Human immunodeficiency virus, restriction factors, and interferon

Abstract

Recent discoveries have revealed previously unappreciated complexity with which retroviruses interact with their hosts. In particular, we have become aware that many mammals, including humans, are equipped with genes encoding so-called "restriction factors," that provide considerable resistance to retroviral infection. Such antiretroviral genes are sometimes constitutively expressed, and sometimes interferon-induced. Thus they can be viewed as comprising an intrinsic immune system that provides a pre-mobilized defense against retroviral infection or, alternatively, as a specialized extension of conventional innate immunity. Antiretroviral restriction factors have evolved at an unusually rapid pace, particularly in primates, and some startling examples of evolutionary change are present in genes encoding restriction factors. Our understanding of the mechanisms by which restriction factors interfere with retroviral replication, and how their effects are avoided by certain retroviruses, is accruing, but far from complete. Such knowledge could allow for novel forms of therapeutic intervention in pathogenic retroviral infections, as well as the development of animal models of human disease.

FIG. 1.

Major host restriction factors capable of inhibiting HIV-1 replication, and their viral antagonists. TRIM5 recognizes incoming HIV-1 capsids and inactivates them; accelerated capsid disassembly accompanies the inactivating lesion. Cyclophilin A also binds to incoming capsids and can affect recognition by TRIM5. APOBEC3 proteins are cytidine deaminases, can be incorporated into assembling HIV-1 particles, and catalyze the deamination of nascent minus strand DNA during the subsequent round of infection. The HIV-1 Vif protein binds to APOBEC3 proteins, and also to a Cullin5-based ubiquitin ligase complex. This results in APOBEC3 protein ubiquitination and degradation in proteasomes. Tetherin is a cell surface protein that causes entrapment of nascent virions on the infected cell surface. Vpu antagonizes tetherin by sequestering tetherin from virions and by reducing the levels of tetherin on the cell surface.