Abstract
BackgroundHIV-1 DNA in blood monocytes is considered a viral source of various HIV-1 infected tissue macrophages, which is also known as “Trojan horse” hypothesis. However, whether these DNA can produce virions has been an open question for years, due to the inability of isolating high titer and infectious HIV-1 directly from monocytes.ResultsIn this study, we demonstrated successful isolation of two strains of M-HIV-1 (1690 M and 1175 M) from two out of four study subjects, together with their in vivo controls, HIV-1 isolated from CD4+ T-cells (T-HIV-1), 1690 T and 1175 T. All M- and T- HIV-1 isolates were detected CCR5-tropic. Both M- HIV-1 exhibited higher levels of replication in monocyte-derived macrophages (MDM) than the two T- HIV-1. Consistent with our previous reports on the subject 1175 with late infection, compartmentalized env C2-V3-C3 sequences were identified between 1175 M and 1175 T. In contrast, 1690 M and 1690 T, which were isolated from subject 1690 with relatively earlier infection, showed homogenous env C2-V3-C3 sequences. However, multiple reverse transcriptase (RT) inhibitor resistance-associated variations were detected in the Gag-Pol region of 1690 M, but not of 1690 T. By further measuring HIV DNA intracellular copy numbers post-MDM infection, 1690 M was found to have significantly higher DNA synthesis efficiency than 1690 T in macrophages, indicating a higher RT activity, which was confirmed by AZT inhibitory assays.ConclusionsThese results suggested that the M- and T- HIV-1 are compartmentalized in the two study subjects, respectively. Therefore, we demonstrated that under in vitro conditions, HIV-1 infected human monocytes can productively release live viruses while differentiating into macrophages.
Highlights
Peripheral blood monocytes can enter a variety of tissues across capillary endothelial walls, undergoing differentiation to become tissue-specific resident macrophages, such as microglia and perivascular macrophages in the brain, alveolar macrophages in the lung and Kupffer cells in the liver [1,2]
Based on these migration and differentiation phenotypes, early investigations implicated HIV-1 infected monocytes, carrying provirus, might be able to differentiate into tissue macrophages and develop HIV1 productive infection in situ [3,4,5,6,7,8,9,10,11,12,13,14]
Evidence include studies from us and others [15,16,17,18,20] demonstrating that monocyte/ macrophages (M/M) are one of the major sources of HIV-1 in vivo, in patients receiving highly active antiretroviral therapy (HAART)
Summary
Peripheral blood monocytes can enter a variety of tissues across capillary endothelial walls, undergoing differentiation to become tissue-specific resident macrophages, such as microglia and perivascular macrophages in the brain, alveolar macrophages in the lung and Kupffer cells in the liver [1,2]. Evidence include studies from us and others [15,16,17,18,20] demonstrating that monocyte/ macrophages (M/M) are one of the major sources of HIV-1 in vivo, in patients receiving highly active antiretroviral therapy (HAART) This deduction is supported by the fact that the HIV-1 DNA in circulating monocytes has been identified as one of the mechanisms of HIV-1-associated neurocognitive disturbances (HAND) progression [21] and other M/M associated HIV diseases, such as atherosclerosis (reviewed in [22]). Whether these DNA can produce virions has been an open question for years, due to the inability of isolating high titer and infectious HIV-1 directly from monocytes
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