A-103 Towards Achieving a State of Reversible HIV-1 Latency in Primary Monocyte-Derived Macrophages (MDM) by M1 Polarization

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Background:We have previously reported that short-term exposure of primary MDM to pro-inflammatory cytokines (IFN-γ plus TNF-α), ie, “M1 polarization”, partially prevented productive virus infection and reduced proviral transcription.Materials and Methods:M1-polarized MDM were restimulated with M1 cytokines 7 days after R5 HIV-1 infection (M1×2 protocol). Cell cultures were monitored for supernatant-associated RT activity, HIV-1 DNA load, APOBEC3G/3A expression, and for cell reactivation by coculture with T cell blasts.Results:We observed a significant, further reduction of virus replication down to near undetectable levels by RT activity over 30 days of culture. HIV-1 DNA levels were ca. 100- and 1000-foldlower in M1-MDM and M12-MDM vs. control, unpolarized cells, respectively. APOBEC3A, but not APOBEC3G, was significantly upregulated by the M12 protocol protocol 15 days post-infection. No effect of T cell blast coculture on control, infected MDM was observed, whereas significant levels of RT activity were induced in M12-MDM by this approach.Discussion:Stimulation of already infected M1-MDM with pro-inflammatory, M1-cytokines counter-intuitively resulted in a further, significant inhibition of virus replication down to “near-latency” levels in terms of RT activity and viral DNA levels and upregulation of APOBEC3A expression. Recovery of virus production was achieved by cocultivation of M12-infected MDM with allogeneic T cell blasts, indicating the existence of a pool of infected cells carrying inducible proviruses.

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