In this task, you're given a paragraph from the research paper and your task is to generate a suitable title for the research paper based on the given paper. Under 100 words is a good title length.

Q: Recently identified broadly neutralizing antibodies (bnAbs) show great potential for clinical interventions against HIV-1 infection. However, resistant strains may impose substantial challenges. Here, we report on the identification and characterization of a panel of HIV-1 strains with broad and potent resistance against a large number of bnAbs, particularly those targeting the CD4-binding site (CD4bs). Site-directed mutagenesis revealed that several key epitope mutations facilitate resistance and are located in the inner domain, loop D, and β23/loop V5/β24 of HIV-1 gp120. The resistance is largely correlated with binding affinity of antibodies to the envelope trimers expressed on the cell surface. Our results therefore demonstrate the existence of broadly resistant HIV-1 strains against CD4bs neutralizing antibodies. Treatment strategies based on the CD4bs bnAbs must overcome such resistance to achieve optimal clinical outcomes. Recently identified broadly neutralizing antibodies (bnAbs) show great potential for clinical interventions against HIV-1 infection. Among the bnAbs isolated to date, those targeting the CD4bs are the most abundant and thoroughly studied as they disrupt the crucial step of viral interaction with the cellular receptor molecule CD4. Despite the superior potency and breadth of these CD4bs bnAbs, each fails to neutralize a small but significant portion of pseudotyped virus panels. Here, we report on the identification and characterization of a panel of HIV-1 strains with broad and potent resistance against a large number of bnAbs, particularly those targeting the CD4bs. Resistance is largely attributed to mutated residues within the epitopes or steric hindrance imposed by the bulky side-chain or glycan shield of the mutated residues, and is largely correlated with reduced binding avidity of the antibody to the quaternary trimeric envelope protein expressed on the PLOS Pathogens | https://doi.surface of the transfected cells. Treatment strategies based on the CD4bs bnAbs therefore must overcome such resistance to achieve optimal clinical outcomes. Recent scientific advances have identified a growing number of broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus type I (HIV-1), providing promising candidates for HIV-1 prevention and treatment [1] [2] [3] [4] [5] . Compared with bnAbs isolated in earlier studies, these bnAbs demonstrated broader and more potent activity against global HIV-1 panels and displayed impressive safety and efficacy profiles for therapeutic applications in a number of animal models and human clinical trials [1, [6] [7] [8] [9] [10] [11] . These results also offer the opportunity to tailor these antibodies and maximize their prevention and treatment potential. Broadly speaking, these bnAbs recognize six major "vulnerable sites" on the HIV-1 envelope glycoprotein gp160 (gp120 and gp41), which are (1) the CD4-binding site (CD4bs), (2) the V1V2 apex, (3) the V3 glycan, (4) the fusion peptide (FP), (5) subunit interface and (6) membrane proximal external region (MPER) of gp41[1-5]. These bnAbs neutralize HIV-1 by blocking viral entry into the target cells, although additional effector functions are likely at play, particularly in the context of in vivo infection and clinical application[1, 12-16]. Among the bnAbs isolated to date, those targeting the CD4bs are the most abundant and thoroughly studied as they disrupt the first and crucial step of viral interaction with the cellular receptor CD4 [3, 4, 17, 18] . In this step, the trimeric envelope glycoprotein, composed of gp120 and gp41, binds with the target cell through the receptor CD4, with either CCR5 or CXCR4 as co-receptor [19] [20] [21] . This triggers a cascade of conformational changes that fuses the viral envelope with the target membrane and releases the viral genome into the cell [22, 23] .More than two dozen CD4bs bnAbs have been isolated to date. This number is likely to grow with the advent of more specific and high-throughput techniques for isolating antibodies.For instance, the prototype VRC01 and its close relative VRC03, which effectively neutralize a panel of diverse pseudotyped viruses,were isolated from a clade-B infected individual [24] [25] [26] . The more recently isolated CD4bs bnAbs, such as 3BNC117, N6, N49P7, 3BNC60, VRC-PG04, VRC-PG20, NIH45-46, VRC-CH31, 12A12, CH103, 8ANC131, VRC13, and VRC16, have shown similar or even enhanced potency and breadth compared with VRC01 [1-5, 27, 28].The CD4bs bnAbs are classified into two groups based on their mode of recognition and heavy chain characteristics, such as the VRC01 class(3BNC117, N6, N49P7, 3BNC60, VRC-PG04, VRC-PG20, NIH45-46, VRC-CH31 and 12A12) and non-VRC01 classes (CH103, 8ANC131, VRC13 and VRC16) [17, 18] . Structurally, these bnAbs recognize residues within the inner domain, the Loop D, the CD4 binding loop, and the β23/loop V5/β24 region [17, 18, [29] [30] [31] .The V1V2 and V3 loop also impact recognition,particularly in the context of the quaternary trimeric envelope protein [32] [33] [34] [35] [36] .The primary mechanism of neutralization mimics and competes with the CD4 receptorto bind HIV-1 gp120, thereby preventing bound trimers from transitioning to the subsequent steps required for membrane fusion, although evidence indicates that there are differences in the fine details of this process [17, 18, 35, 36] . Despite the superior potency and breadth of these CD4bs bnAbs, each fails to neutralize a small but significant portion of pseudotyped virus panels [17, 25, 27, 28, 37, 38].For instance, VRC01 is unable to neutralize about 10% of tested viruses [25] , and resistant strains have been isolated from patients infected with subtype B, subtype C, CRF07_BC, and CRF08_BC[29, [39] [40] [41] [42] . Furthermore, reports show thatVRC01-, 3BNC117-and N6-resistant strains have emerged in both animal models and human clinical trials [11, 15, [43] [44] [45] [46] [47] , indicating that resistant virus Broadly resistant HIV-1 against CD4bs antibodies PLOS Pathogens | https://doi.org/10.

