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1.  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
2.  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
3.  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
4.  Hepatitis B Virus Genotype Distribution and Its Lamivudine-Resistant Mutants in HIV-Coinfected Patients with Chronic and Occult Hepatitis B 
Hepatitis B virus (HBV) genotypes were examined in HIV-infected patients with chronic and occult HBV infection. From a total population of 593 HIV-infected patients, 22 individuals (prevalence 3.7%) were found to be HBsAg while 72 (12.1%) were found to be anti-HBc alone. From them, 20 and 4 were HBV DNA positive, respectively. These last four patients are therefore considered to be HBV infected in an occult form. The genotypes could be determined in all 24 HBV-infected patients. HBV-A was the most common (20/24; 83.3%), followed by HBV-D (2/24; 8.3%) and HBV-F (1/24; 4.2%). The remaining sample exhibited mixed infection involving genotypes A and D as pure ones, thus also forming part of three intergenotypic recombinant forms exhibiting different mosaic S gene patterns. The sexual route of transmission was predominant among HBV genotype A-infected patients. Among the 24 HBV DNA-positive patients, point mutations related to lamivudine resistance were found in four strains. These viral strains showed a methionine-to-valine substitution at codon 204 (rtM204V) in association with an upstream B-domain change at rtL180M. Additionally, two of them exhibited the additional rtV173L mutation. The value of HBV molecular monitoring including both HBV viral genomic characterization and genotypic resistance profile in HIV-HBV-coinfected individuals is discussed.
doi:10.1089/aid.2006.0172
PMCID: PMC2894418  PMID: 17506609
5.  Increased Mortality in Rural Patients with HIV in New England 
Although patients with human immunodeficiency virus (HIV) infection who live in the rural United States receive less expert care and less antiretroviral treatment, the impact of living in rural areas on mortality from HIV infection is unstudied. We compared mortality rates in 327 rural and 317 urban patients with HIV infection in a retrospective cohort study using a multivariate logistic regression model. Rural patients with HIV infection were older at the end of follow-up (43.4 vs. 41.4 years, p = 0.002), and more likely white (93.0% vs. 77.9%, p < 0.001), and a greater proportion were men who have sex with men (55.5% vs. 36.1%, p < 0.001). While the mean year of diagnosis was 1994 in rural patients and 1995 in urban patients (p < 0.001), the mean CD4+ T cell count at presentation was similar in the two groups: 376 vs. 351 cells/μl (p = 0.298). Rural patients in our cohort were more likely to receive antiretroviral medications at any CD4 count (73.7 vs. 62.1%, p = 0.0016), and received PCP prophylaxis at comparable rates (23.5% vs. 25.6%, p = 0.555). Mortality was higher in rural patients (10.4% vs. 6.0%, p = 0.028). The risk of mortality remained higher in rural patients when adjusting for age, sex, race, HIV risk factors, year of diagnosis, travel time, lack of insurance, and receipt of antiretroviral treatment or PCP prophylaxis in a logistic regression model (OR 2.11, 1.064 to 4.218, p = 0.047). Patients with HIV who live in rural areas have higher mortality rates than urban patients with HIV.
doi:10.1089/aid.2006.0206
PMCID: PMC2872149  PMID: 17530995
6.  First Molecular Surveillance Report of HIV Type 1 in Injecting Drug Users and Female Sex Workers along the U.S.–Mexico Border 
HIV prevalence is increasing among high-risk populations in the Mexican–U.S. border cities of Tijuana and Ciudad Juarez. In 2005, the molecular epidemiology of HIV-1 was studied among injecting drug users (IDU) and female sex workers (FSW) in these cities, which are corridors for over two-thirds of the migrant flow between Mexico and the United States. Eleven samples (eight IDU and three FSW) were successfully amplified, sequenced, and analyzed. The results revealed that all 11 samples were subtype B. There was no phylogenetic clustering or separation of the strains between IDU and FSW or between Tijuana and Ciudad Juarez nor was the Mexican strain phylogenetically distinct from other subtype B strains. Two of three drug naive FSWs had low-level HIV-1 resistance mutations. This community-based study demonstrated that HIV-positive IDUs and FSWs in Ciudad Juarez and Tijuana were predominantly infected with subtype B. Further prevalence studies on HIV-1 resistance mutations among FSWs in these border cities are warranted.
doi:10.1089/aid.2006.0166
PMCID: PMC2734975  PMID: 17331041
7.  Brain Magnetic Resonance Imaging White Matter Lesions Are Frequent in HTLV-I Carriers and Do Not Discriminate from HAM/TSP 
AIDS research and human retroviruses  2007;23(12):1499-1504.
