 trans-infection is a process by which one cell acts as an HIV-1 “escort” to enhance infection of another. There has recently been much debate concerning (i) the types of cells that may act as escorts, (ii) requirements for virus internalization by the escort, and (iii) the sensitivity of trans-infection to inhibition by neutralizing antibodies. To address these questions, trans-infection was monitored by incubating target cells with HIV-1 in the presence or absence of mouse or human cells as candidate escorts in vitro. After a two day culture, target cells were tested for levels of HIV-1 infection. Results showed that a variety of murine and human cells were capable escorts for HIV-1 trans-infection. Cell integrity was not required, as escorts could be freeze/thawed (or fractionated to yield purified membranes/microsomes) prior to their incubation with HIV-1. In fact, the freeze/thawed or fractionated cells were often superior to their viable counterparts as mediators of trans-infection. The process was sensitive to antibody neutralization. Confirmatory experiments were conducted with more than one target cell and more than one source of HIV-1. Results demonstrated that there may be multiple cell types and mechanisms with which trans-infection can be accomplished. Apparently the simple binding of fragmented escort membranes to HIV-1 may be sufficient to enhance virus fusion or endocytosis at the target cell surface. The fact that dead cells or membranes can support this activity may explain, at least in part, the high frequency of human HIV-1 infections at sites of tissue damage.
doi:10.1089/aid.2009.0021
PMCID: PMC2787888  PMID: 19886832
HIV-1 Trans-infection; membranes; microsomes; neutralizing antibodies
13.  Short Communication: The Dead Cell: A Potent Escort for HIV Type 1 Transinfection 
AIDS Research and Human Retroviruses  2009;25(11):1123-1128.
Abstract
HIV-1 transinfection is a process by which one cell acts as an HIV-1 “escort” to enhance infection of another. There has recently been much debate concerning (1) the types of cells that may act as escorts, (2) requirements for virus internalization by the escort, and (3) the sensitivity of transinfection to inhibition by neutralizing antibodies. To address these questions, transinfection was monitored by incubating target cells with HIV-1 in the presence or absence of mouse or human cells as candidate escorts in vitro. After a 2-day culture, target cells were tested for levels of HIV-1 infection. Results showed that a variety of murine and human cells were capable escorts for HIV-1 transinfection. Cell integrity was not required, as escorts could be freeze/thawed (or fractionated to yield purified membranes/microsomes) prior to their incubation with HIV-1. In fact, the freeze/thawed or fractionated cells were often superior to their viable counterparts as mediators of transinfection. The process was sensitive to antibody neutralization. Confirmatory experiments were conducted with more than one target cell and more than one source of HIV-1. Results demonstrated that there may be multiple cell types and mechanisms with which transinfection can be accomplished. Apparently the simple binding of fragmented escort membranes to HIV-1 may be sufficient to enhance virus fusion or endocytosis at the target cell surface. The fact that dead cells or membranes can support this activity may explain, at least in part, the high frequency of human HIV-1 infections at sites of tissue damage.
doi:10.1089/aid.2009.0021
PMCID: PMC2787888  PMID: 19886832
14.  HSV Type 2 Infection Increases HIV DNA Detection in Vaginal Tissue of Mice Expressing Human CD4 and CCR5 
AIDS Research and Human Retroviruses  2009;25(11):1157-1164.
Abstract
The goal of this study was to develop an in vivo murine model that can be used to study the influence of HSV-2 on HIV infection. Mice expressing transgenes for human CD4, CCR5, and Cyclin T1 were infected intravaginally with HSV-2 and 3–7 days later infected with HIV. HIV DNA was detected by real-time PCR. The frequency of detection of HIV DNA was significantly higher (65%) in vaginal tissue of HSV-2-infected mice compared to mock-infected mice (35%) when HIV was given 3 days after HSV-2. HSV-2-infected mice also had significantly higher levels of HIV DNA in vaginal tissue. HIV DNA was not detected in vaginal tissue of mice lacking human CD4. Longer periods (5 or 7 days) between infection with HSV-2 and HIV did not increase the frequency of detection or the amount of HIV DNA detected. HIV DNA was also detected in lymph nodes from some of the mice that were infected intravaginally with HSV-2 and HIV. Flow cytometric and mRNA analysis of human CD4 in vaginal tissue suggested that HSV-2 infection increased the number of T cells expressing human CD4 in vaginal tissue. This study provides evidence that HIV infection of cells occurs in the vagina of mice expressing human CD4, CCR5, and Cyclin T1 and that HSV-2 infection increases HIV infection. These findings demonstrate that this model can be used to study the mechanisms responsible for increased susceptibility to HIV in HSV-2-infected persons and for testing preventative treatments.
