Host restriction factors in retroviral infection: promises in virus-host interaction

Abstract

Retroviruses have an intricate life cycle. There is much to be learned from studying retrovirus-host interactions. Among retroviruses, the primate lentiviruses have one of the more complex genome structures with three categories of viral genes: structural, regulatory, and accessory genes. Over time, we have gained increasing understanding of the lentivirus life cycle from studying host factors that support virus replication. Similarly, studies on host restriction factors that inhibit viral replication have also made significant contributions to our knowledge. Here, we review recent progress on the rapidly growing field of restriction factors, focusing on the antiretroviral activities of APOBEC3G, TRIM5, tetherin, SAMHD1, MOV10, and cellular microRNAs (miRNAs), and the counter-activities of Vif, Vpu, Vpr, Vpx, and Nef.

Figure 1

Schematic illustration of the action of host restriction factors during primate lentivirus replication. In viral producer cells, both A3 and MOV10 proteins are packaged into virions via interaction with Gag and RNA. A3 proteins can be targeted by Vif for proteasomal degradation, and viral RNAs can be targeted by specific microRNAs (miRNAs) for suppression. Vpx is also packaged into virion via direct interaction with Gag. In addition, viral release can be inhibited by the cell surface protein tetherin, but it is counteracted by Vpu or Nef (not shown). In target cells, TRIM5α interacts with incoming Gag proteins and triggers premature viral uncoating, resulting in inhibition of viral reverse transcription and nuclear import. Reverse transcription can also be directly inhibited by MOV10 and A3 proteins, or indirectly by SAMHD1 after depleting intracellular dNTP pool. However, SAMHD1 can be neutralized by Vpx through proteasomal degradation. In addition, A3 proteins catalyze C-to-U cytidine deamination on newly synthesized viral cDNA, and viral RNAs can be targeted by miRNAs, which also result in inhibition of viral replication.

Figure 2

Schematic illustration of seven human A3 proteins. Numbers indicate amino acid positions. The zinc-coordinating cytidine deaminase (Z) domain motifs are indicated. The enzymatically active Z domain is presented in dark blue, and the inactive Z domain is in grey. The Vif-interacting motif (red), virion packaging motif (green), and critical residues affecting the enzymatic activity (blue) are all indicated.

Figure 3

Amino acid sequence homology of known HIV-1 Vif functional motifs. Numbers indicate amino acid positions. At each position, the most common amino acid is identified and plotted as a percentage of all amino acids at that position. Motifs that regulate A3F binding are in green; those that regulate A3G binding are in blue; those that regulate both A3G and A3F binding are in red; and those that regulate Cul5/EloBC binding are in pink.

Figure 4

Schematic illustration of human TRIM5α protein. Numbers indicate amino acid positions. The RING finger (R), B-box (B), coiled-coil motif (CC), two linkers (L1, L2), and SPRY domain are indicated. Four variable regions in SPRY, the critical residue (R121) in the B domain that determines oligomerization, and the critical residue (R332) in V1 region that determines species-specific Gag binding are also indicated.

Figure 5

Configuration models of human tetherin. (A) Schematic illustrations of tetherin and Vpu. Numbers indicate amino acid positions. Critical residues of each protein are indicated. (B) Structure of tetherin. Tetherin comprises a short amino-terminal cytoplasmic tail (CT), followed by an α-helical transmembrane (TM) domain and a coiled-coil extracellular (EC) domain that is linked back to the plasma membrane by a carboxy-terminal glycophosphatidylinositol (GPI) anchor. The EC domain contains N-glycosylation sites and cysteine residues involved in disulfide-bond formation. (C-F) Configuration models of tetherin. (C) The EC self-interaction model. Individual tetherin monomers are anchored at both ends to the same membrane, with interaction between the ECs of cell-bound and virion-bound monomers. (D) Anti-parallel membrane-spanning model. Monomers are anchored in both membranes with opposing orientations. (E) Parallel membrane-spanning model. Monomers are anchored in both membranes with the same orientation. (F) HIV-1 Vpu and tetherin interact through their TM domains. Key amino acids involved in the interaction are depicted in the TM helices. Interaction of Vpu’s CT with the E3 ubiquitin (Ub) ligase via the βTrCP subunit is required for Vpu-induced tetherin down-regulation.

Figure 6

Schematic illustration of Vpx protein from SIVmac and human SAMHD1 protein. SAMHD1 splicing variants are shown on the top. Numbers indicate amino acid positions. The three α-helices of Vpx and the SAM, HD, and the C-terminal variable region of SAMHD1 are indicated. Other critical residues and motifs include nuclear localization signal (NLS), a critical residue that determines Vpx interaction with DCAF1 (Q76), four critical residues in SAMHD1 NLS (¹¹KPPR¹⁴), and four residues in the HD domain (H167, H206, D207, D311) are all indicated.

Figure 7

Schematic illustration of human MOV10 protein. Numbers indicate amino acid positions. The Cys-His-rich (CH) domain, helicase domain, and seven helicase motifs (I, Ia, II, III, IV, V, VI) are indicated. The amino acid sequences of these motifs from MOV10 and MOV10L proteins are aligned. Dots indicate identical residues, and critical residues in each motif are in orange color.