Linkages between HIV-1 specificity for CCR5 or CXCR4 and in vitro usage of alternative coreceptors during progressive HIV-1 subtype C infection

Retrovirology

Paul R Gorry¹  Melissa J Churchill³  Maelenn Gouillou⁶  Katharina Borm⁴  Jacqueline K Flynn¹  Anne Ellett²  Michael Roche¹  Jasminka Sterjovski¹  Martin R Jakobsen⁷  Kieran Cashin⁵ 

[1] Department of Infectious Diseases, Monash University, Melbourne, Australia;Center for Biomedical Research, Burnet Institute, 85 Commercial Rd, Melbourne, Victoria 3004, Australia;Department of Medicine, Monash University, Melbourne, Australia;Department of Microbiology, La Trobe University, Melbourne, Victoria, Australia;Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia;Center for Population Health, Burnet Institute, Melbourne, Australia;Department of Biomedicine, Aarhus University, Aarhus, Denmark

关键词: Pathogenesis;    Alternative coreceptor;    CXCR4;    CCR5;    Subtype C;    Env;    HIV-1;   

Others  :  807249
DOI  :  10.1186/1742-4690-10-98

 received in 2013-07-25, accepted in 2013-09-11,  发布年份 2013

【 摘 要 】

Background

Human immunodeficiency virus type 1 (HIV-1) subtype C (C-HIV) is spreading rapidly and is now responsible for >50% of HIV-1 infections worldwide, and >95% of infections in southern Africa and central Asia. These regions are burdened with the overwhelming majority of HIV-1 infections, yet we know very little about the pathogenesis of C-HIV. In addition to CCR5 and CXCR4, the HIV-1 envelope glycoproteins (Env) may engage a variety of alternative coreceptors for entry into transfected cells. Whilst alternative coreceptors do not appear to have a broad role in mediating the entry of HIV-1 into primary cells, characterizing patterns of alternative coreceptor usage in vitro can provide valuable insights into mechanisms of Env-coreceptor engagement that may be important for HIV-1 pathogenesis.

Results

Here, we characterized the ability of luciferase reporter viruses pseudotyped with HIV-1 Envs (n = 300) cloned sequentially from plasma of 21 antiretroviral therapy (ART)-naïve subjects experiencing progression from chronic to advanced C-HIV infection over an approximately 3-year period, who either exclusively maintained CCR5-using (R5) variants (n = 20 subjects) or who experienced a coreceptor switch to CXCR4-using (X4) variants (n = 1 subject), to utilize alternative coreceptors for entry. At a population level, CCR5 usage by R5 C-HIV Envs was strongly linked to usage of FPRL1, CCR3 and CCR8 as alternative coreceptors, with the linkages to FPRL1 and CCR3 usage becoming statistically more robust as infection progressed from chronic to advanced stages of disease. In contrast, acquisition of an X4 Env phenotype at advanced infection was accompanied by a dramatic loss of FPRL1 usage. Env mutagenesis studies confirmed a direct link between CCR5 and FPRL1 usage, and showed that the V3 loop crown, but not other V3 determinants of CCR5-specificity, was the principal Env determinant governing the ability of R5 C-HIV Envs from one particular subject to engage FPRL1.

Conclusions

Our results suggest that, in the absence of coreceptor switching, the ability of R5 C-HIV viruses to engage certain alternative coreceptors in vitro, in particular FPRL1, may reflect an altered use of CCR5 that is selected for during progressive C-HIV infection, and which may contribute to C-HIV pathogenicity.

【 授权许可】

   
2013 Cashin et al.; licensee BioMed Central Ltd.

【 图 表 】

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