Transmitted HIV-1: Co-Receptor Usage, Sensitivity to Chemokine-Mediated Suppression, and Virulence Phenotype

HIV-1 transmission studies have shown that a form of selection occurs at the moment of infection.  This selection has been hypothesized to be a consequence of the presence of susceptible cells (such as dendritic cells or macrophages) in the submucosa of the new host.  Differential tropism for these cells may result in selection for minor variants of HIV-1 present among the quasispecies of the transmitter inoculum; these minor species are then amplified to become the predominant strain circulating in the peripheral blood of the recipient.  Because tropism is determined to a great extent by HIV-1 second receptor usage and env gene sequence variation, we are examining the relationship between these biological and molecular properties in HIV-1 isolates obtained from transmitter and recipient pairs.  Preliminary results indicate that selection for nonsyncytium-inducing (NSI) variants of HIV-1 which utilize the CCR5 coreceptor occurs at transmission.  This selection occurs in patients infected by both the sexual and parental routes, suggesting that a mucosal barrier is not required to confer a selective advantage on NSI-CCR5 viruses.  In addition, although syncytium-inducing (SI) biological clones which utilize CXCR4 and can infect macrophages may be isolated soon after infection, these variants are suppressed in favor of NSI forms.  Interestingly, SI clones may be isolated from predominantly NSI recipients who have been infected via sexual contact with NSI transmitters, suggesting that such minor variants, although suppressed in the original host, may still be transmitted.

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