Evolution of HIV-1 coreceptor use in relation to pathogenesis

Detta är en avhandling från Institution of Laboratory Medicine

Sammanfattning: HIV-1 uses the coreceptors CCR5 and/or CXCR4 in addition to CD4 to enter the host cell. CCR5-using HIV-1 (R5 phenotype) appears to transmit infection and usually dominates the early stages of disease. Evolution of HIV-1 coreceptor use is usually described as the acquisition of CXCR4-using virus (X4 or R5X4 phenotype), and is linked to accelerated disease progression. However, the switch to CXCR4 use is only detected in approximately one half of HIV-1 infected individuals (switch virus patients). The other half harbors CCR5-using virus throughout the course of disease (nonswitch virus patients). We have studied the evolution of coreceptor use during progressive HIV-1 disease. Not only did we reveal an unprecedented variation in coreceptor use, but we also demonstrated an evolution within the R5 phenotype. This evolution was detected through the use of chimeric receptors between CCR5 and CXCR4. The HIV-1 R5 evolution went from a narrow to a broad use of chimeric receptors, and correlated with time and disease progression. A broad R5 phenotype correlated with increased infectivity and resistance to inhibition with the CCR5 ligand RANTES. We could also show a difference between R5 isolates from switch and nonswitch virus patients. R5 isolates from nonswitch virus patients appeared to be more cytopathic, i.e. more efficiently killed their target cell in ex vivo infected human lymphoid tissue. Early in disease HIV-1 seems to bind to the same regions of CCR5 as RANTES, resulting in competitive binding and inhibition. To escape the inhibition by RANTES the virus may evolve to use a part of CCR5 where RANTES is not binding and thereby becomes resistant to inhibition by RANTES. This appears to happen within nonswitch virus patients. Another evolutionary pathway may be to use yet another part of CCR5, which does not confer RANTES resistance but instead enables a switch to CXCR4 use.

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