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HIV Becomes More Flexible in CCR5 and CXCR4 Use as Infection Progresses
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Targeting HIV Entry: 4th International Workshop, December 8-9, 2008, Rio Grande, Puerto Rico
Mark Mascolini
HIV-1 becomes less dependent on specific CCR5 and CXCR4 binding regions as infection gets worse, according to analyses of viral clones made from HIV collected from 8 people never treated by antiretrovirals [1]. This heightened versatility with advancing HIV disease reflects yet another aspect of HIV's adaptability and may explain increasing resistance to coreceptor inhibitors in later infection, suggested Angelique van't Wout and colleagues from Amsterdam's Academic Medical Center.
HIV that uses the CCR5 coreceptor to enter CD4 cells dominates an infected person's viral population in the early years of infection. In about half of people infected with HIV-1 subtype B, virus that can also use the CXCR4 coreceptor begins to emerge before AIDS develops. CCR5 antagonists like maraviroc and vicriviroc cannot control replication of CXCR4-using HIV. van't Wout and coworkers set out to look at changes in coreceptor binding regions as perhaps this might help in understanding CCR5 antagonists.
The investigators analyzed clones constructed from HIV isolated from 8 antiretroviral-naive members of the Amsterdam Cohort Studies. They collected HIV samples at different points in each person's course of infection and tested them for their ability to infect CD4 cells expressing CCR5 or CXCR4. The researchers also made chimeras--receptors that combined different components of the CCR5 and CXCR4 coreceptors--to study the ability of HIV to latch onto those chimeras at different points of infection.
The analysis involved 76 CCR5 clones and 63 CXCR4 clones. Viruses sampled later in the course of infection latched onto a broader array of chimeric coreceptor cell lines. Clones from CCR5 virus sampled before CXCR4-using HIV emerged needed the CCR5 N-terminus region and the first and second extracellular loops of CCR5 to infect CD4 cells in lab dishes. After CXCR4-using virus emerged in an individual, however, CCR5 clones could infect cells lacking the N-terminus region--and sometimes virus without the first extracellular loop.
Clones made from the first CXCR4-using virus to emerge in each patient typically needed both the first and second extracellular loops of CXCR4 to infect CD4 cells. But clones made from CXCR4-using virus collected later in the course of infection depended less and less on the two extracellular loops to infect CD4 cells. R5 and X4 virus sometimes used the same chimeric coreceptor lines.
The Amsterdam team proposed that the increasing flexibility of the virus in using coreceptors as HIV infection gets worse may explain increased resistance to coreceptor inhibitors in late stages of HIV infection. Their findings suggested that loss of CCR5 use--that is, transition from an R5-X4 virus to a strictly X4 virus--probably does not affect which CXCR4 binding regions the X4 virus uses. The observed binding facility of R5 and X4 viruses, van't Wout argued, represents yet another example of viral adaptability in escaping control by antiretrovirals.
Reference
1. Edo-Matas D, Setiawan LC, Winter D, van't Wout AB, Schuitemaker H. Increasing flexibility of coreceptor use in both co-existing R5 and X4 HIV-1 variants in the course of infection. Targeting HIV Entry: 4th International Workshop. December 8-9, 2008. Rio Grande, Puerto Rico. Abstract 3.
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