Human immunodeficiency virus type-1 (HIV-1) antigenic variation poses a great challenge for vaccine immunogen design to elicit broadly neutralizing antibodies (bNAbs). Over the last 10-15 years, great progress has been made to understand the conserved sites of sensitivity on HIV envelope glycoprotein spikes targeted by bNAbs. Plasma neutralization mapping and monoclonal antibody isolation efforts have revealed five major conserved epitope clusters. Most of this work has focused on subtype B and C-infected Caucasian or African donors. It is not clear if the same epitopes and epitope rank order preferences are also true in donors infected with different HIV-1 subtypes and with different racial backgrounds. To investigate this point, in this study we report the first attempt to profile the bNAb specificities of CRF01_AE-infected Malaysian plasmas. We first measured neutralization titers of 21 plasmas against a subtype A, B, and AE pseudovirus panel. This revealed that 14% (3 of 21) plasmas had cross-clade breadth. Focusing on the cross-neutralizing plasma P9, we used AE and JR-FL mutant pseudoviruses, gp120 monomer interference, and native polyacrylamide gel electrophoresis to better understand the neutralization specificity. P9 demonstrates CD4-binding-site specificity with trimer dependence and D368 independence.
Matched MeSH terms: HIV Envelope Protein gp120/genetics
The HIV-1 genetic variation in 60 infected Malaysian intravenous drug users (IDU) was studied by comparison of the nucleotide sequences and their predicted amino acid sequences in the V3 loop of the external glycoprotein gp120. In this study, HIV-1 B, C and E subtypes were identified among Malaysian IDU, with HIV-1 B being the predominant subtype (91.7%). HIV-1 C and HIV-1 E were minority subtypes among Malaysian IDU. Analysis of the amino acid alignment of the C2-V3 region of the env gene suggests a genetic relationship between Thai and Malaysian B and E subtype strains. This study serves as a baseline for monitoring HIV-1 genetic diversity and spread in Malaysia.
Matched MeSH terms: HIV Envelope Protein gp120/genetics*; HIV Envelope Protein gp120/chemistry
In this study, crude extracts of Ganoderma lucidum (NGCs) were compared to the crude extracts of G. lucidum that has antler-like fruiting bodies (AGCs) for their cytotoxicity, inhibitory effects on the attachment of human immunodeficiency virus (HIV)-1 glycoprotein 120 (gp120) to cluster of differentiation 4 (CD4), identification and molecular docking simulations of chemical compounds to predict the best ligand inhibitor and the binding mechanism. Results showed that AGCs had a higher percentage of inhibition (54.3% ± 6.2%) at 150 ppm and higher cytotoxicity (half maximal cytotoxic concentration [CC50] < 300 ppm) than NGCs (CC50 < 400 ppm). Quadrupole time-of-flight (QTOF) liquid chromatography- mass spectrometry (LC-MS) results successfully identified 32 chemical compounds in AGCs and NGCs, comprising mostly ganoderic acids (62%) and their derivatives. Molecular docking simulations of ganolucidic acid A/D and ganoderic acid A/B predicted the strongest binding affinity via hydrogen bonding, suggesting the inhibition of HIV-1 gp120 attachment to CD4. The highest and lowest occupied molecular orbital (HOMO and LUMO, respectively) gap energies of ganoderic acids tended to have less negative HOMO energy and smaller HOMO-LUMO gap energy, implying increased interactions of ligands to the gp120 protein receptor. AGCs showed higher inhibition against HIV-1 gp120 than NGCs due to a higher abundance of ganoderic and ganolucidic acids, whereby both acids contributed the highest number of hydrogen bonds and polar interactions from the hydroxyl and carboxylic functional groups.
Most HIV-1-specific neutralizing antibodies isolated to date exhibit unusual characteristics that complicate their elicitation. Neutralizing antibodies that target the V1V2 apex of the HIV-1 envelope (Env) trimer feature unusually long protruding loops, which enable them to penetrate the HIV-1 glycan shield. As antibodies with loops of requisite length are created through uncommon recombination events, an alternative mode of apex binding has been sought. Here, we isolated a lineage of Env apex-directed neutralizing antibodies, N90-VRC38.01-11, by using virus-like particles and conformationally stabilized Env trimers as B cell probes. A crystal structure of N90-VRC38.01 with a scaffolded V1V2 revealed a binding mode involving side-chain-to-side-chain interactions that reduced the distance the antibody loop must traverse the glycan shield, thereby facilitating V1V2 binding via a non-protruding loop. The N90-VRC38 lineage thus identifies a solution for V1V2-apex binding that provides a more conventional B cell pathway for vaccine design.
Matched MeSH terms: HIV Envelope Protein gp120/immunology*; HIV Envelope Protein gp120/metabolism; HIV Envelope Protein gp120/chemistry