doi:10.1089/aid.2009.0035
PMCID: PMC2826840  PMID: 19886831
15.  Amplification of Simian Retroviral Sequences from Human Recipients of Baboon Liver Transplants 
Investigations into the use of baboons as organ donors for human transplant recipients, a procedure called xenotransplantation, have raised the specter of transmitting baboon viruses to humans and possibly establishing new human infectious diseases. Retrospective analysis of tissues from two human transplant recipients with end-stage hepatic disease who died 70 and 27 days after the transplantation of baboon livers revealed the presence of two simian retroviruses of baboon origin, simian foamy virus (SFV) and baboon endogenous virus (BaEV), in multiple tissue compartments. The presence of baboon mitochondrial DNA was also detected in these same tissues, suggesting that xenogeneic “passenger leukocytes” harboring latent or active viral infections had migrated from the xenografts to distant sites within the human recipients. The persistence of SFV and BaEV in human recipients throughout the posttransplant period underscores the potential infectious risks associated with xenotransplantation.
PMCID: PMC2963433  PMID: 9671210
16.  Geographic HIV Type 1 Subtype Distribution in Rakai District, Uganda 
AIDS Research and Human Retroviruses  2009;25(10):1045-1048.
Abstract
To analyze HIV-1 subtype distribution, sequence analysis was performed on serum specimens obtained in 1994 from the Rakai Health Sciences community cohort in Uganda. Portions of gag-p24 and env-gp41 were sequenced and HIV subtype was determined for 773 subjects residing in 10 community clusters in rural Uganda. Subtypes A (17%) and D (70%) were the most common strains in the population. Subtype distribution varied by geographic region with significantly more subtype A in northern community clusters compared with southern clusters (21% vs. 8%, p < 0.001) and more subtype D in southern clusters compared with northern clusters (78% vs. 65%, p < 0.008). These data illustrate the geographic complexity of subtype variation, which has important implications for HIV-1 vaccine design.
doi:10.1089/aid.2009.0127
PMCID: PMC2785855  PMID: 19803713
17.  Elevated NT-pro-BNP Levels Are Associated with Comorbidities among HIV-Infected Women 
AIDS Research and Human Retroviruses  2009;25(10):997-1004.
Abstract
HIV infection is associated with left ventricular (LV) dysfunction and accelerated atherosclerosis. These conditions result in elevation of plasma natriuretic peptide (NP) levels. The present study compares N-terminal-pro-BNP (NT-pro-BNP) levels in HIV-infected and -uninfected women and identifies factors influencingNT-pro-BNP levels in HIV-infected women. A total of 454 HIV-infected and 200 HIV-uninfected participants from the Women's Interagency HIV Study (WIHS) had NT-pro-BNP determination. Elevated NT-pro-BNP level was defined using previously determined age stratified cut-off values of >164 ng/liter (age <60 years) and >225 (age ≥ 60 years). HIV-infected women were older (41.6 ± 8.9 vs. 38.9 ± 10.5 years, p < 0.01) and were more likely to have anemia, hepatitis C virus (HCV) antibodies, and kidney dysfunction than HIV-uninfected women. HIV-infected women had significantly higher NT-pro-BNP levels (142.4 ± 524.8 vs. 73.6 ± 115.1 ng/liter, p = 0.01) and a higher prevalence of elevated NT-pro-BNP (12.1% vs. 7.5%; p = 0.08). In univariate analyses, elevated NT-pro-BNP was significantly associated with age, systolic BP, hypertension, anemia, triglyceride levels, kidney disease, and HCV seropositivity, but not HIV infection. In multivariate analysis, elevated NT-pro-BNP levels were significantly associated with anemia and kidney function, and had a borderline association with the presence of HCV antibodies. Among HIV-infected women, NT-pro-BNP levels were not independently associated with measures of severity of infection or with HAART use. Although HIV-infected women have higher NT-pro-BNP levels than HIV-uninfected women, the differences are due to non-HIV factors such as anemia, kidney disease, and HCV coinfection. These findings suggest that natriuretic peptide levels are a global marker of comorbidity in the setting of HIV infection.
