This monoclonal antibody therapy was well tolerated, and all of the HIV + patients who received the highest dose experienced significant decreases in viral load. which also targets the CD4bs, into healthy controls and HIV + patients 48. This monoclonal antibody therapy was well tolerated, and all of the HIV + patients who received the highest dose experienced significant decreases in viral load. Predictably, in some patients, a familiar specter emerged: mutations present within the patients viral quasispecies facilitated escape from 3BNC117 neutralization. Thus, like the scenario that successful antiretroviral drug therapy requires the use of several different inhibitors, passive immunotherapy will likely require the use of a cocktail of bNAbs that target distinct regions of Env. An additional consideration is that bNAbs do not always exhibit complete neutralization took this concept a step further, creating a HDAC6 novel chimeric antibody that is more potent and broad than even the best bNAbs 62. This construct, eCD4-Ig, combines the broad recognition ability of CD4 (a receptor essential for all HIV-1, HIV-2, and simian immunodeficiency virus [SIV] variants) with a sulfated peptide that mimics the co-receptor CCR5. When AAV was used to deliver eCD4-Ig to rhesus macaques, the animals showed no sign of infection for the duration of the study (40 weeks post-therapy), despite escalating intravenous challenges. This represents a stellar example of how a strong basic research program can Diethylstilbestrol lead to innovative and promising approaches 63C 67. Given the difficulties in delivering bNAbs discussed above or in eliciting them by vaccination, some researchers are staying the course to a vaccine by developing approaches to protect against HIV-1 without bNAb. One alternative is to generate antibodies capable of mediating antibody-dependent cellular cytotoxicity (ADCC). Although the RV144 vaccine trial generated antibody responses with minimal neutralization capabilities, these same antibodies were capable of mediating ADCC 68. Thus, it is worth revisiting the protective potential of non-neutralizing antibodies, which could be more amenable to elicitation by a vaccine 57, 69C 71. Another option is to delve into the antibody ontogeny of more HIV-1-infected patients, looking for more attainable antibody goals as well as identifying viral and immunological roadblocks that prevent the development of neutralization breadth. Rather than trying to coax the immune system into making rare antibodies, one could focus on strategies to elicit antibodies with moderate breadth, limited somatic hypermutation, typical CDR H3 lengths, and commonly used VH germline precursors 72. Perhaps eliciting combinations of these more common types of antibodies would provide some level of protection in the end. Summary The past several years have seen major advances in terms of antibody-mediated protection and therapy against HIV-1. bNAbs, though rare, are generated in multiple HIV-1-infected individuals. Insight into Diethylstilbestrol bNAb ontogeny during natural infection has revealed novel strategies for vaccination, but at the same time these studies have highlighted the difficulties that will need to be overcome. Other avenues for passive therapy and protection have become possible because of the new generation of bNAbs, some of which can neutralize up to 90% of genetically diverse isolates tested and could be even more effective when combined optimally Diethylstilbestrol 73. Innovative design of Env immunogens, chimeric antibodies, and enhanced bNAbs may also yield protective or therapeutic benefits. Finally, bNAb-independent approaches that involve more moderate neutralization breadth or non-neutralizing effector functions may also hold promise. Abbreviations AAV, adeno-associated virus; ADCC, antibody-dependent cellular cytotoxicity; bNAb, broadly neutralizing antibody; CD4bs, CD4-binding site; CDR H3, complementarity determining region H3; Env, envelope glycoprotein; SHIV, chimeric simian-human immunodeficiency virus; V1V2, gp120 hyper-variable domains 1 and 2; V3, gp120 variable domain 3; VH, immunoglobulin variable domain heavy-chain segment. Notes [version 1; referees: 2 approved] Funding Statement CAD and SAS are supported by NIH-R01-AI58706. em I confirm that the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. /em Notes Editorial Note on the Review Process F1000 Faculty Reviews are commissioned from members of the prestigious F1000.

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