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Genetic and phenotypic features of blood and genital viral populations of clinically asymptomatic and antiretroviral-treatment-naive clade a human immunodeficiency virus type 1-infected women.

ABSTRACT: In the present study, we assessed whether human immunodeficiency virus type 1 (HIV-1) genetic compartmentalization was associated with phenotypic CCR5 (R5) or CXCR4 (X4) coreceptor usage differences between the systemic and the genital viral populations. Four clinically asymptomatic and treatment-naïve clade A HIV-1-infected patients were selected from a cohort of 274 African women, because they were free of all the biological cofactors known to modify the kinetics of viral production in the genital tract. HIV RNA envelope sequences (V1 to V3) derived from plasma and cervicovaginal secretions (CVS) were amplified, subcloned, and sequenced. CCR5 or CXCR4 coreceptor usage was determined by production of recombinant viral particles, followed by single-cycle infection assays of indicator cell lines, using the tropism recombinant test. In these four selected patients, CVS-derived sequences appeared to be genetically distinct from blood-derived sequences (P < or = 0.001). Two patients were found to harbor virus populations with only the R5 phenotype in both compartments, whereas viruses using CXCR4 in addition to CCR5 were detected in two other patients. In particular, one woman harbored genital virus populations with mixed R5 and X4 phenotypes associated with peripheral blood populations with only the R5 phenotype. These results demonstrate genetic compartmentalization of HIV between the plasma and genital secretions of clinically asymptomatic, treatment-naïve, clade A-infected women. Also, for one patient, we report phenotypic coreceptor usage differences between the systemic (R5) and genital (R5/X4) viral populations. These features may be critical for the development of further mucosal vaccines, therapies, or new preventive strategies to block heterosexual transmission.

SUBMITTER: Andreoletti L

PROVIDER: S-EPMC1933108 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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Genetic and phenotypic features of blood and genital viral populations of clinically asymptomatic and antiretroviral-treatment-naive clade a human immunodeficiency virus type 1-infected women.

Andreoletti Laurent L Skrabal Katharina K Perrin Virginie V Chomont Nicolas N Saragosti Sentob S Gresenguet Gerard G Moret Helene H Jacques Jerome J Longo Jean de Dieu Jde D Matta Mathieu M Mammano Fabrizio F Belec Laurent L

Journal of clinical microbiology 20070425 6

In the present study, we assessed whether human immunodeficiency virus type 1 (HIV-1) genetic compartmentalization was associated with phenotypic CCR5 (R5) or CXCR4 (X4) coreceptor usage differences between the systemic and the genital viral populations. Four clinically asymptomatic and treatment-naïve clade A HIV-1-infected patients were selected from a cohort of 274 African women, because they were free of all the biological cofactors known to modify the kinetics of viral production in the gen ...[more]

PMID: 17460054

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Project description:The development of viral diversity during the course of human immunodeficiency virus type 1 (HIV-1) infection may significantly influence viral pathogenesis. The paradigm for HIV-1 evolution is based primarily on studies of male cohorts in which individuals were presumably infected with a single virus variant of subtype B HIV-1. In this study, we evaluated virus evolution based on sequence information of the V1, V2, and V3 portions of HIV-1 clade A envelope genes obtained from peripheral blood and cervical secretions of three women with genetically heterogeneous viral populations near seroconversion. At the first sample following seroconversion, the number of nonsynonymous substitutions per potential nonsynonymous site (dn) significantly exceeded substitutions at potential synonymous sites (ds) in plasma viral sequences from all individuals. Generally, values of dn remained higher than values of ds as sequences from blood or mucosa evolved. Mutations affected each of the three variable regions of the envelope gene differently; insertions and deletions dominated changes in V1, substitutions involving charged amino acids occurred in V2, and sequential replacement of amino acids over time at a small subset of positions distinguished V3. The relationship among envelope nucleotide sequences obtained from peripheral blood mononuclear cells, plasma, and cervical secretions was evaluated for each individual by both phylogenetic and phenetic analyses. In all subjects, sequences from within each tissue compartment were more closely related to each other than to sequences from other tissues (phylogenetic tissue compartmentalization). At time points after seroconversion in two individuals, there was also greater genetic identity among sequences from the same tissue compartment than among sequences from different tissue compartments (phenetic tissue compartmentalization). Over time, temporal phylogenetic and phenetic structure was detectable in mucosal and plasma viral samples from all three women, suggesting a continual process of migration of one or a few infected cells into each compartment followed by localized expansion and evolution of that population.