doi:10.1089/aid.2009.0038
PMCID: PMC2791362  PMID: 19803714
18.  Genotypic Susceptibility Scores and HIV Type 1 RNA Responses in Treatment-Experienced Subjects with HIV Type 1 Infection 
This study compared the role of genotypic susceptibility scores (GSS) as a predictor of virologic response in a group (n = 234) of HIV-infected, protease inhibitor (PI)-experienced subjects. Two scoring methods [discrete genotypic susceptibility score (dGSS) and continuous genotypic susceptibility score (cGSS)] were developed. Each drug in the subject's regimen was given a binary susceptibility score using Stanford inferred drug resistance scores to calculate the dGSS. In contrast to the dGSS, the cGSS model was designed to reflect partial susceptibility to a drug. Both GSS were independent predictors of week 16 virologic response. We also compared the GSS to a phenotypic susceptibility score (PSS) model on a subset of subjects that had both GSS and PSS performed, and found that both models were predictive of virologic response. Genotypic analyses at enrollment showed that subjects who were virologic nonresponders at week 16 revealed enrichment of several mutated codons associated with nucleoside reverse transcriptase inhibitors (NRTI) (codons 67, 69, 70, 118, 215, and 219) or PI resistance (codons 10, 24, 71, 73, and 88) compared to subjects who were virologic responders. Regression analyses revealed that protease mutations at codons 24 and 90 were most predictive of poor virologic response, whereas mutations at 82 were associated with enhanced virologic response. Certain NNRTI-associated mutations, such as K103N, were rapidly selected in the absence of NRTIs. These data indicate that GSS may be a useful tool in selecting drug regimens in HIV-1-infected subjects to maximize virologic response and improve treatment outcomes.
doi:10.1089/aid.2007.0127
PMCID: PMC2928289  PMID: 18462083
19.  Genomic Analysis of HIV Type 1 Strains Derived from a Mother and Child Pair of Long-Term Nonprogressors 
To investigate the viral features of long-term nonprogressive HIV-1 infection and the selection of viral genomes, we studied serial complete HIV-1 sequences obtained from a mother–child pair, both long-term nonprogressors. Analysis of four genomic sequences demonstrated that all viral genes were intact, lacking major deletions or premature stop codons to easily explain the slow disease progression. These data suggest that viral attenuation, if present, was caused by subtle sequence variations or virus–host interactions. Serial sequences from an HIV-1-infected mother–child pair afforded us the opportunity to examine the immune selection of HIV-1 sequences years after transmission between individuals. We demonstrated that the daughter's strains were most likely subjected to immunoselection or immunoediting according to the presence of novel MHC class I alleles that differed between mother and daughter. An analysis of nef-specific cytotoxic T-lymphocyte responses in the child, whose HIV-1 nef sequence differed from the maternal nef, supported this interpretation. This study highlights the potential of full genome analysis in the investigation of pathogenesis and immune selection during HIV-1 evolution.
doi:10.1089/aid.2006.0180
PMCID: PMC2925658  PMID: 17331038
20.  Altered bystander apoptosis induction and pathogenesis of Enfuvirtide resistant HIV-1 Env mutants 
In previous studies on mechanisms of HIV-1 mediated pathogenesis we showed that bystander apoptosis mediated by cell surface expressed HIV-1 Env correlated with the fusogenic properties of the gp41 subunit of Env. A crucial step in HIV gp41-mediated fusion is the re-folding of the protein into a six helix bundle along the N- and C-terminal coiled coil domains. These domains have been targeted by peptide inhibitors that inhibit gp41 mediated fusion. One of these inhibitors, Enfuvirtide, is the first such drug approved for therapy. More recently, clinical data suggests that the beneficial effects of Enfuvirtide extend beyond virus suppression and are associated with certain resistance mutations in gp41. In this study we characterized the bystander apoptosis inducing potential of mutants associated with increased CD4 counts that arise during Enfuvirtide therapy. While all mutant clones were reduced in both cell to cell fusion activity and apoptosis induction there was limited effect on virus infection or replication. The viruses found to have apoptosis inducing activity in the order WT>V38M>V38A>G36D>V38E which correlated with cell to cell fusion but not infection. Interestingly, the level of resistance as determined by IC50 of Enfuvirtide also correlated inversely with both cell fusion and apoptosis in that the most resistant Envs were least fusogenic and pathogenic. This suggests the beneficial effects of Enfuvirtide therapy beyond virus suppression maybe mediated by selecting less pathogenic HIV isolates over time.
