EcoHIV infection of mice establishes latent viral reservoirs in T cells and active viral reservoirs in macrophages that are sufficient for induction of neurocognitive impairment

• DOI: 10.1371/journal.ppat.1007061
• Publication Date: 2018-06-07T17:26:18Z
• Authors: Chao-Jiang Gu; Alejandra Borjabad; Eran Hadas; Jennifer Kelschen...; Boe-Hyun Kim; Wei Chao; Ottavio Arancio; Jin Suh; Bruce Polsky; JoEllyn McMillan; Benson Edagwa; Howard E. Gendelman; Mary Jane Potash; David J. Volsky
• Keywords: CD4-Positive T-Lymphocytes; Male; 0301 basic medicine; QH301-705.5; Neurocognitive Disorders; 610; Mice, Nude; HIV Infections; Mice; 03 medical and health sciences; 616; Animals; Humans; Biology (General); Aged; Disease Reservoirs; Macrophages; Brain; HIV; Mild cognitive impairment; RC581-607; Middle Aged; Adoptive Transfer; Antiretroviral agents; 3. Good health; Mice, Inbred C57BL; Anti-Retroviral Agents; Macrophages, Peritoneal; Medicine; Female; Immunologic diseases. Allergy; Spleen; Research Article; Plasmids; HIV infections

Suppression of HIV replication by antiretroviral therapy (ART) or host immunity can prevent AIDS but not other HIV-associated conditions including neurocognitive impairment (HIV-NCI). Pathogenesis in HIV-suppressed individuals has been attributed to reservoirs of latent-inducible virus in resting CD4+ T cells. Macrophages are persistently infected with HIV but their role as HIV reservoirs in vivo has not been fully explored. Here we show that infection of conventional mice with chimeric HIV, EcoHIV, reproduces physiological conditions for development of disease in people on ART including immunocompetence, stable suppression of HIV replication, persistence of integrated, replication-competent HIV in T cells and macrophages, and manifestation of learning and memory deficits in behavioral tests, termed here murine HIV-NCI. EcoHIV established latent reservoirs in CD4+ T lymphocytes in chronically-infected mice but could be induced by epigenetic modulators ex vivo and in mice. In contrast, macrophages expressed EcoHIV constitutively in mice for up to 16 months; murine leukemia virus (MLV), the donor of gp80 envelope in EcoHIV, did not infect macrophages. Both EcoHIV and MLV were found in brain tissue of infected mice but only EcoHIV induced NCI. Murine HIV-NCI was prevented by antiretroviral prophylaxis but once established neither persistent EcoHIV infection in mice nor NCI could be reversed by long-acting antiretroviral therapy. EcoHIV-infected, athymic mice were more permissive to virus replication in macrophages than were wild-type mice, suffered cognitive dysfunction, as well as increased numbers of monocytes and macrophages infiltrating the brain. Our results suggest an important role of HIV expressing macrophages in HIV neuropathogenesis in hosts with suppressed HIV replication.