Studies in a Murine Model Confirm the Safety of Griffithsin and Advocate Its Further Development as a Microbicide Targeting HIV-1 and Other Enveloped Viruses

Kouokam, Joseph Calvin; Lasnik, Amanda B.; Palmer, Kenneth E.

Subtle toxicity can be indirectly assessed by evaluating the effect of a drug on plasma concentrations of blood chemistry markers. A difference was observed in cholesterol levels, which were increased as a result of single 50 mg/kg or chronic 10 mg/kg doses of GRFT. However, the differences between the vehicle and GRFT groups were sharply reduced after recovery, as shown above. It has been suggested that splenomegaly could result from an increased uptake of unesterified Chol (and other circulating lipids) by splenic macrophages after a case study of a 31 year old man presenting a homogeneously enlarged spleen with an elevated serum total cholesterol [27] . Despite the observed increase in plasma Chol levels after GRFT administration, it is not clear whether high Chol levels are responsible for the described spleen enlargement or vice versa and there are insufficient data to correlate the two anomalies. After chronic treatment with 10 mg/kg GRFT, elevated ALP was observed, but the difference between control and treatment was reduced after recovery. Recently, we reported similar findings in GRFT treated guinea pigs [17] . Normal adult serum mainly contains liver-type ALP with small and variable amounts of intestinal and bone enzyme [28] . At this point, it is unclear whether the increased ALP levels observed reflected liver toxicity. Indeed, no changes were recorded for the other markers of liver toxicity assessed here, including Alb, TBILI, and ALP. Importantly, improvement of spleen enlargement, splenocyte activation, and Chol and ALP levels occurred only a few days post-treatment, indicating that even at high levels, GRFT does not cause irreparable damages to the spleen or the animal as a whole. These findings suggest that in a therapeutic setting, it might be more appropriate to administer the drug at longer time intervals, e.g., every other day, twice weekly, or weekly, rather than daily injections, if the dose of 10 mg/kg is to be maintained.