Research Article: Naturally Occurring Mutations in HIV-1 CRF01_AE Capsid Affect Viral Sensitivity to Restriction Factors

Date Published: April 01, 2018

Publisher: Mary Ann Liebert, Inc.

Author(s): Emi E. Nakayama, Akatsuki Saito, Tahmina Sultana, Zhuan Jin, Kyotaro Nohata, Masato Shibata, Miho Hosoi, Kazushi Motomura, Tatsuo Shioda, Somchai Sangkitporn, Ruangchai Loket, Siriphan Saeng-aroon.


TRIM5α and MxB are known as restriction factors that inhibit the early step of intracellular HIV-1 replication cycle. Both factors are believed to interact with the incoming virus core to suppress HIV-1 infection. The extreme diversity of HIV-1 is thought to be a consequence of its propensity to mutate to escape immune responses and host restriction factors. We recently determined the capsid sequences for 144 HIV-1 CRF01_AE viruses obtained in Thailand from 2005 to 2011. In this study, we further analyzed the amino acid variations among the capsid sequences of 204 HIV-1 CRF01_AE obtained in Thailand and China, including 84 of the aforementioned 144 viruses, to detect mutations permitting escape from restriction by host factors. We found a characteristic combination of E79D, V83T, and H87Q in sequences from Chinese viruses and subsequently showed that this combination conferred partial resistance to MxB. Interestingly, this combination conferred resistance to human TRIM5α as well. The H87Q mutation alone conferred resistance to MxB in the CRF01_AE background, but not in subtype B virus. In contrast, the H87Q mutation alone conferred resistance to human TRIM5α in both the CFR01_AE and subtype B backgrounds. BLAST analysis revealed the presence of the E79D, V83T, and H87Q combination in CRF01_AE viruses isolated not only in China but also in many other countries. Although the mechanistic details as well as precise role of MxB antiviral activity in infected individuals remain to be clarified, our data suggest an interaction between MxB and the HIV-1 capsid in vivo.

Partial Text

Four major restriction factors capable of suppressing HIV replication have been reported: human ApoB mRNA editing catalytic subunit (APOBEC) 3G1–3; human Tetherin, also known as BST2 or CD3174,5; human SAMHD1 (a cellular protein SAM and HD domain-containing protein)6–8; and monkey TRIM5α/TRIMCyp.9,10 Recently, human MxB (but not MxA) was reported as another restriction factor induced by type 1 interferon (IFN). Monkey TRIM5αs exhibit relatively strong anti-HIV-1 effects, while the anti-HIV-1 activity of human TRIM5αs is comparatively weaker.11 Human MxB12 exhibits a strong anti-HIV-1 effect, while MxA does not. The precise mechanism of MxB-mediated inhibition of HIV-1 is unknown,13,14 but it is clear that the expression of MxB is induced by type 1 IFN.12,15 Among these restriction factors, APOBEC3G, BST2, and SAMHD1 are degraded through proteasomal pathways, and their antiviral activities are inhibited in the presence of viral proteins HIV-1 vif,16–18 HIV-1 vpu,4,5 and HIV-2 vpx,8,19 respectively. In contrast, HIV accessory proteins are unable to counteract MxB and TRIM5α, since HIV interacts with those factors through the viral capsid.20–22 However, it is currently unknown whether HIV-1 is able to evolve to evade MxB-mediated inhibition. One way to address this question is to determine whether MxB-resistant HIV-1 strains exist in infected individuals. Therefore, in this study, we analyzed 204 HIV-1 sequences, most of which were derived from recent cases infected through sexual contact. We show, in this study, that characteristic mutations found in isolates obtained in China indeed confer partial resistance to MxB.

We found that the DTQ mutations in CRF01_AE capsid conferred partial resistance to MxB and human TRIM5α. Initially, our sequence analysis suggested that the DTQ mutations were present exclusively in the sequences of isolates from Beijing.36 However, when we performed a homology search (by BLAST) using the protein sequence DWDRTHPVQAGPIPPGQIREPRGSDIAGTTSNLQEQIAWMTN [corresponding to residues 79 to 120 of a capsid protein, including (as indicated by underlining) the DTQ mutations along with M96I, T110N, and G116A; clone 49L] as a query, multiple viruses with identical sequences were returned, as shown in Supplementary Table S3. All of these viruses sorted as CRF01_AE viruses and were isolated from cities in China, including Beijing, Guangxi, Jiangsu, and Shijiazhuang.




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