Broadly neutralizing antibodies (bNAbs) against HIV-1 provide both effective pre-exposure prophylaxis and treatment of HIV-1 infection in murine and nonhuman primate models, suggesting their ...potential use in humans. Although much is known about the role of variable domains in the neutralization breadth and potency of these bNAbs, the contribution of Fc domains to their activities is, by contrast, poorly characterized. Assessment of the in vivo activity of several bNAbs revealed that FcγR-mediated effector function contributes substantially to their capacity to block viral entry, suppress viremia, and confer therapeutic activity. Enhanced in vivo potency of anti-HIV-1 bNAbs was associated with preferential engagement of activating, but not inhibitory FcγRs, and Fc domain-engineered bNAb variants with selective binding capacity for activating FcγRs displayed augmented protective activity. These findings reveal key roles for Fc effector function in the in vivo activity of anti-HIV-1 bNAbs and provide strategies for generating bNAbs with improved efficacy.
The Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has outcompeted previously prevalent variants and become a dominant strain worldwide. We report the structure, ...function, and antigenicity of its full-length spike (S) trimer as well as those of the Gamma and Kappa variants, and compare their characteristics with the G614, Alpha, and Beta variants. Delta S can fuse membranes more efficiently at low levels of cellular receptor angiotensin converting enzyme 2 (ACE2), and its pseudotyped viruses infect target cells substantially faster than the other five variants, possibly accounting for its heightened transmissibility. Each variant shows different rearrangement of the antigenic surface of the amino-terminal domain of the S protein but only makes produces changes in the receptor binding domain (RBD), making the RBD a better target for therapeutic antibodies.
Latent reservoirs of HIV-1-infected cells are refractory to antiretroviral therapies (ART) and remain the major barrier to curing HIV-1. Because latently infected cells are long-lived, ...immunologically invisible, and may undergo homeostatic proliferation, a “shock and kill” approach has been proposed to eradicate this reservoir by combining ART with inducers of viral transcription. However, all attempts to alter the HIV-1 reservoir in vivo have failed to date. Using humanized mice, we show that broadly neutralizing antibodies (bNAbs) can interfere with establishment of a silent reservoir by Fc-FcR-mediated mechanisms. In established infection, bNAbs or bNAbs plus single inducers are ineffective in preventing viral rebound. However, bNAbs plus a combination of inducers that act by independent mechanisms synergize to decrease the reservoir as measured by viral rebound. Thus, combinations of inducers and bNAbs constitute a therapeutic strategy that impacts the establishment and maintenance of the HIV-1 reservoir in humanized mice.
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•bNAbs can be used for postexposure prophylaxis (PEP) in humanized mice•bNAb PEP efficacy requires Fc-receptor binding•bNAbs plus a single inducer of HIV-1 transcription do not reduce viral rebound•bNAbs plus a combination of inducers significantly reduce viral rebound
A combination of broadly neutralizing antibodies and viral inducers reduce the frequency of viral rebound in the humanized mouse model of HIV-1 infection.
Given the absence of an effective vaccine for protection against HIV-1 infection, passive immunization strategies that utilize potent broadly neutralizing antibodies (bnAbs) to block acquisition of ...HIV-1 are being rigorously pursued in the clinical setting. bnAbs have demonstrated robust protection in preclinical animal models, and several leading bnAb candidates have shown favorable safety and pharmacokinetic profiles when tested individually or in combinations in early phase human clinical trials. Furthermore, passive administration of bnAbs in HIV-1 infected individuals has resulted in prolonged suppression of viral rebound following interruption of combination antiretroviral therapy, and robust antiviral activity when administered to viremic individuals. Recent results from the first efficacy trials testing repeated intravenous administrations of the anti-CD4 binding site bnAb VRC01 have demonstrated positive proof of concept that bnAb passive immunization can confer protection against HIV-1 infection in humans, but have also highlighted the considerable barriers that remain for such strategies to effectively contribute to control of the epidemic. In this review, we discuss the current status of clinical studies evaluating bnAbs for HIV-1 prevention, highlight lessons learned from the recent Antibody Mediated Prevention (AMP) efficacy trials, and provide an overview of strategies being employed to improve the breadth, potency, and durability of antiviral protection.
