HIV biological variability unveiled: frequent isolations and chimeric receptors reveal unprecedented variation of coreceptor use.
OBJECTIVE
To follow the evolution of coreceptor use in HIV-1-infected individuals with varying rates of disease progression.


METHODS
The coreceptor use of 278 sequential HIV-1 isolates from 23 individuals was tested by infection of two human cell lines, U87.CD4 and GHOST(3), expressing CD4 and CCR1, CCR2b, CCR3, CCR5, CXCR4, CXCR6 or BOB. Differences in coreceptor use were further dissected by testing chimeric coreceptors constructed by exchanging successively larger parts of CCR5 for corresponding regions of CXCR4.


RESULTS
Three patterns of coreceptor use were distinguished: no evolution, evolution to CXCR4 use, and fluctuation. No evolution with stable CCR5 use (R5 phenotype) was linked to slow progression over 8-10 years in four patients. CXCR4-using virus was present from the onset (five patients) or appeared during clinical progression in all other patients, while taking zidovudine or didanosine monotherapy. The fluctuating pattern of coreceptor use, defined as reappearance of virus with R5 phenotype, was observed in five patients and, interestingly, followed initiation of highly active antiretroviral therapy in three of these. Monotropic R5 or X4 viruses were more selective in chimeric receptor use than R5X4 or multitropic viruses. Most importantly, the efficiency of chimeric receptor use increased over time.


CONCLUSIONS
The increase in efficiency of chimeric receptor use allows a new interpretation of evolution of HIV-1 coreceptor use. Evolution could be a continuous process that may lead to changes in the way a coreceptor is used, with the potential of profound alteration in signalling at that receptor.
Karlsson
Ingrid
I
Division of Virology, Department of Medical Microbiology, Dermatology and Infection, Lund University, Lund, Sweden.
Antonsson
Liselotte
L
Shi
Yu
Y
Karlsson
Anders
A
Albert
Jan
J
Leitner
Thomas
T
Olde
Björn
B
Owman
Christer
C
Fenyö
Eva Maria
EM
D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D018791:CD4 Lymphocyte Count; D002460:Cell Line; D016049:Didanosine / Q000627:therapeutic use; D018450:Disease Progression; D019143:Evolution, Molecular; D014644:Genetic Variation; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D010641:Phenotype; D019713:Receptors, CCR5 / Q000032:analysis; D019718:Receptors, CXCR4 / Q000032:analysis; D015728:Receptors, HIV / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000032:analysis*; D014779:Virus Replication / Q000235:genetics; D015215:Zidovudine / Q000627:therapeutic use
D044966:Anti-Retroviral Agents; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D015728:Receptors, HIV; D011993:Recombinant Fusion Proteins; D015215:Zidovudine; D016049:Didanosine