The restriction factors of human immunodeficiency virus

Abstract

Cellular proteins called "restriction factors" can serve as powerful blockades to HIV replication, but the virus possesses elaborate strategies to circumvent these barriers. First, we discuss general hallmarks of a restriction factor. Second, we review how the viral Vif protein protects the viral genome from lethal levels of cDNA deamination by promoting APOBEC3 protein degradation; how the viral Vpu, Env, and Nef proteins facilitate internalization and degradation of the virus-tethering protein BST-2/tetherin; and how the viral Vpx protein prevents the premature termination of reverse transcription by degrading the dNTPase SAMHD1. These HIV restriction and counter-restriction mechanisms suggest strategies for new therapeutic interventions.

FIGURE 1.

Hallmarks of a restriction factor. A, four defining hallmarks of an HIV restriction factor include dominant restriction of viral replication (no-go sign; clockwise from top left), a virus-encoded counteraction mechanism (shield sign), interferon responsiveness (promoter sign), and positive selection signatures (plus sign). B, histogram depicting viral infectivity in the presence of a restriction factor and a dose response of the relevant counter-restriction mechanism.

FIGURE 2.

HIV restriction by APOBEC3 proteins. APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H can encapsidate into HIV virions and result in the deamination of cytosines to uracils in viral cDNA upon initiation of reverse transcription (RT) in target cells. Uracil templates adenine upon second-strand synthesis, resulting in a guanine-to-adenine mutation. These proviral cDNAs are subsequently degraded or integrated (although many are rendered nonfunctional). HIV-1 Vif overcomes the APOBEC3 restriction block in the producer cell by binding CBFβ and recruiting an E3 ubiquitin (Ub) ligase complex to polyubiquitinate the APOBEC3 proteins and target them for degradation by the 26 S proteasome. The figure was adapted from Ref. and reproduced with permission.

FIGURE 3.

HIV restriction by tetherin. Tetherin acts to physically tether budding virions to the cell surface of productively infected T cells. HIV-1 Vpu or HIV-2 Env overcomes tetherin restriction by internalizing and sequestering tetherin in compartments away from sites of viral budding. HIV-1 Vpu can also recruit an E3 ubiquitin ligase complex that ubiquitinates tetherin and targets it for degradation in lysosomes. SIV Nef (not shown) can also counteract tetherin.

FIGURE 4.

HIV restriction by SAMHD1. SAMHD1 acts to block HIV-1 reverse transcription (RT) by depletion of cellular dNTPs in myeloid target cells. HIV-2/SIV Vpx and some Vpr variants can overcome the SAMHD1 restriction block by acting as an adaptor to an E3 ubiquitin (Ub) ligase complex that polyubiquitinates SAMHD1 and targets it for degradation by the 26 S proteasome.