A case of ganciclovir-resistant cytomegalovirus (CMV) retinitis in a patient with AIDS: longitudinal molecular analysis of the CMV viral load and viral mutations in blood compartments

OBJECTIVE: To study the temporal relationships between cytomegalovirus (CMV) viral load and specific UL97 mutations in polymorphonuclear leukocytes (PMNL) and plasma samples from a patient with AIDS who developed ganciclovir-resistant CMV retinitis. METHODS: Sequential PMNL and plasma samples were analysed for determination of the CMV viral load using non-molecular methods and a quantitative polymerase chain reaction (PCR) assay. Screening of the same samples for the most common mutations conferring ganciclovir resistance was performed using nested PCR and restriction enzyme analysis. RESULTS: At the time of progression of CMV retinitis (after 6 months of ganciclovir), a rapid increase in the CMV DNA load was found in both PMNL and plasma samples. This increase paralleled the emergence of a specific mutation (V594) in the same samples and recovery of ganciclovir-resistant blood isolates. In this patient, however, the only tests that substantially predicted the progression of CMV disease were the quantitative PCR assay using PMNL and to a lesser extent the pp65 antigenemia assay. CONCLUSIONS: Quantitative evaluation of the CMV viral load in PMNL using sensitive assays such as PCR appears to be a promising approach for monitoring antiviral therapy in subjects with AIDS. In addition, common mutations conferring ganciclovir resistance can be detected directly in PMNL and plasma samples.     

HIV-1 viral load: comparative evaluation of three commercially available assays in Argentina

Autosomal recessive nonsyndromic hearing loss (ARNSHL) is the most common form of hereditary hearing impairment (HHI). To date, 16 different loci have been reported, making ARNSHL an extremely heterogeneous disorder. One of these loci, DFNB4, was mapped to a 5-cM interval of 7q31 in a large Middle-Eastern Druze family. This interval also includes the gene for Pendred syndrome. We report on three new families with HHI from the Madras region of southern India that demonstrate linkage to 7q. Their pedigrees are compatible with autosomal recessive inheritance. Furthermore, the largest family identifies a novel locus (DFNB17) telomeric to the DFNB4 and Pendred intervals. A 3-cM region of homozygosity by descent between markers D7S486 and D7S2529 is present in all affected individuals in this family and generates a multipoint LOD score of 4.24. The two other families map to the previously reported DFNB4 region but have insufficient power to attain significant LOD scores. However, mutations in the Pendred syndrome gene are present in one of these families.     

Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA

Although cytotoxic T lymphocytes (CTLs) are thought to be involved in the control of human immunodeficiency virus-type 1 (HIV-1) infection, it has not been possible to demonstrate a direct relation between CTL activity and plasma RNA viral load. Human leukocyte antigen-peptide tetrameric complexes offer a specific means to directly quantitate circulating CTLs ex vivo. With the use of the tetrameric complexes, a significant inverse correlation was observed between HIV-specific CTL frequency and plasma RNA viral load. In contrast, no significant association was detected between the clearance rate of productively infected cells and frequency of HIV-specific CTLs. These data are consistent with a significant role for HIV-specific CTLs in the control of HIV infection and suggest a considerable cytopathic effect of the virus in vivo.     

Neuropsychiatric HIV-1 infection study: in Kenya and Zaire cross-sectional phase I and II

The objective of the study was to determine the prevalence and natural history of human immunodeficiency virus type 1 (HIV-1) associated psychiatric, neuropsychological and neurological abnormalities. A total of 408 subjects were recruited in Nairobi and Kinshasa. The study consisted of a cross sectional phase and a longitudinal follow up. Assessment was made by a data collection instrument including six modules. The intercentre and intracentre reliability in the use of the each module have been formally evaluated. The mean global score on the Montgomery-Asberg Depression Rating Scale was significantly higher in symptomatic seropositive individuals than in matched seronegative controls. In conclusion, these data suggest that the risk of subtle cognitive deficits may be increased in asymptomatic stages of HIV-1 infection.     