A: Broadly resistant HIV-1 against CD4-binding site neutralizing antibodies
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Q: A family with a high prevalence of Parkinson's disease, schizophrenia, neoplasms, syndrome-X, rheumatoid arthritis and epilepsy has been described. The psychological behavioural patterns of the family were as follows -creativity and high IQ, hypersexual behaviour, reduced appetite and eating behaviour, insomnia and reduced sleep patterns, increased tendency for spirituality, increased tendency for addiction, less of bonding and affectionate behaviour and left handedness. Digoxin, an endogenous Na þ -K þ ATPase inhibitor secreted by the hypothalamus, was found to be elevated and RBC membrane Na þ -K þ ATPase activity was found to be reduced in all the disorders and in the indexed family studied. Hypothalamic digoxin can modulate conscious perception and its dysfunction may lead to schizophrenia. Digoxin can also preferentially upregulate tryptophan transport over tyrosine resulting in increased levels of depolarising tryptophan catabolites -serotonin, quinolinic acid, strychnine and nicotine and decreased levels of hyperpolarising tyrosine catabolites dopamine, noradrenaline and morphine contributing to membrane Na þ -K þ ATPase inhibition in all the above disorders and the indexed family. Digoxin induced membrane Na þ -K þ ATPase inhibition can result in increased intracellular Ca 2þ and reduced Mg þþ levels leading to glutamate excitotoxicity, oncogene activation and immune activation. Digoxin induced altered Ca þþ =Mg þþ ratios, reduced ubiquinone and increased dolichol can affect glycoconjugate metabolism, membrane formation and structure and mitochondrial function leading to the diverse disorders described above including those in the indexed family. The isoprenoid pathway and neurotransmitter patterns were compared in right-handed/left hemispheric dominant and left-handed/right hemispheric dominant individuals. The biochemical patterns in the indexed family and the diverse disorders studied correlated with those obtained in right hemispheric dominance. The hyperdigoxinemic state indicates right hemispheric dominance. Hypothalamic digoxin can thus function as the master conductor of the neuroimmunoendocrine orchestra and co-ordinate the functions of various cellular organelles. ª

A: Hypothalamic digoxin -central role in conscious perception, neuroimmunoendocrine integration and coordination of cellular function -relation to hemispheric dominance
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Q: Several human monoclonal antibodies (hmAbs) including b12, 2G12 and 2F5 exhibit relatively potent and broad HIV-1 neutralizing activity. However, their elicitation in vivo by vaccine immunogens based on the HIV-1 envelope glycoprotein (Env) has not been successful. We have hypothesized that HIV-1 has evolved a strategy to reduce or eliminate the immunogenicity of the highly conserved epitopes of such antibodies by using "holes" (absence or very weak binding to these epitopes of germline antibodies that is not sufficient to initiate and/or maintain an efficient immune response) in the human germline B cell receptor (BCR) repertoire. To begin to test this hypothesis we have designed germline-like antibodies corresponding most closely to b12, 2G12 and 2F5 as well as to X5, m44 and m46 which are cross-reactive but with relatively weak neutralizing activity as natively occurring antibodies due to size and/or other effects. The germline-like X5, m44 and m46 bound with relatively high affinity to all tested Envs. In contrast, germline-like b12, 2G12 and 2F5 lacked measurable binding to Envs in an ELISA assay although the corresponding mature antibodies did. These results provide initial evidence that Env structures containing conserved vulnerable epitopes may not initiate humoral responses by binding to germline antibodies. Even if such responses are initiated by very weak binding undetectable in our assay it is likely that they will be outcompeted by responses to structures containing the epitopes of X5, m44, m46, and other antibodies that bind germline BCRs with much higher affinity/avidity. This hypothesis, if further supported by data, could contribute to our understanding of how HIV-1 evades immune responses and offer new concepts for design of effective vaccine immunogens.

A:
Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: implications for evasion of immune responses and design of vaccine immunogens NIH Public Access Author Manuscript
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