Abstract
BackgroundIn patients with HIV/AIDS receiving antiretroviral therapy (ART), HIV-1 persistence in brain tissue is a vital and unanswered question. HIV-1 infects and replicates in resident microglia and trafficking macrophages within the brain although the impact of individual ART drugs on viral infection within these brain myeloid cells is unknown. Herein, the effects of contemporary ART drugs were investigated using in vitro and in vivo models of HIV-1 brain infection.ResultsThe EC50 values for specific ART drugs in HIV-infected human microglia were significantly higher compared to bone marrow-derived macrophages and peripheral blood mononuclear cells. Intracellular ART drug concentrations in microglia were significantly lower than in human lymphocytes. In vivo brain concentrations of ART drugs in mice were 10 to 100-fold less in brain tissues compared with plasma and liver levels. In brain tissues from untreated HIV-infected BLT mice, HIV-encoded RNA, DNA and p24 were present in human leukocytes while ART eradicated viral RNA and DNA in both brain and plasma. Interruption of ART resulted in detectable viral RNA and DNA and increased human CD68 expression in brains of HIV-infected BLT mice. In aviremic HIV/AIDS patients receiving effective ART, brain tissues that were collected within hours of last ART dosing showed HIV-encoded RNA and DNA with associated neuroinflammatory responses.ConclusionsART drugs show variable concentrations and efficacies in brain myeloid cells and tissues in drug-specific manner. Despite low drug concentrations in brain, experimental ART suppressed HIV-1 infection in brain although HIV/AIDS patients receiving effective ART had detectable HIV-1 in brain. These findings suggest that viral suppression in brain is feasible but new approaches to enhancing ART efficacy and concentrations in brain are required for sustained HIV-1 eradication from brain.
Highlights
In patients with HIV/AIDS receiving antiretroviral therapy (ART), HIV-1 persistence in brain tissue is a vital and unanswered question
After HIV-1YU2 infection at matched input titers (MOI = 0.1), bone marrow-derived macrophages (BMDMs) showed increased release of HIV-1 p24 in supernatants over time compared to human fetal microglia (HFM), with peak p24 release at Day 12 post-infection (Fig. 1c)
Both BMDMs and HFM supported HIV-1 replication but BMDM exhibited higher viral production levels, possibly due to increased CD4 and CCR5 expression in keeping with previous observations suggesting there is higher viral replication in macrophages compared to microglia [23]
Summary
In patients with HIV/AIDS receiving antiretroviral therapy (ART), HIV-1 persistence in brain tissue is a vital and unanswered question. HIV-1 infects and replicates in resident microglia and trafficking macrophages within the brain the impact of individual ART drugs on viral infection within these brain myeloid cells is unknown. Productive HIV-1 infection is evident in trafficking macrophages (bone marrow-derived macrophages) and resident microglia, but few if any infected T cells are observed [8,9,10,11]. These myeloid cell populations in the brain constitute a unique reservoir in which HIV-1 replicates because of the paucity of resident lymphoid cells within the brain and the blood–brain barrier’s impervious structure, which limits drug penetration. Recent studies of cerebrospinal fluid (CSF) show higher than expected rates of viral escape in CSF that were associated with brain injury in the setting of undetectable virus in plasma [17]
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