doi:10.1089/aid.2009.0010
PMCID: PMC2791676  PMID: 19619009
21.  Altered Bystander Apoptosis Induction and Pathogenesis of Enfuvirtide-Resistant HIV Type 1 Env Mutants 
Abstract
In previous studies on mechanisms of HIV-1-mediated pathogenesis we showed that bystander apoptosis mediated by cell surface-expressed HIV-1 Env correlated with the fusogenic properties of the gp41 subunit of Env. A crucial step in HIV gp41-mediated fusion is the refolding of the protein into a six-helix bundle along the N- and C-terminal coiled-coil domains. These domains have been targeted by peptide inhibitors that inhibit gp41-mediated fusion. One of these inhibitors, enfuvirtide, is the first such drug approved for therapy. More recently, clinical data suggest that the beneficial effects of enfuvirtide extend beyond virus suppression and are associated with certain resistance mutations in gp41. In this study we characterized the bystander apoptosis-inducing potential of mutants associated with increased CD4 counts that arise during enfuvirtide therapy. Whereas all mutant clones were reduced in both cell-to-cell fusion activity and apoptosis induction there was limited effect on virus infection or replication. The viruses were found to have apoptosis-inducing activity in the order WT > V38M > V38A > G36D > V38E, which correlated with cell-to-cell fusion but not infection. Interestingly, the level of resistance as determined by the IC50 of enfuvirtide also correlated inversely with both cell fusion and apoptosis in that the most resistant Envs were the least fusogenic and pathogenic. This suggests the beneficial effects of enfuvirtide therapy beyond virus suppression may be mediated by selecting less pathogenic HIV isolates over time.
doi:10.1089/aid.2009.0010
PMCID: PMC2791676  PMID: 19619009
22.  Analysis of HIV Type 1 gp41 and Enfuvirtide Susceptibility among Men in the United States Who Were HIV Infected Prior to Availability of HIV Entry Inhibitors 
We analyzed HIV gp41 from 195 men in the United States who were HIV-1 infected between 1999 and 2002, before enfuvirtide (ENF) was approved for clinical use in the United States. gp41 genotyping results were obtained for 175 samples. None of the samples had major ENF resistance mutations. Six (3.4%) samples had minor ENF resistance mutations in the HR1 region (V38G, N43K, L44M, L45M). Twenty-eight (16%) samples had the N42S polymorphism, which is associated with ENF hypersusceptibility. Accessory mutations in the HR2 region were identified in some samples (E137K, S138A). Five of the six samples with HR1 resistance mutations were analyzed with a phenotypic assay; one sample had reduced ENF susceptibility (a sample with N42S + L44M + E137K). Prior to the availability of ENF, some men in the United States were infected with HIV that contained mutations associated with ENF resistance or hypersusceptibility. However, most of the mutations were not associated with phenotypic ENF resistance.