Human T lymphotropic virus (HTLV)-I is known to cause HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and other pronounced disease in less than 4% of those infected. However, evidence is accumulating that a proportion of HTLV-I carriers have neurological and urological symptoms without fulfilling criteria for HAM/TSP. Brain white matter (WM) lesions on magnetic resonance imaging (MRI) are frequently seen in HAM/TSP. HTLV-I carriers with MRI scans for other neurological diagnoses have WM lesions more frequently than expected. We studied 10 patients with HAM/TSP and 20 HTLV-I carriers without overt neurological disease and evaluated clinical characteristics, viral load, total, small, large, confluent WM lesion number, and lesion volume on MRI. Cerebral WM lesions were found in of 85% of HTLV-I carriers and 80% of HAM/TSP patients. Lesion number, size or location was no different between carriers and HAM/TSP. Cognitive function was lower in HAM/TSP (p = 0.045) but did not correlate with WM lesion number. Viral load and peripheral blood mononuclear cell interferon-γ production correlated positively (p = 0.001) but did not correlate with lesion number or volume. Conventional brain MRI frequently shows WM lesions in HTLV-I-infected individuals suggesting potential early central nervous system inflammation with rare development of progressive disease.
doi:10.1089/aid.2007.0077
PMCID: PMC2593463  PMID: 18160007
8.  Clinical Manifestations Associated with HTLV Type I Infection: A Cross-Sectional Study 
Human T-lymphotropic virus type I (HTLV-I) causes HTLV-I-associated myelopathy/tropical spastic paraparesis and adult T cell leukemia in a small percentage of infected individuals. HTLV-I infection is increasingly associated with clinical manifestations. To determine the prevalence of clinical manifestations in HTLV-I infected individuals, we conducted a cross-sectional study of 115 HTLV-I-infected blood donors without myelopathy and 115 age- and sex-matched seronegative controls. Subjects answered a standardized questionnaire and underwent physical examination. Compared with controls, HTLV-I-infected subjects were more likely to report arm or leg weakness (OR = 3.8, 95% CI: 1.4–10.2; OR = 4.0, 95% CI: 1.6–9.8, respectively), hand or foot numbness (OR = 2.1, 95% CI: 1.1–3.9; OR = 4.8, 95% CI: 2.0–11.7, respectively), arthralgia (OR = 3.3, 95% CI: 1.7–6.4), nocturia (OR = 2.7, 95% CI: 1.04–6.8), erectile dysfunction (OR = 4.0, 95% CI: 1.6–9.8), and to have gingivitis (OR = 3.8, 95% CI: 1.8–7.9), periodontitis (OR = 10.0, 95% CI: 2.3–42.8), and dry oral mucosa (OR = 7.5, 95% CI: 1.7–32.8). HTLV-I infection is associated with a variety of clinical manifestations, which may occur in patients who have not developed myelopathy.
doi:10.1089/aid.2006.0140
PMCID: PMC2593454  PMID: 17411369
9.  Inhibition of HIV-1 replication in CD4+ and CD14+ cells purified from HIV-1-infected individuals by the 2-5A agonist immunomodulator, 2-5AN6B 
Two major interferon (IFN)-mediated antiviral defense enzymes are double-stranded (ds)RNA-dependent 2′,5′-oligoadenylate (2-5A) synthetase (2-5OAS) and p68 kinase (PKR). When activated by dsRNA, 2-5OAS synthesizes 2-5A, which binds to and activates RNase L. Activated RNase L hydrolyzes single-stranded viral RNA, thereby inhibiting viral protein synthesis. HIV-1 inhibits the IFN-mediated intracellular antiviral pathways. We have reported the synthesis and characterization of a nuclease-resistant 2-5A agonist (2-5AN6B) that overcomes the HIV-1 induced blockades by restoring the 2-5OAS/RNase L antiviral pathway (Homan, J.W., et al., J Acquir Immune Defic Syndr 2002;30:9–20). The objective of this study was to test the effect of 2-5AN6B on chronically infected CD4+ T lymphocytes and CD14+ monocytes derived from HIV-1 seropositive individuals. Wild type HIV-1 replication was effectively inhibited by 2-5AN6B in CD4+ T lymphocytes and CD14+ monocytes purified from HIV-1 seropositive individuals (n = 18) compared to untreated cells. We also assessed the cytotoxicity of 2-5AN6B and report that 2-5AN6B exerts its anti-HIV-1 activity with no evidence of cytotoxicity (IC90 > 100,000 nM). Furthermore, 2-5AN6B did not alter the cellular RNA profile, affect CCR5 or CXCR4 co-receptor expression, or activate caspase-dependent apoptosis. Evidence is also provided to show that 2-5AN6B, and naturally occurring 2-5A4, act as ligands to activate human Toll-like receptor 4. These results indicate that the 2-5A agonist, 2-5AN6B, has potential to enhance host cell innate and acquired immune defense mechanisms against HIV-1 infection.
doi:10.1089/aid.2005.0091
PMCID: PMC1941645  PMID: 17263642
2-5A agonist; HIV-1 replication; 2-5OAS/RNase L antiviral pathway; CD4+ and CD14+ cells; Toll-like receptor

Results 1-9 (9)