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The human immunodeficiency virus type 1 (HIV-1) envelope (Env) spike, comprising three gp120 and three gp41 sub-units, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a post-fusion state. As the sole viral antigen on the HIV-1 virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.5 A resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22. This structure reveals the prefusion conformation of gp41, indicates rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition. Pre-fusion gp41 encircles amino- and carboxy- terminal strands of gp120 with four helices that form a membrane-proximal collar, fastened by insertion of a fusion peptide-proximal methionine into a gp41-tryptophan clasp. Spike rearrangements required for entry involve opening the clasp and expelling the termini. N-linked glycosylation and sequence- variable regions cover the pre-fusion closed spike; we used chronic cohorts to map the prevalence and location of effective HIV-1-neutralizing responses, which were distinguished by their recognition of N-linked glycan and tolerance for epitope-sequence variation., Over the last 50 years, more than 70 million people have been infected or killed by the human immunodeficiency virus type 1 (HIV-1) (1). A dominant contributing factor has been [...]

Neutralizing antibodies are likely to play a crucial part in a preventative HIV-1 vaccine. Although efforts to elicit broadly cross-neutralizing (BCN) antibodies by vaccination have been unsuccessful (1-3), a minority of individuals naturally develop these antibodies after many years of infection (4-7). How such antibodies arise, and the role of viral evolution in shaping these responses, is unknown. Here we show, in two HIV-1-infected individuals who developed BCN antibodies targeting the glycan at Asn332 on the gp120 envelope, that this glycan was absent on the initial infecting virus. However, this BCN epitope evolved within 6 months, through immune escape from earlier strain-specific antibodies that resulted in a shift of a glycan to position 332. Both viruses that lacked the glycan at amino acid 332 were resistant to the Asn332-dependent BCN monoclonal antibody PGT128 (ref. 8), whereas escaped variants that acquired this glycan were sensitive. Analysis of large sequence and neutralization data sets showed the 332 glycan to be significantly under-represented in transmitted subtype C viruses compared to chronic viruses, with the absence of this glycan corresponding with resistance to PGT128. These findings highlight the dynamic interplay between early antibodies and viral escape in driving the evolution of conserved BCN antibody epitopes., Although the role of glycans in shielding neutralizing epitopes has long been known (9-11), it has only recently become clear that many BCN responses directly target glycans, including the one [...]

Increased plasma level of leptin appears to be a ubiquitous feature of pregnant mammals. The mechanisms by which leptin levels are increased may be species specific, however, with some species upregulating adipose leptin production and others expressing leptin in the placenta. Placental leptin expression was examined in representative species of the two most abundant mammalian orders, Rodentia and Chiroptera, and in cultured human choriocarcinoma (BeWo) cells. Leptin mRNA was expressed in BeWo cells and in placentas of Myotis lucifugus (little brown bat), Eptesicus fuscus (big brown bat), and Rattus norvegicus (laboratory rat), but not the common laboratory mouse Mus musculus, cAMP stimulated secretion of leptin from BeWo cells and also stimulated leptin mRNA expression in the cells. In addition to adipose and placental tissue, leptin transcript in M. lucifugus was detectable in heart, spleen, and liver, but not in lung, brain, and kidney. Hepatic expression was also observed in E. fuscus, but not in mice or rats, and did not appear to result from hepatic fat deposition. Leptin cDNA was cloned and sequenced from M. lucifugus placenta and shared up to 95% homology with other mammalian leptin cDNAs. It is concluded that 1) placental leptin expression and secretion are species-specific traits, 2) placental leptin production represents one of three major mechanisms for achieving high circulating maternal leptin levels during pregnancy, the others being upregulation of adipose leptin production and production of circulating leptin-binding proteins, and 3) hepatic leptin expression in pregnant insectivorous bats may be an adaptation resulting from the presence of extremely low amounts of subcutaneous fat during pregnancy and lactation in these species. bats; adipose tissue; energy homeostasis; reproduction; placenta

Increased plasma level of leptin appears to be a ubiquitous feature of pregnant mammals. The mechanisms by which leptin levels are increased may be species specific, however, with some species upregulating adipose leptin production and others expressing leptin in the placenta. Placental leptin expression was examined in representative species of the two most abundant mammalian orders, Rodentia and Chiroptera, and in cultured human choriocarcinoma (BeWo) cells. Leptin mRNA was expressed in BeWo cells and in placentas of Myotis lucifugus (little brown bat), Eptesicus fuscus (big brown bat), and Rattus norvegicus (laboratory rat), but not the common laboratory mouse Mus musculus. cAMP stimulated secretion of leptin from BeWo cells and also stimulated leptin mRNA expression in the cells. In addition to adipose and placental tissue, leptin transcript in M. lucifugus was detectable in heart, spleen, and liver, but not in lung, brain, and kidney. Hepatic expression was also observed in E. fuscus, but not in mice or rats, and did not appear to result from hepatic fat deposition. Leptin cDNA was cloned and sequenced from M. lucifugus placenta and shared up to 95% homology with other mammalian leptin cDNAs. It is concluded that 1) placental leptin expression and secretion are species-specific traits, 2) placental leptin production represents one of three major mechanisms for achieving high circulating maternal leptin levels during pregnancy, the others being upregulation of adipose leptin production and production of circulating leptin-binding proteins, and 3) hepatic leptin expression in pregnant insectivorous bats may be an adaptation resulting from the presence of extremely low amounts of subcutaneous fat during pregnancy and lactation in these species. [ABSTRACT FROM AUTHOR]

