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.

Ex Input:
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.

Ex Output:
Broadly resistant HIV-1 against CD4-binding site neutralizing antibodies


Ex Input:
Herpes simplex virus (HSV) infections can be treated with direct acting antivirals like acyclovir and foscarnet, but long-term use can lead to drug resistance, which motivates research into broadly-acting antivirals that can provide a greater genetic barrier to resistance. Photodynamic inactivation (PDI) employs a photosensitizer, light, and oxygen to create a local burst of reactive oxygen species that inactivate microorganisms. The botanical plant extract Orthoquin TM is a powerful photosensitizer with antimicrobial properties. Here we report that Orthoquin also has antiviral properties. Photoactivated Orthoquin inhibited herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) infection of target cells in a dose-dependent manner across a broad range of sub-cytotoxic concentrations. HSV inactivation required direct contact between Orthoquin and the inoculum, whereas pre-treatment of target cells had no effect. Orthoquin did not cause appreciable damage to viral capsids or premature release of viral genomes, as measured by qPCR for the HSV-1 genome. By contrast, immunoblotting for HSV-1 antigens in purified virion preparations suggested that higher doses of Orthoquin had a physical impact on certain HSV-1 proteins that altered protein mobility or antigen detection. Orthoquin PDI also inhibited the non-enveloped adenovirus (AdV) in a dose-dependent manner, whereas Orthoquin-mediated inhibition of the enveloped vesicular stomatitis virus (VSV) was light-independent. Together, these findings suggest that the broad antiviral effects of Orthoquin-mediated PDI may stem from damage to viral attachment proteins. facilitate attachment and entry into host cells. While HSV-1 and HSV-2 are similar, they share onlỹ 55% nucleotide identity. Lytic HSV infection of a cell begins with initial attachment to negatively charged cell surface heparan sulfate and chondroitin sulfate glycosaminoglycans, followed by stable attachment of viral glycoproteins to cell surface receptors and fusion of the viral envelope to the plasma membrane or internal membranes [2] . Fusion of viral and host membranes enables delivery of the viral nucleocapsid and tegument proteins to the cytoplasm. After the HSV nucleocapsid arrives at the nucleus and delivers the viral genome, HSV genes are expressed in an ordered temporal cascade. Viral egress requires primary envelopment of the genome-containing capsid at the inner nuclear membrane, fusion with the outer nuclear membrane and final envelopment at the trans-Golgi network. Mature virions then exit through the cellular secretory system. All stages of the HSV replication cycle offer potential targets for direct-acting antiviral (DAA) therapy. However, DAAs can be undermined by the emergence of drug resistant mutant viruses. Anti-HSV DAAs acyclovir and foscarnet offer examples of the hazards of drug resistance. These drugs interrupt HSV genome replication by different mechanisms of action. Acyclovir is a nucleoside analogue prodrug that selectively targets HSV infected cells through the action of the HSV thymidine kinase (TK) enzyme, which efficiently phosphorylates acyclovir and facilitates incorporation into nascent viral DNA genomes by the HSV DNA polymerase enzyme; incorporation of acyclovir into viral DNA terminates genome replication [3] . By contrast, the pyrophosphate analogue foscarnet blocks viral genome replication by directly inhibiting HSV DNA polymerase activity [4] . Though resistance to acyclovir occurs at a low prevalence (≤1%) in immunocompetent patients [5], immunocompromised patients experience much higher rates (4-10%) [6] . Unsurprisingly, resistance to acyclovir, and its derivatives, and to foscarnet, has been mapped to mutations in the viral thymidine kinase and the DNA polymerase catalytic subunit, respectively [7] . Currently, Abreva (n-docosanol) is the only over-the-counter topical antiviral for herpes labialis. Abreva is incorporated into the cellular plasma membrane and prevents fusion steps essential for HSV-1 entry into epithelial cells [8] . However, it must be applied repeatedly throughout the day due to rapid plasma membrane turnover and the subsequent loss of n-docosanol [9] . This host-targeted antiviral mechanism prevents development of viral resistance, but Abreva is only approved for perioral lesions, so there is a still a gap in treatment for lesions in other areas of the body. Like Abreva, there is potential for more broadly-acting antiviral drugs that exploit the physical structure of the HSV virion and block early stages of infection, such as attachment and penetration. In this study, we explored the potential of the plant-derived photosensitizing agent Orthoquin TM to mediate photodynamic inactivation (PDI) [10] of virions. The clinical utility of Orthoquin PDI of oral biofilms is an area of active investigation and there is clear potential for wider range of clinical applications. The basis of PDI is the photodynamic effect, which has been exploited in photodynamic therapy (PDT) [11, 12] for treatment of cancers [13] and age-related macular degeneration [14] . In PDT, photosensitizer compounds when exposed to visible light react with oxygen to generate reactive oxygen species (ROS) that include singlet oxygen [15] . ROS damage proteins, nucleic acids and lipids, which can lead to cell death. Some of the most well-known photosensitizing molecules for PDT are based on a tetrapyrrolic core and are found in naturally occurring pigments, such as heme, chlorophyll, and bacteriochlorophyll [16] . The accepted phototoxic mechanism for these types of photosensitizers involves the formation of an excited triplet state upon light absorption that can participate in electron (Type 1) or energy (Type 2) transfer processes. Type 1 electron transfer reactions typically lead to the formation of radical species like superoxide or hydroxyl radicals, whereas Type 2 energy transfer produces cytotoxic singlet oxygen. It is possible for a photosensitizer to initiate both Type 1 and 2 photoprocesses simultaneously, depending on the specific chemistry of the photosensitizing agent and its environment [16] . Due to the high reactivities and short lifetimes of oxidizing molecules, it is expected that only viral structures in close proximity to activated photosensitizing compounds will be affected.

Ex Output:
Photodynamic Inactivation of Herpes Simplex Viruses


Ex Input:
To ensure the safety of wastewater reuse for irrigation of food crops and drinking water pathogenic viruses must be reduced to levels that pose no significant risk. To achieve this goal minimum reduction of viruses by treatment trains have been suggested. For use of edible crops a 6-log reduction and for production of potable drinking water a 12-log reduction has been suggested. These reductions were based on assuming infective virus concentrations of 10 5 to 10 6 per liter. Recent application of molecular methods suggests that some pathogenic viruses may be occurring in concentrations of 10 7 to 10 9 per liter. Factors influencing these levels include the development of molecular methods for virus detection, emergence of newly recognized viruses, decrease in per capita water use due to conservation measures, and outbreaks. Since neither cell culture nor molecular methods can assess all the potentially infectious virus in wastewater conservative estimates should be used to assess the virus load in untreated wastewater. This review indicates that an additional 2-to 3-log reduction of viruses above current recommendations may be needed to ensure the safety of recycled water. Information is needed on peak loading of viruses. In addition, more virus groups need to be quantified using better methods of virus quantification, including more accurate methods for measuring viral infectivity in order to better quantify risks from viruses in recycled water.

Ex Output:

How much reduction of virus is needed for recycled water: A continuous changing need for assessment?