Sexual selection is the differential reproductive success of individuals, resulting from competition for mates, mate choice, or success in fertilization. In primates, this selective pressure often ...leads to the development of exaggerated traits which play a role in sexual competition and successful reproduction. In order to gain insight into the mechanisms driving the development of sexually selected traits, we used an unbiased genome-wide approach across 21 primate species to correlate individual rates of protein evolution to relative testes size and sexual dimorphism in body size, 2 anatomical hallmarks of sexual selection in mammals. Among species with presumed high levels of sperm competition, we detected strong conservation of testes-specific proteins responsible for spermatogenesis and ciliary form and function. In contrast, we identified accelerated evolution of female reproductive proteins expressed in the vagina, cervix, and fallopian tubes in these same species. Additionally, we found accelerated protein evolution in lymphoid tissue, indicating that adaptive immune functions may also be influenced by sexual selection. This study demonstrates the distinct complexity of sexual selection in primates revealing contrasting patterns of protein evolution between male and female reproductive tissues.
Several fast-spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become the dominant circulating strains in the COVID-19 pandemic. We report here cryo-electron ...microscopy structures of the full-length spike (S) trimers of the B.1.1.7 and B.1.351 variants, as well as their biochemical and antigenic properties. Amino acid substitutions in the B.1.1.7 protein increase both the accessibility of its receptor binding domain and the binding affinity for receptor angiotensin-converting enzyme 2 (ACE2). The enhanced receptor engagement may account for the increased transmissibility. The B.1.351 variant has evolved to reshape antigenic surfaces of the major neutralizing sites on the S protein, making it resistant to some potent neutralizing antibodies. These findings provide structural details on how SARS-CoV-2 has evolved to enhance viral fitness and immune evasion.
The identification of a new generation of potent broadly neutralizing HIV-1 antibodies (bnAbs) has generated substantial interest in their potential use for the prevention and/or treatment of HIV-1 ...infection. While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit. We assessed the neutralizing activity of 15 bnAbs targeting four distinct epitopes of Env, including the CD4-binding site (CD4bs), the V1/V2-glycan region, the V3-glycan region, and the gp41 membrane proximal external region (MPER), against a panel of 200 acute/early clade C HIV-1 Env pseudoviruses. A mathematical model was developed that predicted neutralization by a subset of experimentally evaluated bnAb combinations with high accuracy. Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations. The most promising bnAb combinations were identified based not only on breadth and potency of neutralization, but also other relevant measures, such as the extent of complete neutralization and instantaneous inhibitory potential (IIP). By this set of criteria, triple and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo. These results provide a rationale for advancing bnAb combinations with the best in vitro predictors of success into clinical trials for both the prevention and treatment of HIV-1 infection.
Selective pressures and their effects on protein structure and function can be found by comparing genes or proteins from different organisms. These pressures can take varying forms. Sexual selection, ...a form of natural selection, occurs when an organism acquires traits that give it an advantage in mating and producing offspring. An example can be seen in hominid seminal proteins. Hominids exhibit different mating systems which has resulted in seminal proteins being affected by varying degrees of sperm competition. This can result in variation both in the sequences of these genes and the function of the gene products. One such gene, ACPP, is used to generate the protein prostatic acid phosphatase (PAP). This protein is known to dephosphorylate a number of targets in seminal plasma, and it functions as a phosphatase in the acidic pH range. It has been suggested computationally by comparing dN/dS ratios that ACPP may be under strong positive selection in chimpanzees (a species with high sperm competition) and purifying selection in humans and gorillas (both species with weaker sperm competition). We hypothesize that varying degrees of sperm competition have resulted in sequence and functional variation at ACPP/PAP among hominids. ACPPcoding sequences for human, chimp, and gorilla homologs were each inserted into a mammalian expression vector with a C‐terminal His6 tag and transfected into HEK‐293T cells. The phosphatase activities of the PAP homologs were compared using a DiFMUP fluorescent substrate assay. Each protein was tested for pH optima, phosphatase activity at a fixed substrate concentration, and kcat/km. The PAP orthologs exhibited similar pH profiles, with a pH optimum between pH 5.0‐6.0. However, it was found that chimp PAP exhibited elevated phosphatase activity when compared to the other hominids, and this was consistent across a varying pH range. These results suggest that positive selection of chimp ACPPhas resulted in a more efficient PAP protein with elevated activity when compared to human and gorilla PAP, perhaps due to strong sperm competition. Gorilla PAP showed the lowest activity, which is interesting considering that many genes that code for male reproductive proteins have become pseudogenes in gorillas, a species with very low sperm competition. Overall, the results suggest that the varying mating systems of the hominid primates have resulted in functional differences in the PAP homologs of humans, chimpanzees, and gorillas. By bridging together functional and computational techniques such as in this research, we are beginning to understand the effects of specific selective pressures on the function of male reproductive proteins.
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