Emergence of CD134 cysteine-rich domain 2 (CRD2)-independent strains of feline immunodeficiency virus (FIV) is associated with disease progression in naturally infected cats

Abstract

Background: Feline immunodeficiency virus (FIV) infection is mediated by sequential interactions with CD134 and CXCR4. Field strains of virus vary in their dependence on cysteine-rich domain 2 (CRD2) of CD134 for infection.

Findings: Here, we analyse the receptor usage of viral variants in the blood of 39 naturally infected cats, revealing that CRD2-dependent viral variants dominate in early infection, evolving towards CRD2-independence with disease progression.

Conclusions: These findings are consistent with a shift in CRD2 of CD134 usage with disease progression.

Figure 1

Representative example of results obtained from receptor utilisation assay testing six autologous Env variants isolated from cat M31 and two reference Envs, GL8 (CRD2-dependent) and B2542 (CRD2-independent). The mean luciferase counts per minute (cpm) for each cell line with standard errors (n = 3) are presented for MCC cells [35] expressing the entire human CD134 molecule (HHH, open bars), cells expressing the human x feline CD134 containing the human CRD2 domain (FFHH, hatched bars) and cells expressing the entire feline CD134 molecule (FFF and CLL-CD134 cells [29], shown in chequered and grey bars respectively). Note the differences in titres on cells expressing the human x feline CD134 chimaera containing the human CRD2 domain (FFHH cells, hatched bars) and subsequent pseudotype classification as CRD2-dependent or –independent.

Figure 2

CRD2-independent Env variants were isolated more frequently from cats displaying signs of immunodeficiency and disease progression. Cats were classified into 3 groups: 1) alive/deceased, 2) clinically healthy/sick, 3) CD4⁺ T cell counts > or <350 cells/μl. Cats which died during the study, displayed clinical signs (sick) or had CD4⁺ T cell counts <350 cells/μl were more likely to harbour at least one CRD2-independent variant (chequered bars). Conversely, CRD2-dependent variants were associated with the alive, clinically healthy cats with CD4⁺ T cell counts >350 cells/μl (grey bars). P-values (Fisher’s exact test) were shown below the x-axis.