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1.  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
2.  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
3.  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
4.  Cellulose Acetate 1,2-Benzenedicarboxylate Inhibits Infection by Cell-Free and Cell-Associated Primary HIV-1 Isolates 
Cellulose acetate 1,2-benzenedicarboxylate (CAP), a pharmaceutical excipient used for enteric film coating of capsules and tablets, was previously shown to have potent inhibitory activity against infection by human immunodeficiency virus type 1 (HIV-1) T cell line-adapted (TCLA) strains. In the present study, we determined the inhibitory activity of CAP against infection by cell-free and cell-associated primary HIV-1 isolates with distinct genotypes and biotypes in cervical explants, peripheral blood mononuclear cells (PBMCs), monocyte-derived macrophages (MDMs), and CEMx174 5.25M7 cells. CAP blocked infection by cell-free and cell-associated HIV-1 in cervical explants. It inhibited infection by cell-free primary HIV-1 isolates (clades A to G and group O) in PBMCs, MDMs, and CEMx174 5.25M7 cells and blocked transmissions of the cell-associated primary HIV-1 isolates from dendritic cells (DCs) to PBMCs, from MDMs to PBMCs, and from PBMCs to CEMx174 5.25M7 cells. The inhibitory activity of CAP on infection by the cell-free and cell-associated primary HIV-1 isolates is independent of viral subtypes and coreceptor usage. These data suggest that CAP is a good microbicide candidate that can be further developed for preventing sexual transmission of HIV-1.
doi:10.1089/aid.2006.22.411
PMCID: PMC2788998  PMID: 16706617
5.  Lack of Correlation Between SIV-Nef Evolution and Rapid Disease Progression in Morphine-dependent Non-Human Primate model of AIDS 
Six morphine-dependent and two control macaques were infected in a SIV/SHIV non-human primate model of AIDS. Three animals in the morphine group rapidly developed clinical disease and died within the timeframe of this study. The sequence evolution of nef in plasma virus was assessed at 4, 12 and 20 weeks post infection. Cloned sequences were compared phylogenetically against each other as well as against the inoculum virus clones to determine the effect of morphine and rate of disease progression on diversity and divergence, respectively. Unlike our earlier studies of tat and env, nef evolution was not affected by morphine abuse or by rapid disease progression. The results suggest that although the evolution of other loci are inversely correlated to the onset and rate of clinical disease, differential evolution of nef is related neither to drug abuse nor rapid progression within the first twenty weeks of infection.
doi:10.1089/aid.2006.22.817
PMCID: PMC2761833  PMID: 16910840
6.  N88D Facilitates the Co-occurrence of D30N and L90M and the Development of Multidrug Resistance in HIV Type 1 Protease following Nelfinavir Treatment Failure 
AIDS research and human retroviruses  2006;22(12):1300-1305.
Nelfinavir was once one of the most commonly used protease inhibitors (PIs). To investigate the genetic mechanisms of multidrug resistance in protease isolates with the primary nelfinavir resistance mutation D30N, we analyzed patterns of protease mutations in 582 viruses with D30N from 460 persons undergoing HIV-1 genotypic resistance testing at Stanford University Hospital from 1997 to 2005. Three patterns of mutational associations were identified. First, D30N was positively associated with N88D but negatively associated with N88S. Second, D30N and L90M were negatively associated except in the presence of N88D, which facilitated the cooccurrence of D30N and L90M. Third, D30N + N88D + L90M formed a stable genetic backbone for the accumulation of additional protease inhibitor (PI) resistance mutations. In 16 patients having isolates with more than one combination of mutations at positions 30, 88, and 90, all exhibited one of the steps in the following progression: D30N → D30N + N88D → D30N + N88D + L90M → D30N + N88D + L90M + (L33F ± I84V or M46I/L ± I54V). Although nelfinavir is now used less frequently than other PIs, the well-delineated mutational pathway we describe is likely to influence patterns of cross-resistance in viruses from persons who experience virologic failure while receiving this PI.