Project description:Micronutrient deficiencies occur early in human immunodeficiency virus (HIV) infection, and supplementation with micronutrients may be beneficial; however, its effectiveness has not been investigated early in HIV disease among adults who are antiretroviral therapy (ART) naive.To investigate whether long-term micronutrient supplementation is effective and safe in delaying disease progression when implemented early in adults infected with HIV subtype C who are ART-naive.Randomized clinical trial of supplementation with either daily multivitamins (B vitamins and vitamins C and E), selenium alone, or multivitamins with selenium vs placebo in a factorial design for 24 months. The study was conducted in 878 patients infected with HIV subtype C with a CD4 cell count greater than 350/?L who were not receiving ART at Princess Marina Hospital in Gaborone, Botswana, between December 2004 and July 2009.Daily oral supplements of B vitamins and vitamins C and E, selenium alone, or multivitamins plus selenium, compared with placebo.Reaching a CD4 cell count less than 200/?L until May 2008; after this date, reaching a CD4 cell count of 250/?L or less, consistent with the standard of care in Botswana for initiation of ART at the time of the study.There were 878 participants enrolled and randomized into the study. All participants were ART-naive throughout the study. In intent-to-treat analysis, participants receiving the combined supplement of multivitamins plus selenium had a significantly lower risk vs placebo of reaching CD4 cell count 250/?L or less (adjusted hazard ratio [HR], 0.46; 95% CI, 0.25-0.85; P?=?.01; absolute event rate [AER], 4.79/100 person-years; censoring rate, 0.92; 17 events; placebo AER, 9.22/100 person-years; censoring rate, 0.85; 32 events). Multivitamins plus selenium in a single supplement, vs placebo, also reduced the risk of secondary events of combined outcomes for disease progression (CD4 cell count ?250/?L, AIDS-defining conditions, or AIDS-related death, whichever occurred earlier [adjusted HR, 0.56; 95% CI, 0.33-0.95; P?=?.03; AER, 6.48/100 person-years; censoring rate, 0.90; 23 events]). There was no effect of supplementation on HIV viral load. Multivitamins alone and selenium supplementation alone were not statistically different from placebo for any end point. Reported adverse events were adjudicated as unlikely to be related to the intervention, and there were no notable differences in incidence of HIV-related and health-related events among study groups.In ART-naive HIV-infected adults, 24-month supplementation with a single supplement containing multivitamins and selenium was safe and significantly reduced the risk of immune decline and morbidity. Micronutrient supplementation may be effective when started in the early stages of HIV disease.

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Project description:INTRODUCTION:Replication of the human immunodeficiency virus involves an obligatory step of reverse transcription of the viral ribonucleic acid genome into a double-stranded deoxyribonucleic acid, and subsequent integration of the deoxyribonucleic acid into the human chromatin to form the proviral deoxyribonucleic acid. This proviral human immunodeficiency virus deoxyribonucleic acid is a critical marker for the diagnosis of acute infections, mother-to-child transmissions and for the confirmation of indeterminate serological reactions. We describe a case of a human immunodeficiency virus positive woman, naïve to antiretroviral treatment, who was persistently negative for human immunodeficiency virus proviral deoxyribonucleic acid polymerase chain reaction. This observation, to the best of our knowledge, is the first time that it has been described in Africa. CASE PRESENTATION:A 28-year-old Gabonese woman living in Cameroon requested a human immunodeficiency virus diagnosis in our laboratory. She had an unprotected heterosexual contact 6 months earlier while on vacation in Gabon. The request for a human immunodeficiency virus test was as a result of apprehensions developed after the exposure episode. Human immunodeficiency virus serological examinations were ambiguous and confirmatory tests (including human immunodeficiency virus proviral deoxyribonucleic acid polymerase chain reaction) were carried out. Apart from the human immunodeficiency virus proviral deoxyribonucleic acid polymerase chain reaction that was persistently negative, all other polymerase chain reactions carried out were positive. The deoxyribonucleic acid sequences have been submitted to the GenBank database with accession numbers: KC626022, KC626023 and KC626024 for the protease, reverse transcriptase and gp41 genes respectively. CONCLUSION:The persistently negative human immunodeficiency virus proviral deoxyribonucleic acid polymerase chain reaction in a person with a confirmed human immunodeficiency virus infection is of immense importance in the human immunodeficiency virus diagnostic field. This could highlight the fact that cases of false negative human immunodeficiency virus proviral deoxyribonucleic acid polymerase chain reactions exist especially with the high genetic variations observed with human immunodeficiency virus. The challenges presented by such false negative tests in the identification of acute infections, mother-to-child transmissions and the confirmation of indeterminate serological reactions are daunting. These data therefore would be invaluable especially to clinicians in Africa where non-B human immunodeficiency virus subtypes circulate.

Project description:Background:Human immunodeficiency virus (HIV)-infected individuals are at increased risk of age-associated functional impairment, even with effective antiretroviral therapy (ART). A concurrent characterization of skeletal muscle, physical function, and immune phenotype in aviremic middle-aged HIV-infected adults represents a knowledge gap in prognostic biomarker discovery. Methods:We undertook a prospective observational study of 170 middle-aged, HIV-infected ambulatory men and women with CD4+ T-cell counts of at least 350/µL and undetectable plasma viremia while on effective ART, and uninfected control participants. We measured biomarkers for inflammation and immune activation, fatigue, the Veterans Aging Cohort Study mortality index, and physical function. A subset also received a skeletal muscle biopsy and computed tomography scan. Results:Compared to the uninfected participants, HIV-infected participants displayed increased immune activation (P < .001), inflammation (P = .001), and fatigue (P = .010), and in a regression model adjusting for age and sex displayed deficits in stair-climb power (P < .001), gait speed (P = .036), and predicted metabolic equivalents (P = .019). Skeletal muscle displayed reduced nuclear peroxisome proliferator-activated receptor-γ coactivator 1α-positive myonuclei (P = .006), and increased internalized myonuclei (P < .001) that correlated with immune activation (P = .003) and leukocyte infiltration (P < .001). Internalized myonuclei improved a model for HIV discrimination, increasing the C-statistic from 0.84 to 0.90. Conclusions:Asymptomatic HIV-infected middle-aged adults display atypical skeletal muscle profiles, subclinical deficits in physical function, and persistent inflammation and immune activation. Identifying biomarker profiles for muscle dysregulation and risk for future functional decline in the HIV-infected population will be key to developing and monitoring preventive interventions. Clinical Trials Registration:NCT03011957.

Dataset Information

Genetic and phenotypic features of blood and genital viral populations of clinically asymptomatic and antiretroviral-treatment-naive clade a human immunodeficiency virus type 1-infected women.

Publications

Genetic and phenotypic features of blood and genital viral populations of clinically asymptomatic and antiretroviral-treatment-naive clade a human immunodeficiency virus type 1-infected women.

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