doi:10.1089/aid.2009.0014
PMCID: PMC2746939  PMID: 19552592
23.  Short Communication: In Utero HIV Infection Is Associated with an Increased Risk of Nevirapine Resistance in Ugandan Infants Who Were Exposed to Perinatal Single Dose Nevirapine 
Use of single dose nevirapine (sdNVP) to prevent HIV mother-to-child transmission is associated with the emergence of NVP resistance in many infants who are HIV infected despite prophylaxis. We combined results from four clinical trials to analyze predictors of NVP resistance in sdNVP-exposed Ugandan infants. Samples were tested with the ViroSeq HIV Genotyping System and a sensitive point mutation assay (LigAmp, for detection of K103N, Y181C, and G190A). NVP resistance was detected at 6–8 weeks in 36 (45.0%) of 80 infants using ViroSeq and 33 (45.8%) of 72 infants using LigAmp. NVP resistance was more frequent among infants who were infected in utero than among infants who were diagnosed with HIV infection after birth by 6–8 weeks of age. Detection of NVP resistance at 6–8 weeks was not associated with HIV subtype (A vs. D), pre-NVP maternal viral load or CD4 cell count, infant viral load at 6–8 weeks, or infant sex. NVP resistance was still detected in some infants 6–12 months after sdNVP exposure. In this study, in utero HIV infection was the only factor associated with detection of NVP resistance in infants 6–8 weeks after sdNVP exposure.
doi:10.1089/aid.2009.0003
PMCID: PMC2752753  PMID: 19552593
24.  Comparison of Laboratory Methods for Analysis of Non-nucleoside Reverse Transcriptase Inhibitor Resistance in Ugandan Infants 
Abstract
Detailed comparisons of HIV drug resistance assays are needed to identify the most useful assays for research studies, and to facilitate comparison of results from studies that use different methods. We analyzed nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance in 40 HIV-infected Ugandan infants who had received nevirapine (NVP)-based prophylaxis using the following assays: an FDA-cleared HIV genotyping assay (the ViroSeq HIV-1 Genotyping System v2.0), a commercially available HIV genotyping assay (GeneSeq HIV), a commercially available HIV phenotyping assay (PhenoSense HIV), and a sensitive point mutation assay (LigAmp). ViroSeq and GeneSeq HIV results (NVP resistance yes/no) were similar for 38 (95%) of 40 samples. In 6 (15%) of 40 samples, GeneSeq HIV detected mutations in minor subpopulations that were not detected by ViroSeq, which identified two additional infants with NVP resistance. LigAmp detected low-level mutations in 12 samples that were not detected by ViroSeq; however, LigAmp testing identified only one additional infant with NVP resistance. GeneSeq HIV and PhenoSense HIV determinations of susceptibility differed for specific NNRTIs in 12 (31%) of the 39 samples containing mixtures at relevant mutation positions. PhenoSense HIV did not detect any infants with NVP resistance who were not identified with GeneSeq HIV testing. In this setting, population sequencing-based methods (ViroSeq and GeneSeq HIV) were the most informative and had concordant results for 95% of the samples. LigAmp was useful for the detection and quantification of minority variants. PhenoSense HIV provided a direct and quantitative measure of NNRTI susceptibility.
doi:10.1089/aid.2008.0235
PMCID: PMC2799186  PMID: 19621988
25.  Use of Tissue Culture Cell Lines to Evaluate HIV Antiviral Resistance 
Most current assays of HIV antiviral resistance are based on either sequencing of viral genes (genotypic assays) or amplification and insertion of these genes into standardized virus backbones and culture. These latter are called phenotypic assays. But the only generally accepted phenotypic assay is based upon culture of intact patient virus, performed in phytohemagglutinin-activated peripheral blood mononuclear cells (PHA blasts) in the presence of differing drug concentrations. However, PHA blast culture is difficult and not always reproducible. Therefore we have sought cell lines that may produce more predictable results, yet faithfully mirror results in PHA blasts. We have compared 10 different cell lines for receptor and coreceptor expression, growth of laboratory-adapted strains of HIV, growth by direct inoculation of PBMC from infected patients, and in assays of antiviral drug effects. One of these cell lines, C8166-R5, is statistically not inferior to CD8-depleted PHA blasts for culturing HIV from the peripheral blood cells of patients. The effective concentrations of antiviral drugs of all classes were similar when assayed in C8166-R5 or PHA blasts. Known drug-resistant isolates grown in C8166-R5 demonstrated the predicted effects. We followed a patient longitudinally and demonstrated that resistance testing in C8166-R5 was predictive of clinical outcome. These experiments represent the first steps in developing a clinically useful phenotypic drug resistance assay based upon culturing the patient’s own virus.
doi:10.1089/aid.2007.0242
PMCID: PMC2895164  PMID: 18671478

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