Use of low-dose rapamycin, a CCR5 suppressant, to increase potency of T-20 in vitro
Simon Collins, HIV i-Base
While difficulties of administration and side effects have generally restricted the use of T-20 to a relatively small number of patients, an independent investigator produced poster suggested a mechanism for increasing potency.
Alonso Heredia from University of Maryland evaluated the effects of CCR5 and CD4 density levels on primary CD4 T cells, on the replication efficiency and T-20 susceptibility of R5-tropic HIV-1.
They found that replication of R5 HIV-1 varied as much as 12-fold among donors and that this was positively correlated with CCR5 density levels on donor CD4 T cells (r = 0.55, p = 0.011), but not with CD4 density levels. In addition, sensitivity of R5 HIV-1 to T-20 varied approximately 100-fold among donors and CCR5 density levels were positively correlated with decreased susceptibility of R5 HIV-1 to T-20 (r = 0.84, p = 0.00004).
The researchers then looked at the effects rapamycin, an immunosuppressant used in transplant surgery, which also reduces CCR5 expression, and found that it increased T-20s antiviral activity in a cell-cell fusion and infectivity assays. The relative dose needed was 5-10% of clinical doses, at a level that would be unlikely to result in CD4 suppression.
It would be interesting to know whether this research could have any impact on potency of CCR5 inhibitor. Given the recent announcement that Roche are no longer to continue in partnership with Trimeris on second generation fusion inhibitors (see press release reported later in this issue of HTB), it is unlikely that they will look to fund this research potential for T-20.
- Heredia A, Gilliam B, Latinovic O et al. CCR5 Density Levels on Primary CD4 T Cells Affect the Replication and Enfuvirtide Susceptibility of R5 HIV-1: Clinical Implications. Abstract 498.