Mode of Transmission Affects the Sensitivity of Human Immunodeficiency Virus Type 1 to Restriction by Rhesus TRIM5α

Abstract

Rhesus TRIM5␣ (rhTRIM5␣), but not human TRIM5␣ (huTRIM5␣), potently inhibits human immunodeficiency virus (HIV) infection and is thus a potentially valuable therapeutic tool. Primary human CD4 T cells engineered to express rhTRIM5␣ were highly resistant to cell-free HIV type 1 (HIV-1) infection. However, when cocultured with unmodified T cells, rhTRIM5␣-expressing cells became highly permissive to HIV-1 infection. Physical separation of rhTRIM5␣-expressing cells and unmodified cells revealed that rhTRIM5␣ efficiently restricts cell-free but not cell-associated HIV transmission. Furthermore, we observed that HIV-infected human cells could infect rhesus CD4 T cells by cell-to-cell contact, but the infection was self-limiting. Subsequently, we noted that a spreading infection ensued when HIV-1-infected rhTRIM5␣-expressing human cells were cultured with huTRIM5␣-but not rhTRIM5␣-expressing cells. Our results suggest that cellassociated HIV transmission in humans is blocked only when both donor and recipient cells express rhTRIM5␣. These studies further define the role of rhTRIM5␣ in cell-free and cell-associated HIV transmission and delineate the utility of rhTRIM5␣ in anti-HIV therapy.

SAMHD1 Restricts HIV-1 Cell-to-Cell Transmission and Limits Immune Detection in Monocyte-Derived Dendritic Cells

“…The antiviral activity of some restriction factors is saturable. For instance, Trim5a, which targets incoming lentiviral capsids, does not prevent cell-to-cell transmission (45). In contrast, tetherin, which sequesters budding virions at the cell surface, inhibits this mode of viral spread (46,47).…”

Multiploid Inheritance of HIV-1 during Cell-to-Cell Infection

“…Related quasispecies variants would also be iteratively shuffled by repeated coinheritance and recombination. Third, the simultaneous entry of multiple viruses may saturate endogenous restriction factors and enhance viral infection (2,24). Fourth, multicopy cell-to-cell infection can explain the viral quasispecies concept, which suggests that selection acts not on individual genomes but rather on a group of different genomes that make up a consensus sequence (19).…”

Generation of human TRIM5α mutants with high HIV-1 restriction activity

“…It may also result in TRIM5a targeting susceptible retroviruses not just at post-entry stages but also at later stages of the retroviral life cycle. 60 We thus aimed at analyzing the potency of the R332/R335 double mutants in the context of cell to cell transmissions. 'Classical' virus spreading assays are initiated by adding cell-free virus on a culture of T cells.…”