An understanding of how broadly neutralizing activity develops in HIV-1-infected individuals is needed to guide vaccine design and immunization strategies. Here we used a large panel of 44 HIV-1 envelope variants (subtypes A, B, and C) to evaluate the presence of broadly neutralizing antibodies in serum samples obtained 3 years after seroconversion from 40 women enrolled in the CAPRISA 002 acute infection cohort. Seven of 40 participants had serum antibodies that neutralized more than 40% of viruses tested and were considered to have neutralization breadth. Among the samples with breadth, CAP257 serum neutralized 82% (36/44 variants) of the panel, while CAP256 serum neutralized 77% (33/43 variants) of the panel. Analysis of longitudinal samples showed that breadth developed gradually starting from year 2, with the number of viruses neutralized as well as the antibody titer increasing over time. Interestingly, neutralization breadth peaked at 4 years postinfection, with no increase thereafter. The extent of cross-neutralizing activity correlated with CD4+ T cell decline, viral load, and CD4+ T cell count at 6 months postinfection but not at later time points, suggesting that early events set the stage for the development of breadth. However, in a multivariate analysis, CD4 decline was the major driver of this association, as viral load was not an independent predictor of breadth. Mapping of the epitopes targeted by cross-neutralizing antibodies revealed that in one individual these antibodies recognized the membrane-proximal external region (MPER), while in two other individuals, cross-neutralizing activity was adsorbed by monomeric gp120 and targeted epitopes that involved the N-linked glycan at position 332 in the C3 region. Serum antibodies from the other four participants targeted quaternary epitopes, at least 2 of which were PG9/16-like and depended on the N160 and/or L165 residue in the V2 region. These data indicate that fewer than 20% of HIV-1 subtype C-infected individuals develop antibodies with cross-neutralizing activity after 3 years of infection and that these antibodies target different regions of the HIV-1 envelope, including as yet uncharacterized epitopes. [ABSTRACT FROM AUTHOR]

Ibogaine is a psychedelic alkaloid being investigated as a possible treatment for opioid use disorder. Ibogaine has a multi-receptor profile with affinities for mu and kappa opioid as well as NMDA receptors amongst others. Due to the sparsity of research into ibogaine's effects on white matter integrity and given the growing evidence that opioid use disorder is characterized by white matter pathology, we set out to investigate ibogaine's effects on two markers of myelination, 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) and myelin basic protein (MBP). Fifty Sprague Dawley rats were randomly assigned to five experimental groups of n = 10; (1) a saline control group received daily saline injections for 10 days, (2) a morphine control group received escalating morphine doses from 5 to 15 mg/kg over 10 days, (3) an ibogaine control group that received 10 days of saline followed by 50 mg/kg ibogaine hydrochloride, (4) a combination morphine and ibogaine group 1 that received the escalating morphine regime followed by 50 mg/kg ibogaine hydrochloride and (5) a second combination morphine and ibogaine group 2 which followed the same morphine and ibogaine regimen yet was terminated 72 h after administration compared to 24 h in the other groups. White matter from the internal capsule was dissected and qPCR and western blotting determined protein and gene expression of CNP and MBP. Morphine upregulated CNPase whereas ibogaine alone had no effect on CNP mRNA or protein expression. However, ibogaine administration following repeated morphine administration had an immediate effect by increasing CNP mRNA expression. This effect diminished after 72 h and resulted in a highly significant upregulation of CNPase protein at 72 h post administration. Ibogaine administration alone significantly upregulated protein expression yet downregulated MBP mRNA expression. Ibogaine administration following repeated morphine administration significantly upregulated MBP mRNA expression which increased at 72 h post administration resulting in a highly significant upregulation of MBP protein expression at 72 h post administration. These findings indicate that ibogaine is able to upregulate genes and proteins involved in the process of remyelination following opioid use and highlights an important mechanism of action of ibogaine's ability to treat substance use disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Govender, Moloko, Papathanasopoulos, Tumba, Owen and Calvey.)