Increased susceptibility of differentiated mononuclear phagocytes to productive infection with human immunodeficiency virus-1 (HIV-1).

Abstract

Differences in susceptibility to infection of most mononuclear phagocytes with HIV-1 are not known. We investigated the relative susceptibility of autologous freshly isolated blood monocytes (MN), MN cultured in vitro to allow differentiation (CM), and alveolar macrophages (AM) from healthy subjects to productive infection with HIV-1. Cells were infected with the macrophage tropic strain HIV-1jRFL and p24 gag antigen levels measured in supernatants by ELISA. Freshly isolated MN had negligible levels of p24 in supernatants. In contrast AM had peak p24 levels of 4145±1456 pg/ml, mean±SE, and CM 9216±3118. As a measure of entry and extent of reverse transcription, levels of viral DNA in infected mononuclear phagocytes were analyzed by quantitative polymerase chain reaction (PCR). The data using primers that amplify all transcripts including incompletely formed reverse transcripts indicated that differences in entry of the virus may contribute to differences in virus production observed with MN, AM, and CM. Other primer pairs that detect intermediate and full-length doublestranded DNA showed that the ability to complete reverse transcription was similar among these mononuclear phagocytes. Since the lung is a major site of opportunistic infection and noninfectious complications in HIV-1-infected individuals, this increase in productive infection with HIV-1 in AM compared with MN could contribute to the immunopathogenesis of the lung disorders seen in the acquired immunodeficiency syndrome. (J. Clin. Invest. 1992.89:176-183.)

Human immunodeficiency virus type 1 strains in the lungs of infected individuals evolve independently from those in peripheral blood and are highly conserved in the C-terminal region of the envelope V3 loop.

“…Because HIV-1 DNA in BAL was found almost exclusively in the macrophage-enriched fraction, these findings raise the possibility that this V3 loop (12) and cellular localization ofviral RNA and DNA (10,27,28). These cells are much more susceptible to HIV-1 infection than are circulating monocytes and produce far higher levels of infectious virus after primary inoculation with macrophage tropic viral isolates (29). Once infection becomes established, the mechanisms allowing for the persistence of viral infection in tissue macrophages remain unresolved.…”

Inhibition of Anti-HIV MicroRNA Expression

“…It is well-known that monocytes are refractory to HIV infection in vitro and in vivo. [37][38][39][40][41] This refractory property to HIV infection could be because monocytes express high levels of intracellular innate anti-HIV factors, including miRNAs. 23 We were particularly interested in miRNA-28, miRNA-125b, miRNA-150, miRNA-223, and miR-382 because these miRNAs can target a highly conserved region of HIV, present in all HIV clades.…”

Characterization of Restrictions to Human Immunodeficiency Virus Type 1 Infection of Monocytes

“…Several studies indicate that circulating monocytes also serve as a viral reservoir in infected individuals (15)(16)(17)33). The infection of circulating monocytes in vivo is at odds with in vitro studies, where monocytes acquire the ability to support productive viral infection only after their differentiation to macrophages (2,4,5,19,20,23,25). While most studies have suggested that the viral replication cycle in monocytes is restricted at a point prior to establishment of the provirus, the exact point of restriction is a matter of debate.…”