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Prevention and treatment of HIV infection and cognitive disease in mice by innate immune responses.

ABSTRACT: HIV associated neurocognitive impairment afflicts roughly half of infected individuals on antiretroviral therapy. This disease currently has no treatment. We have previously shown that type I interferon is induced by and partially controls infection and neuropathogenesis in mice infected by chimeric HIV, EcoHIV. Here we investigate the intentional ligation of the pattern recognition receptor Toll-like receptor 3 (TLR3) by polyinosinic-polycytidylic acid (poly I:C) for its ability to prevent or control infection and associated cognitive disease in EcoHIV infected mice. We tested topical, injection, and intranasal application of poly I:C in mice during primary infection through injection or sexual transmission or in established infection. We measured different forms of HIV DNA and RNA in tissues by real-time PCR and the development of HIV-associated cognitive disease by the radial arm water maze behavioral test. Our results indicate that poly I:C blocks primary EcoHIV infection of mice prior to reverse transcription and reduces established EcoHIV infection. Prevention or control of viral replication by poly I:C prevents or reverses HIV associated cognitive disease in mice. These findings indicate that poly I:C or other innate immune agonists may be useful in control of HIV cognitive disease.

SUBMITTER: Dong B

PROVIDER: S-EPMC7375446 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Induction of innate immune responses reverses HIV cognitive disease in mice: profile by RNAseq in the brain

Project description:The extent of HIV immunodeficiency and related diseases has been greatly reduced by suppressive antiretroviral therapy but roughly 50% of infected people continue to develop mild neurocognitive disorder. We established an experimental approach to investigate HIV brain disease by infection of wildtype mice with the chimeric HIV, EcoHIV. The toll-like receptor 3 ligand, polyinosinic-polycytodylic acid (poly I:C), was used to induce innate immune responses prior to or during EcoHIV infection resulting in prevention of infection or reduced virus burden and reversed behavioral disease, respectively. Here we employed RNAseq to profile brain gene expression in EcoHIV infected mice at the time of cognitive impairment and its reversal in infected, poly I:C treated mice. We confirmed RNAseq findings by QPCR of a small set of transcripts. The major pathways down-regulated by infection involved neuronal function and this dysregulation was largely reversed by poly I:C treatment. Innate immune responses were the major functional pathways induced in infected, poly I:C treated mice that were absent in infected, untreated mice. Our findings provide a framework to identify essential brain cell genes dysregulated by HIV infection and identify a complementary set of immune response genes that block infection and its associated brain disease.

2023-10-24 | GSE245947 | GEO

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