All ETDs from UAB

Advisory Committee Chair

Randall Q Cron

Advisory Committee Members

Paul A Goepfert

Olaf Kutsch

Phillip D Smith

Lesley E Smythies

Chad Steele

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Polarization of macrophages is critical for an effective host immune response against invading pathogens. However, the HIV-1 virus can alter the cytokine/chemokine profile of polarized macrophages which may ultimately lead to their increased susceptibility to viral infection. M1 monocyte-derived macrophages (MDM) have been shown to suppress CCR5-tropic HIV-1 replication, while M2 MDM promote it. We generated M1 (GM-CSF + IFN-γ + LPS) and M2 (M-CSF + IL-4) MDM with predicted phenotypes and exposed them to a CCR5 (R5) “highly macrophage-tropic” viral strain, HIV-1BaL. M2 MDM had notably higher levels of HIV-1 infection than M1 MDM. We also investigated R5 HIV-1 transmitted founder (T/F) virus infection in polarized MDM, which had not been previously explored. Similarly, M2 MDM had higher levels of T/F infection than M1 MDM but lower compared to HIV-1BaL. Previous in vitro studies by our lab and others have shown that CD4 regulatory T cells (Tregs) suppress HIV-1 infection of primary human CD4 T cells and of neighboring non-Treg CD4 T cells. The effect of Tregs on HIV-1 infection of polarized M1 and M2 macrophages, however, remains largely unknown. We report here that Treg cells co-cultured with polarized MDM significantly increased HIV-1 infection in polarized M1 and M2 MDM. Interestingly, the results also showed that Treg co-cultures decreased HIV-1 infection in M1 MDM, but increased infection in M2 MDM (compared to conventional effector CD4 T cells) in a mechanism that was cell contact dependent. These findings suggest a role for Tregs in HIV-1 infection and tissue resident macrophages of M1 and M2 phenotype, which may contribute to the establishment and pathogenesis of HIV-1 disease.

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