Infection of HIV-1 Transgenic Mice with Mycobacterium avium Induces the Expression of Infectious Virus Selectively from a Mac-1-Positive Host Cell Population

• Published in: The Journal of immunology (1950) 1999-08, Vol.163 (3), p.1506-1515
• Main Authors: Doherty, T. Mark, Chougnet, Claire, Schito, Marco, Patterson, Bruce K, Fox, Cecil, Shearer, Gene M, Englund, George, Sher, Alan
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Animals; Cells, Cultured; Gene Products, gag - genetics; HIV Core Protein p24 - blood; HIV-1 - genetics; HIV-1 - growth & development; HIV-1 - immunology; Humans; Macrophage-1 Antigen - biosynthesis; Macrophages - immunology; Macrophages - virology; Mice; Mice, Inbred Strains; Mice, Transgenic; Mycobacterium avium - immunology; Organ Specificity - genetics; RNA, Messenger - metabolism; Spleen - cytology; Spleen - virology; Toxoplasma - immunology; Toxoplasmosis, Animal - genetics; Toxoplasmosis, Animal - immunology; Toxoplasmosis, Animal - virology; Tuberculosis - genetics; Tuberculosis - immunology; Tuberculosis - pathology; Tuberculosis - virology; Virion - growth & development; Virion - pathogenicity; Virus Activation - genetics; Virus Activation - immunology; Virus Replication - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.163.3.1506

Infection of HIV-1-transgenic mice with Mycobacterium avium, a common opportunistic pathogen in AIDS patients, was shown to result in increased tissue expression of viral specific transcripts. Moreover, by coculturing splenocytes from the transgenic animals with human T cells it was possible to demonstrate that the elevation in HIV-1 mRNA triggered by M. avium infection reflects increased production of infectious virions. Viral immune activation was also shown to correlate with a marked elevation of p24 in supernatants of ex vivo-cultured tissues and, more importantly, in systemic increases in the HIV-1 protein in plasma. Interestingly, these tissue and systemic p24 responses were found to be differentially regulated. Thus, while in vitro p24 production by cultured splenocytes increased concurrently with bacterial loads during the first 6 wk of infection, levels of the Ag in plasma actually decreased. In situ localization experiments together with FACS analysis of HIV-1-expressing splenocytes indicated that virus production is restricted largely to cells of the monocyte/macrophage lineage. Indeed, in vitro p24 expression by cells from noninfected transgenic mice was up-regulated by polyclonal stimulation of macrophages but not T cells. Together these results underscore the importance of the macrophage reservoir in persistent virus expression and establish a convenient and relevant animal model for studying the factors responsible for immune activation of HIV-1 induced by mycobacterial as well as other common coinfections encountered by AIDS patients.