Peptide inhibitors of HIV-1 protease and viral infection of peripheral blood lymphocytes based on HIV-1 Vif

We recently reported that HIV-1 Vif (virion infectivity factor) inhibits HIV-1 protease in vitro and in bacteria, suggesting that it may serve as the basis for the design of new protease inhibitors and treatment for HIV-1 infection. To evaluate this possibility, we synthesized peptide derivatives from the region of Vif, which inhibits protease, and tested their activity on protease. In an assay of cleavage of virion-like particles composed of HIV-1 Gag precursor polyprotein, full-length recombinant Vif, and a peptide consisting of residues 21-65 of Vif, but not a control peptide or BSA, inhibited protease activity. Vif21-65 blocked protease at a molar ratio of two to one. We then tested this peptide and a smaller peptide, Vif41-65, for their effects on HIV-1 infection of peripheral blood lymphocytes. Both Vif peptides inhibited virus expression below the limit of detection, but control peptides had no effect. To investigate its site of action, Vif21-65 was tested for its effect on Gag cleavage by protease during HIV-1 infection. We found that commensurate with its reduction of virus expression, Vif21-65 inhibited the cleavage of the polyprotein p55 to mature p24. These results are similar to those obtained by using Ro 31-8959, a protease inhibitor in clinical use. We conclude that Vif-derived peptides inhibit protease during HIV-1 infection and may be useful for the development of new protease inhibitors.     

Polymorphonuclear neutrophils in saliva and blood: a comparative study of morphology, function and phenotype

Sixteen beagle dogs were injected intradermally with Rickettsia rickettsii. The dogs were divided into four groups (n = 4): 1) infected, non-treated control; 2) infected, treated with doxycycline; 3) infected, treated with doxycycline and an anti-inflammatory dose of corticosteroid; and 4) infected, treated with doxycycline and an immunosuppressive dose of corticosteroid. Thoracic radiographs were made and ocular fluorescein angiography was performed on days 6, 10, 17 post-inoculation. A mild interstitial lung opacity was noted in 4/16 dogs on day 6, 5/16 on day 10 and 3/16 on day 17 post-inoculation. Increased retinal vascular permeability was noted in 8/16 dogs on day 6, 3/16 on day 10 and 1/16 on day 17 post-inoculation. Correlation between the presence of radiographic and retinal lesions was not significant (p = 0.08). Eleven, naturally infected, dogs with thoracic radiographs and a final diagnosis of RMSF were also evaluated. Four of the 11 dogs had an unstructured interstitial pattern. Dogs with acute, experimentally-infected or naturally-occurring RMSF may have subtle pulmonary changes characterized by an unstructured interstitial pattern.     

Genetic characterization of viral quasispecies in blood and cervical secretions of HIV-1- and HIV-2-infected women

We evaluated cervical samples from 11 HIV-1- and 25 HIV-2-infected individuals. The rate of viral shedding was 36.4% for HIV-1 and 16% for HIV-2, after repeat PCRs. We sequenced multiple clones of the C2-C3 env region from cervical secretions and PBMC samples from three HIV-2-infected individuals, and the C2-V3 env region from four HIV-1-infected individuals. In most cases, phylogenetic analysis showed that the viral sequences from blood and genital secretions were intermingled and subclusters did not segregate according to sample site. In rare cases, however, tissue-specific sequences were observed, suggesting a complex relationship between quasispecies in the two sites where preferential transmission of HIV variants may be due to multiple factors.     

Immune markers and viral load after HIV-1 seroconversion as predictors of disease progression in a cohort of haemophilic men