doi:10.1089/aid.2006.22.1300
PMCID: PMC2573402  PMID: 17209774
7.  Elevations in IL-10, TNF-α, and IFN-γ from the Earliest Point of HIV Type 1 Infection 
Perturbations of plasma IL-10, IL-12, IL-13, TNF-α, and IFN-γ were measured longitudinally in HIV-1 se-roconverting plasma donors and were compared to subjects with symptomatic primary HIV-1 infection. Control groups included uninfected patients with symptoms and risks for primary HIV-1, healthy controls, and asymptomatic plasma donors with primary HCV. IL-10, TNF-α, and IFN-γ rapidly rose in acute HIV-1 infection, while IL-13 predominated in acute HCV. Subjects with symptomatic primary HIV-1 had higher cytokine levels than asymptomatic subjects, statistically significant for TNF-α. Cytokine alterations occurred within 7 days of detectable HIV-1 viremia, emphasizing the need to study the earliest events of infection.
doi:10.1089/aid.2006.22.757
PMCID: PMC2431151  PMID: 16910831
8.  HIV VprR77Q mutation does not influence clinical response of individuals initiating Highly Active Antiretroviral Therapy 
VprR77Q has been associated with long-term nonprogressive (LTNP) HIV infection. We wished to investigate the prevalence, clinical correlates, and effect on treatment response of VprR77Q in a cohort of antiretroviral-naïve individuals initiating Highly Active Antiretroviral Therapy (HAART). Baseline plasma samples from 728 subjects were genotyped using RT-PCR and direct DNA sequencing. Cox proportional hazards regression was used to model the effects of VprR77Q on virologic and immunologic responses, and survival following initiation of HAART, over a median 4.5 years follow-up. We found that 308 subjects (42.3%) harbored VprR77Q alone or in combination with another amino acid, while 420 (57.7%) harbored an amino acid other than Q. A cross-sectional analysis found no correlation between R77Q and baseline plasma viral load (pVL), CD4 count, diagnosis of AIDS, or sociodemographic characteristics including age, gender and history of injection drug use (p > 0.1). In multivariate analyses, no significant associations between VprR77Q and initial pVL and CD4 responses to HAART (p > 0.1) or survival following initiation of treatment were observed. The high prevalence and the lack of association with pre-therapy clinical parameters in this cohort argue against an association of R77Q with LTNP status. These results do not support an association between R77Q and HAART response.
doi:10.1089/aid.2006.22.615
PMCID: PMC2423217  PMID: 16831085
HIV; Vpr; R77Q; antiretroviral therapy response; HOMER cohort
9.  Longitudinal Assessment of de Novo T Cell Production in Relation to HIV-Associated T Cell Homeostasis Failure 
Loss of circulating CD4+ T cells in HIV-1 disease is balanced by CD8+ lymphocytosis to maintain normal CD3+ T cell counts [blind T cell homeostasis (TCH)]. However, for unknown reasons TCH generally fails 1.5−2.5 years before clinically defined AIDS. We investigated whether TCH failure was associated with changes in thymic production of T cells. Using specimens stored prospectively in the Multicenter AIDS Cohort Study (MACS), we measured expression of signal-joint T cell receptor excision circles (sjTRECs), a marker for thymic T cell production, and the fraction of proliferating naive and memory T cells during a 6−8 year period bracketing TCH failure. Segmented regression modeling assessed (1) rates of change in TREC levels before and after TCH failure, and (2) whether these were affected by cellular proliferation, which may dilute sjTREC levels. TCH failure was associated with a large decline in sjTREC (median 1109-fold, p = 0.028); the rate of this decline was only slightly affected when increased proliferation of naive T cells or other peripheral lymphocytes was taken into account. Preferential loss of naive CD4+ T cells was also noted before TCH failure, as has been seen in other studies. These results suggest that deficits in de novo T cell production, either through the decline of thymic function or the destruction of naive T cells, are likely to play an important role in TCH failure and progression of HIV-1 disease.
