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

Rhesus TRIM5 alpha (rhTRIM5 alpha), but not human TRIM5 alpha (huTRIM5 alpha), potently inhibits human immunodeficiency virus (HIV) infection and is thus a potentially valuable therapeutic tool. Primary human CD4 T cells engineered to express rhTRIM5 alpha were highly resistant to cell-free HIV type 1 (HIV-1) infection. However, when cocultured with unmodified T cells, rhTRIM5 alpha-expressing cells became highly permissive to HIV-1 infection. Physical separation of rhTRIM5 alpha-expressing cells and unmodified cells revealed that rhTRIM5 alpha 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 alpha-expressing human cells were cultured with huTRIM5 alpha- but not rhTRIM5 alpha-expressing cells. Our results suggest that cell-associated HIV transmission in humans is blocked only when both donor and recipient cells express rhTRIM5 alpha. These studies further define the role of rhTRIM5 alpha in cell-free and cell-associated HIV transmission and delineate the utility of rhTRIM5 alpha in anti-HIV therapy.