The highly polymorphic cyclophilin A-binding loop in HIV-1 capsid modulates viral resistance to MxB

• DOI: 10.1186/s12977-014-0129-1
• Publication Date: 2015-01-08T19:34:57Z
• Authors: Zhenlong Liu; Qinghua Pan; Zhibin Liang; Wentao Qiao; Shan Cen; Chen Liang
• Keywords: Myxovirus Resistance Proteins; 0301 basic medicine; Short Report; HIV Core Protein p24; Mutation, Missense; 3. Good health; 03 medical and health sciences; Infectious Diseases; Virology; Host-Pathogen Interactions; HIV-1; Humans; Mutant Proteins; Selection, Genetic; Cyclophilin A; Immune Evasion; Protein Binding

The human myxovirus-resistance protein B (MxB, also called Mx2) was recently reported to inhibit HIV-1 infection by impeding the nuclear import and integration of viral DNA. However, it is currently unknown whether there exist MxB-resistant HIV-1 strains in the infected individuals. Answer to this question should address whether MxB exerts an inhibitory pressure on HIV-1 in vivo and whether HIV-1 has evolved to evade MxB inhibition.We have examined ten transmitted founder (T/F) HIV-1 strains for their sensitivity to MxB inhibition by infecting CD4+ T cell lines SupT1 and PM1 that were stably transduced to express MxB. Two T/F stains, CH040.c and RHPA.c, were found resistant and this resistance phenotype was mapped to the amino acid positions 87 and 208 in viral capsid. The H87Q mutation is located in the cyclophilin A (CypA) binding loop and has a prevalence of 21% in HIV-1 sequences registered in HIV database. This finding prompted us to test other frequent amino acid variants in the CypA-binding region and the results revealed MxB-resistant mutations at amino acid positions 86, 87, 88 and 92 in capsid. All these mutations diminished the interaction of HIV-1 capsid with CypA.Our results demonstrate the existence of MxB-resistant T/F HIV-1 strains. The high prevalence of MxB-resistant mutations in the CypA-binding loop indicates the significant selective pressure of MxB on HIV-1 replication in vivo especially given that this viral resistance mechanism operates at expense of losing CypA.