OBJECTIVE: To assess the prognostic value of HIV RNA levels measured shortly after HIV seroconversion and whether markers of immune response (CD4+ and CD8+ T-cell counts, IgA and IgG) measured at the same time, continue to provide prognostic information once the HIV RNA level is known. DESIGN AND METHODS: HIV RNA levels were measured approximately 2.5 years after seroconversion in 97 haemophilic men followed for up to 17 years. Levels of CD4+ and CD8+ T cells, IgA and IgG were measured within 1 year of the HIV RNA level. The relationships between these markers and progression to AIDS and death were studied using Kaplan-Meier plots and proportional hazards regression models. RESULTS: High HIV RNA levels were associated with faster progression to AIDS and shorter survival in univariate Cox regression models. High IgA and IgG levels were also associated with faster disease progression. In multivariate models, high HIV RNA levels remained independently associated with faster disease progression [relative hazard (RH), 1.86; P = 0.01 for AIDS; RH, 1.66; P = 0.05 for death). However, high IgA and IgG levels provided strong independent prognostic information for AIDS and death (IgA: RH, 1.38; P = 0.006 for AIDS; RH, 1.33; P = 0.07 for death; IgG: RH, 1.10; P = 0.02 for AIDS; RH, 1.12; P = 0.01 for death). CONCLUSIONS: Our results confirm the importance of the HIV RNA level in assessing the long-term prognosis in individuals infected with HIV. However, our results suggest that immune activation markers, rather than merely reflecting high HIV RNA levels are important in assessing prognosis in their own right. These findings may improve our understanding of HIV pathogenesis and may aid clinical management of patients.     

Increases in depressive symptomatology in the rural elderly: Results from a cross-sectional and longitudinal study.

Depressive symptomatology was examined in a large sample of noninstitutionalized older adults using the Center for Epidemiological Studies-Depression scale (CES-D). Both cross-sectional and longitudinal data showed age-related increases in mean CES-D scores and increases in the percentage of respondents scoring at or above the cutoff score of 16. Variables collected at baseline in the longitudinal study from 2,032 participants 65 yrs of age and older were significant predictors of depressive symptomatology 3 and 6 yrs later. Baseline CES-D scores accounted for the largest proportion of the variance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Rate of HIV-1 decline following antiretroviral therapy is related to viral load at baseline and drug regimen

OBJECTIVES AND DESIGN: The dynamics uf viral decline following the initiation of antiretroviral treatment were studied in 29 HIV-1-infected patients participating in a two-arm trial comparing immediate (group A: ritonavir, zidovudine and lamivudine) and delayed (group B: ritonavir supplemented by zidovudine and lamivudine on day 21) triple therapy. Parameters underlying viral dynamics were estimated using mathematical models tailored to these treatment protocols. RESULTS: The decline in plasma HIV-1 density between day 0 and 21 was steeper in group A (-2.27+/- 0.46 log10) than group B (-1.87+/-0.56 log10). In a subset of patients amenable to full mathematical analysis, a short-lived productively infected cell compartment (producing approximately 97% of total virions) decayed with a half-life of 1.0-2.5 days, whereas a long-lived infected cell compartment decayed with a half-life of 18.8-32.8 days. Estimates for the time for the elimination of virus from these two cell populations ranged from 474 to 802 days. The rate of loss of productively infected CD4+ T cells was positively correlated with baseline viral load in group A and in the combined dataset. CONCLUSIONS: These results suggest that HIV-infected cell populations may have a faster turnover in patients with higher viral loads due to higher infection rate parameters, higher rates of virus production, or lower virus clearance rates.     

Value of HIV-1 viral load and CD4 lymphocyte count as determinants of progression to AIDS and survival

BACKGROUND: HIV-1 viral load is regarded as a better surrogate marker for progression and death than CD4+ cell counts. Both markers are analysed in a cohort of patients with unknown seroconversion date and advanced HIV infection. PATIENTS AND METHODS: Retrospective cohort analysis of 421 patients, most on antiretroviral therapy, with a median initial CD4+ cell count of 209 x 10(6)/l and a median initial viral load of 4.7 log copies/ml. One thousand two hundred and eighty-six samples were analysed. Univariate and bivariate analysis were performed with initial and sequential CD4+ cell counts and viral load values to estimate the risk of progression and death by Cox regression models. RESULTS: After a median follow up of 763 days, 124 patients developed AIDS and 117 died. Relative risks of progression related to the group that maintained viral load values always < 35,000 copies/ml were: 5-fold (95% CI: 1.4-17.0; p < 0.05) for patients with any viral load value > 35,000 copies/ml but always < 200,000 copies/ml; and 13.6 fold (95% CI: 5.4-34.2; p < 0.0001) for patients who could not maintain viral load < 200.000 copies/ml. CD4+ counts = 100 x 10(6)/l and viral load = 220,000 copies/ml were the threshold values that best fitted to estimate the probability of survival by a bivariate analysis. CONCLUSIONS: The maintenance of sequential viral load values < 35.000 copies/ml is associated with a lower risk of progression. The maintenance of sequential viral load values < 150,000 copies/ml is associated with higher short-term survival rates.     

