Lentiviral Infections Persist in Brain despite Effective Antiretroviral Therapy and Neuroimmune Activation.

HIV infection persists in different tissue reservoirs among people with HIV (PWH) despite effective antiretroviral therapy (ART). In the brain, lentiviruses replicate principally in microglia and trafficking macrophages. The impact of ART on this viral reservoir is unknown. We investigated the activity of contemporary ART in various models of lentivirus brain infection. HIV-1 RNA and total and integrated DNA were detected in cerebral cortex from all PWH (n = 15), regardless of ART duration or concurrent plasma viral quantity and, interestingly, integrated proviral DNA levels in brain were significantly higher in the aviremic ART-treated group (P < 0.005). Most ART drugs tested (dolutegravir, ritonavir, raltegravir, and emtricitabine) displayed significantly lower 50% effective concentration (EC50) values in lymphocytes than in microglia, except tenofovir, which showed 1.5-fold greater activity in microglia (P < 0.05). In SIV-infected Chinese rhesus macaques, despite receiving suppressive (n = 7) or interrupted (n = 8) ART, brain tissues had similar SIV-encoded RNA and total and integrated DNA levels compared to brains from infected animals without ART (n = 3). SIV and HIV-1 capsid antigens were immunodetected in brain, principally in microglia/macrophages, regardless of ART duration and outcome. Antiviral immune responses were comparable in the brains of ART-treated and untreated HIV- and SIV-infected hosts. Both HIV-1 and SIV persist in brain tissues despite contemporary ART, with undetectable virus in blood. ART interruption exerted minimal effect on the SIV brain reservoir and did not alter the neuroimmune response profile. These studies underscore the importance of augmenting ART potency in different tissue compartments. IMPORTANCE Antiretroviral therapy (ART) suppresses HIV-1 in plasma and CSF to undetectable levels. However, the impact of contemporary ART on HIV-1 brain reservoirs remains uncertain. An active viral reservoir in the brain during ART could lead to rebound systemic infection after cessation of therapy, development of drug resistance mutations, and neurological disease. ART's impact, including its interruption, on brain proviral DNA remains unclear. The present studies show that in different experimental platforms, contemporary ART did not suppress viral burden in the brain, regardless of ART component regimen, the duration of therapy, and its interruption. Thus, new strategies for effective HIV-1 suppression in the brain are imperative to achieve sustained HIV suppression.

Sickle-cell disease in febrile children living in a rural village of Madagascar and association with malaria and respiratory infections.

BACKGROUND: In Madagascar, the last study on sickle cell disease (SCD) was done in the early 1980s. The country is known as endemic for malaria and respiratory infections. The main objective of this study was to estimate the prevalence of SCD; the secondary objective was to evaluate its association with malaria and respiratory infections. METHODS: This is a cross-sectional study which was carried out in a rural village in the south east coast of Madagascar between May 2011 and November 2013. Participants were children aged between 2-59 months presenting with fever measured by axillary temperature ≥37.5 °C at inclusion. Genotyping of haemoglobin S was done by PCR and malaria was diagnosed by Rapid Diagnostic Test. Research for viral and atypical bacterial respiratory pathogens was performed on nasopharyngeal swabs. Uni-and multivariate polytomous logistic regression was done to assess associations between microbiological results and SCD status, with HbAA phenotype as reference. RESULTS: A total of 807 children were analysed. Prevalence of SCD among febrile children was 2.4% (95% CI, 1.5-3.7%) and that of SCT was 23.8% (95% CI, 20.9-26.9%). There was no difference in the prevalence of malaria infection according to haemoglobin status (p = 0.3). Rhinovirus (22.5%), adenovirus (14.1%), and bocavirus (11.6%) were the most common respiratory pathogens detected. After univariate analysis, patients with SCD were more frequently infected by parechovirus (p = 0.01), while patients with SCT were more prone to RSV A or B infection (p = 0.01). After multivariate analysis, HbAS phenotype was associated with higher risk of RSV A and B infection compared to HbAA (adjusted OR = 1.9; 95% CI: 1.2-3.1, p = 0.009), while HbSS phenotype was associated with higher risk of parechovirus infection (adjusted OR = 6.0; 95% CI: 1.1-31.3, p = 0.03) compared to HbAA, independently of age, gender, period per quarter, and the other viruses. CONCLUSION: The prevalence of SCD among under-five children presenting with fever was high in the study population. No association was found between SCT and malaria but few viruses, especially parechovirus, seem to play an important role in the occurrence of pneumoniae among SCD patients.

Viral and atypical bacterial etiology of acute respiratory infections in children under 5 years old living in a rural tropical area of Madagascar.

BACKGROUND: In Madagascar, very little is known about the etiology and prevalence of acute respiratory infections (ARIs) in a rural tropical area. Recent data are needed to determine the viral and atypical bacterial etiologies in children with defined clinical manifestations of ARIs. METHODS: During one year, we conducted a prospective study on ARIs in children between 2 to 59 months in the community hospital of Ampasimanjeva, located in the south-east of Madagascar. Respiratory samples were analyzed by multiplex real-time RT-PCR, including 18 viruses and 2 atypical bacteria. The various episodes of ARI were grouped into four clinical manifestations with well-documented diagnosis: "Community Acquired Pneumonia"(CAP, group I), "Other acute lower respiratory infections (Other ALRIs, group II)", "Upper respiratory tract infections with cough (URTIs with cough, group III)"and "Upper respiratory tract infections without cough (URTIs without cough, group IV)". RESULTS: 295 children were included in the study between February 2010 and February 2011. Viruses and/or atypical bacteria respiratory pathogens were detected in 74.6% of samples, the rate of co-infection was 27.3%. Human rhinovirus (HRV; 20.5%), metapneumovirus (HMPV A/B, 13.8%), coronaviruses (HCoV, 12.5%), parainfluenza virus (HPIV, 11.8%) and respiratory syncytial virus A and B (RSV A/B, 11.8%) were the most detected. HRV was predominantly single detected (23.8%) in all the clinical groups while HMPV A/B (23.9%) was mainly related to CAP (group I), HPIV (17.3%) to the "Other ALRIs" (group II), RSV A/B (19.5%) predominated in the group "URTIs with cough" (group III) and Adenovirus (HAdV, 17.8%) was mainly detected in the "without cough" (group IV). INTERPRETATION: This study describes for the first time the etiology of respiratory infections in febrile children under 5 years in a malaria rural area of Madagascar and highlights the role of respiratory viruses in a well clinically defined population of ARIs.