doi:10.1089/aid.2006.22.501
PMCID: PMC2365916  PMID: 16796525
10.  Distinct Sequence Patterns Characterize the V3 Region of HIV Type 1 gp120 from Subtypes A and C 
The known sequences of HIV-1 viruses have been categorized into subtypes based on the phylogenetic partitioning of their env and gag gene sequences. The env gene encodes the protein gp120, which contains five sequence-variable regions (V1 to V5), of which the V3 loop is of central importance to viral infectivity. The V3 loop consensus sequences of HIV-1 subtype A and C viruses are similar, and more similar to one another than the V3 consensus sequences of any other two HIV-1 subtypes. However, using a position-specific statistical comparison, we found that the V3 region of these two subtypes is statistically distinct (p = ~0.0). (The p-value calculated to the lowest limit of representation on the computer used to run the calculation. This lowest limit was 10−16. Although theoretically a p-value cannot be equal to 0.0, the p-value for the comparisons in question can be intuitively considered to be extremely small, or ~0.0.)
doi:10.1089/aid.2006.22.703
PMCID: PMC1868395  PMID: 16831095
11.  Modulation of Osteoclastogenesis Induced by Nucleoside Reverse Transcriptase Inhibitors 
AIDS research and human retroviruses  2006;22(11):1131-1141.
Osteopenia is a common and debilitating side-effect of HAART, yet little is known concerning the effects of HAART on bone metabolism. We reported previously that zidovudine (AZT) stimulates osteoclastogenesis in vitro and causes osteopenia in mice. Here, we confirmed that the AZT-induced osteoclastogenesis is dependent on RANKL in that osteoclastogenesis is blocked by osteoprotegestin. Alendronate, which is used for the treatment of osteopenia and osteoporosis, failed to inhibit AZT-induced osteoclastogenesis in vitro. Osteoclastogenesis in vitro was not affected by tumor necrosis factor-α. Two other NRTI drugs, ddl and 3TC, also induced osteoclastogenesis in vitro and induced osteopenia in mice. The osteopenia was associated with an elevation of parameters of osteoclasts, but not with osteoblasts. Combinations of the NRTIs did not result in additive or synergistic effects in vitro or in vivo. Finally, AZT induced osteoclastogenesis of human osteoclast precursors in a RANKL-dependent manner. This in vitro osteoclastogenesis assay using human peripheral blood mononuclear cells could be useful in evaluating bone turnover and the risk of developing osteopenia in AIDS patients on HAART.
doi:10.1089/aid.2006.22.1131
PMCID: PMC1994207  PMID: 17147500
12.  Longitudinal Population Analysis of Dual Infection with Recombination in Two Strains of HIV Type 1 Subtype B in an Individual from a Phase 3 HIV Vaccine Efficacy Trial 
This study documents a case of coinfection (simultaneous infection of an individual with two or more strains) of two HIV-1 subtype B strains in an individual from a Phase 3 HIV-1 vaccine efficacy trial, conducted in North American and the Netherlands. We examined 86 full-length gp120 (env) gene sequences from this individual collected from nine different time points over a 20-month period. We estimated evolutionary relationships using maximum likelihood and Bayesian methods and inferred recombination breakpoints and recombinant sequences using phylogenetic and substitutional methods. These analyses identified two strongly supported monophyletic clades (clades A and B) of 14 and 69 sequences each and a small paraphyletic recombinant clade of three sequences. We then studied the genetic characteristics of these lineages by comparing estimates of genetic diversity generated by mutation and recombination and adaptive selection within a coalescent and maximum likelihood framework. Our results suggest significant differences on the evolutionary dynamics of these strains. We then discuss the implications of these results for vaccine development.
doi:10.1089/aid.2006.22.968
PMCID: PMC1982842  PMID: 17067266

Results 1-12 (12)