BackgroundFor most classes of drugs, rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety, and pharmacokinetic profiles. Fully human monoclonal antibodies (mAbs) provide an attractive method to overcome many of these hurdles to rapidly produce therapeutics for emerging diseases.MethodsIn this study, we deployed a platform to generate, test, and develop fully human antibodies to Zaire ebolavirus. We obtained specific anti-Ebola virus (EBOV) antibodies by immunizing VelocImmune mice that use human immunoglobulin variable regions in their humoral responses.ResultsOf the antibody clones isolated, 3 were selected as best at neutralizing EBOV and triggering FcγRIIIa. Binding studies and negative-stain electron microscopy revealed that the 3 selected antibodies bind to non-overlapping epitopes, including a potentially new protective epitope not targeted by other antibody-based treatments. When combined, a single dose of a cocktail of the 3 antibodies protected nonhuman primates (NHPs) from EBOV disease even after disease symptoms were apparent.ConclusionsThis antibody cocktail provides complementary mechanisms of actions, incorporates novel specificities, and demonstrates high-level postexposure protection from lethal EBOV disease in NHPs. It is now undergoing testing in normal healthy volunteers in preparation for potential use in future Ebola epidemics.

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In order to understand the impact of zidovudine resistance and thymidine analog mutations (TAMs) on subtype C human immunodeficiency virus type 1, we created mutants in subtype C reverse transcriptase (RT). The subtype B RT was placed in a subtype C backbone to act as a control. Mutants and wild-type (WT) virus were competed in a head-to-head competition assay to determine how different clones grew in the same culture. Different viruses were distinguished by sequence tags in nef and a quantitative-PCR assay. The 67N and 70R accessory mutations gave an advantage over the WT in subtype C, but these mutations in subtype B had replication capacities similar to that of the WT. Of the triple mutants examined, the TAM-1 types, 41L210W215Y, were the most fit in both subtypes, but only in subtype C was the replication capacity the same as that of the WT. The TAM-2 mutants, 67N70R215F, had the slowest replication in both clones. The mixed TAM pathway mutant, 67N70R215Y, in subtype C had a significant advantage over the TAM-2 mutant, but this was not seen in subtype B. When the WT viruses were competed with each other, the subtype B RT had enhanced replication relative to subtype C. The increased capacities of the 67N and 70R mutations may indicate that there will be greater transmitted resistance and persistence in a subtype C setting than what is known for subtype B.Human immunodeficiency virus type 1 (HIV-1) remains a leading cause of morbidity and mortality worldwide. With the advent of highly active antiretroviral therapy (HAART), the life expectancy for those on treatment has increased dramatically. Given HIV-1's ability to replicate and mutate quickly, drug resistance has been a significant problem since treatment began. While drug resistance has been studied extensively in the developed world, HIV-1 subtypes that affect developing countries are rarely targeted for drug resistance research (9).Sub-Saharan Africa continues to bear the bulk of the burden of the HIV-1 epidemic, with 22.5 million infections out of the 33.2 million global infections (22). However, the developed world has begun to take notice by contributing unprecedented amounts of money and expertise to combat the epidemic. Much of the support for developing countries has gone toward drug treatment programs for those in need, making research into drug resistance of paramount importance. As more and more people get the treatment they require, drug resistance will increasingly play a major role in the epidemic in these hard-hit areas, where expertise and laboratory tests for clinical monitoring are often not available.Some in vivo data point to different patterns of resistance between subtypes. Brenner et al. (3) have shown for subtype C that the 65R mutation occurs faster in cell culture in response to tenofovir pressure than it does in subtype B. A study from Brazil looked at 160 sequences from treatment-experienced HIV-1-infected individuals (21). It was found that subtype C viruses accumulated drug resistance mutations at a lower rate than subtype B i...

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