Background
Recent studies characterizing primary isolates of HIV-1 from acute timepoints, rebound after treatment interruption, chronic viremia, and the persistent reservoir have identified key phenotypic differences between these viruses when replicating in primary CD4 T cells. Here, we leverage these HIV-1 isolates to probe effects of virus clade, isolate origin, and cell donor sex on replication kinetics in peripheral monocyte derived macrophages (MDMs).
Methods
MDMs from 4 male and 5 female healthy donors were infected at an MOI of 0.1 with primary HIV-1 isolates: Clade B/C transmitted/founder (TF) viruses (n=4), Clade B/C rebound viruses (n=4), Clade B/C chronic viruses (n=5), and Clade D TF viruses (n=4). We assessed longitudinal area under the curve of HIVp24 (total HIVp24) for the 17 primary isolates in MDMs over 20 days of infection, segregating total HIVp24 into quartiles to compare replication kinetics.
Results
Across MDM from all donors, we found minimal differences in replication between Clade B/C TF viruses, Clade B/C rebound, and Clade B/C chronic viruses, except for the well-characterized brain-derived chronic virus YU2, which replicated in the highest quartile. All four Clade D TF viruses showed robust replication in MDMs, falling in the upper two quartiles. When infections in MDMs were segregated by cell donor sex, primary viruses replicated significantly better in male MDMs than female MDMs across all viruses (Two-way ANOVA, Interaction P=0.0013). In post-test comparison, the average percent difference in replication kinetics comparing male to female MDMs was 39.5% for 7 of 17 primary isolates (FDR, Q<0.05).
Conclusions
In MDM, the sex of cell donor was a significant determinant of HIV-1 replication, while virus origin (TF, rebound, or chronic) was not. As previously shown, brain-derived and Clade D viruses replicated efficiently in MDMs. Studies to better understand the mechanism of biological sex as a determinate of HIV-1 replication in myeloid cells are needed. Ongoing studies will build upon these results by characterizing growth kinetics of primary HIV-1 isolates in in vitro models of resident myeloid cells, such as tissue macrophages and microglia. Our results suggest biological sex should be considered in future translational studies of HIV persistence and cure strategies.
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