Viral resistance to a vaginal microbicide in macaques

Several years ago it was shown that very high doses of an entry inhibitor-based microbicide protect macaques from infection with SHIV162-p3. [1] A paper in J Virology now raises some important caveats about this approach, including the first reported example of a microbicide selecting for drug-resistant virus. [2]

The microbicide in question is a CCR5 inhibitor called PSC-RANTES. The challenge virus used in the studies is called SHIV162-p3, a lab-created SIV/HIV hybrid in which an HIV envelope that uses CCR5 to gain entry into CD4 T cells is inserted into an SIV genome instead of the SIV envelope.

The new paper, authored by Dawn Dudley and colleagues from Case Western Reserve University and the Tulane Primate Research Center, is based on an analysis of macaques given lower doses of PSC-RANTES that were not protective against SHIV162-p3 infection. In most cases, viruses in these animals showed mutations that were deemed unrelated to PSC-RANTES because similar mutations were seen in controls that were challenged with the same virus in the absence of the microbicide. But the virus in one macaque contained two mutations, K315R in gp120 and N640D in gp41, which were very rare in the challenge virus stock (after infection, compared to their frequency in the challenge virus, these mutations were increased at least 25-fold and 75-fold). Importantly, PSC-RANTES failed to completely inhibit this mutant SHIV, even at high concentrations that inhibited the parent SHIV162-p3 and all other R5-using HIV isolates tested.

Dudley and colleagues acknowledge that this apparent example of resistance was only seen in 1/25 macaques studied, and there is an outlying possibility that the mutations represent a random adaptation of the virus to better replicate in macaque cells. However, they argue that the weight of evidence supports their conclusion that the mutations arose from drug selection which the emergence of resistance would have been considered unlikely.

Discussing the implications for microbicides generally, they note that the positive results reported to date with entry inhibitor-based microbicides (PSC-RANTES, BMS-378806, CMPD167, and C52L) have all involved administering relatively high doses and the SHIV162-p3 challenge virus (which is exquisitely sensitive to many entry inhibitors). As a result, they believe that the barrier for selecting resistance to an anti-HIV microbicide (such as PSC-RANTES) has been set very high and possibly beyond physiological relevance. To address these concerns, the authors recommend the development of macaque models that use multiple R5-SHIVs as a challenge in order to better duplicate the diversity of viruses to which individuals are typically exposed. Because the resistance described in their study was associated with a dose of PSC-RANTES lower than that which conferred full protection, they also caution that waning microbicide levels after application could conceivably provide the conditions necessary for the emergence of drug resistance.