Thymic pathogenicity of an HIV-1 envelope is associated with increased CXCR4 binding efficiency and V5-gp41-dependent activity, but not V1/V2-associated CD4 binding efficiency and viral entry.
We previously described a thymus-tropic HIV-1 envelope (R3A Env) from a rapid progressor obtained at the time of transmission. An HIV-1 molecular recombinant with the R3A Env supported extensive replication and pathogenesis in the thymus and did not require Nef. Another Env from the same patient did not display the same thymus-tropic pathogenesis (R3B Env). Here, we show that relative to R3B Env, R3A Env enhances viral entry of T cells, increases fusion-induced cytopathicity, and shows elevated binding efficiency for both CD4 and CXCR4, but not CCR5, in vitro. We created chimeric envelopes to determine the region(s) responsible for each in vitro phenotype and for thymic pathogenesis. Surprisingly, while V1/V2 contributed to enhanced viral entry, CD4 binding efficiency, and cytopathicity in vitro, it made no contribution to thymic pathogenesis. Rather, CXCR4 binding efficiency and V5-gp41-associated activity appear to independently contribute to thymic pathogenesis of the R3A Env. These data highlight the contribution of unique HIV pathogenic factors in the thymic microenvironment and suggest that novel mechanisms may be involved in Env pathogenic activity in vivo.
Meissner
Eric G
EG
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
Coffield
Vernon M
VM
Su
Lishan
L
D015704:CD4 Antigens / Q000502:physiology; D002459:Cell Fusion; D002478:Cells, Cultured; D003588:Cytopathogenic Effect, Viral; D015700:HIV Envelope Protein gp41 / Q000502:physiology*; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D008561:Membrane Fusion; D011485:Protein Binding; D016865:Reassortant Viruses; D019718:Receptors, CXCR4 / Q000502:physiology*; D013601:T-Lymphocytes / Q000821:virology; D013950:Thymus Gland; D014759:Viral Envelope Proteins / Q000235:genetics / Q000502:physiology*; D014774:Virulence; D014779:Virus Replication
D015704:CD4 Antigens; D015700:HIV Envelope Protein gp41; D019718:Receptors, CXCR4; D014759:Viral Envelope Proteins