Changes in maximal exercise ventilation and breathing pattern in boys during growth: a mixed cross-sectional longitudinal study

The aim of this mixed cross-sectional longitudinal study covering a total age range of 11-17 years, i.e. the entire pubertal growth period, was (1) to specify the changes in maximal breathing pattern during incremental exercise; (2) to determine what parts of the changes are due to anthropometric characteristics, physical fitness and inspiratory or expiratory muscle strength; and (3) to determine if the role of these variables is identical before, during and after pubertal growth spurt. This study was conducted in 44 untrained schoolboys separated into three groups, with an initial age of 11.2 +/- 0.2 years for group A, 12.9 +/- 0.25 years for group B, and 14.9 +/- 0.26 years for group C. These children were subsequently followed for 3 years, during the same time period each year. The maximal inspiratory and expiratory pressures (PI max and PE max) were used as an index of the respiratory muscle strength. During an incremental exercise test, maximal ventilation (VE max), tidal volume (VT max), breathing frequency (fmax), inspiratory and expiratory times (tI max and tE max) and mean inspiratory flow (VT/tI max) were measured at maximal oxygen uptake (VO2max). Our study showed that there was a marked increase with age in VE max, VT max, and VT/tI max, and no significant changes in fmax, tI max and tE max. PI max and PE max showed a general trend towards an increase between 11 and 17 years. The study of the linear correlations between maximal breathing pattern and the anthropometric characteristics, physical fitness and inspiratory or expiratory muscle strength showed that, in the three groups of children, (1) lean body mass was the major determinant of VE max, VT max and VT/tI max and the relationships were significantly different before, during and after the pubertal growth spurt; (2) physical fitness was the main determinant of tI max, tE max and fmax before and after the pubertal growth spurt; and (3) maximal respiratory strength did not play a significant role. In conclusion, this mixed cross-sectional longitudinal study showed, at maximal exercise, a significant increase in VE max during growth due only to a significant increase in VT max and VT/tI max, and that the relationships of anthropometric characteristics and physical fitness with maximal breathing pattern change during growth.     

Personality differences predict health-risk behaviors in young adulthood: evidence from a longitudinal study

In a longitudinal study of a birth cohort, the authors identified youth involved in each of 4 different health-risk behaviors at age 21: alcohol dependence, violent crime, unsafe sex, and dangerous driving habits. At age 18, the Multidimensional Personality Questionnaire (MPQ) was used to assess 10 distinct personality traits. At age 3, observational measures were used to classify children into distinct temperament groups. Results showed that a similar constellation of adolescent personality traits, with developmental origins in childhood, is linked to different health-risk behaviors at 21. Associations between the same personality traits and different health-risk behaviors were not an artifact of the same people engaging in different health-risk behaviors; rather, these associations implicated the same personality type in different but related behaviors. In planning campaigns, health professionals may need to design programs that appeal to the unique psychological makeup of persons most at risk for health-risk behaviors.     

Stability and change in personality disorder symptomatology: findings from a longitudinal study of HIV+ and HIV- men

A longitudinal study was conducted to investigate the stability of personality disorders (PDs) over a 2-year interval, as well as the association between change in PD symptomatology and change in psychological distress. Structured clinical interviews and questionnaires assessing PDs and psychological distress were administered to a community sample of 118 gay men (80 HIV seropositive men and 38 HIV seronegative men) at a baseline session and readministered 2 years later. Results indicated that PD symptom levels tended to be moderately stable, that PD diagnoses had low stability and that changes in PD symptom levels were associated with changing levels of psychological distress but not with progression of HIV infection.