Serum glycan-binding IgG antibodies in HIV-1 infection and during the development of broadly neutralizing responses

Abstract

Background The HIV-1 envelope is covered with glycans that provide structural integrity and protect conserved regions from host antibody responses. However, these glycans are often the target of broadly neutralizing antibodies (bNAbs) that emerge in some HIV infected individuals. We aimed to determine whether anti-glycan IgG antibodies are a general response to HIV-1 infection or specific to individuals who develop bNAbs. Methods IgG binding to glycans was assessed using arrays that contained 245 unique components including N-linked carbohydrates, glycolipids and Tn-peptides. Sera from 20 HIV negative and 27 HIV positive women (including 12 individuals who developed bNAbs) were profiled longitudinally. HIV-1 gp120 proteins were used to compete for binding to the array. Results Anti-glycan IgG antibodies fluctuated over a three-year period irrespective of HIV infection. However, HIV positive individuals had elevated binding to 40 components on the array that included Man8, Man9, Tn-peptides, heat shock protein and glycolipids. Competition experiments confirmed that a proportion of these glycan-binding IgG antibodies were HIV-1 specific, some of which were higher in individuals who developed bNAbs. Conclusions HIV-1 infection is associated with elevated levels of IgG antibodies to specific glycans. Furthermore, some anti-glycan IgG antibodies were more abundant in individuals with bNAbs, suggesting a unique phenotype that may be informative for HIV vaccine design.

Development of a Multiplex Glycan Microarray Assay and Comparative Analysis of Human Serum Anti-Glycan IgA, IgG, and IgM Repertoires

“…We previously profiled anti-glycan IgG and IgM antibodies present in serum samples from 20 healthy individuals obtained yearly over a 3-year time frame. 15 To facilitate a better understanding of our new results, we carried out additional analyses on that data. Over this longer timer interval, anti-glycan antibody profiles were very consistent but had a slightly higher level of variability than over weeks to months.…”

Glycan Microarrays as Chemical Tools for Identifying Glycan Recognition by Immune Proteins

“…Pooled IgG from healthy donors and IVIG (von Gunten et al, 2009;Schneider et al, 2015) have been profiled on a variety of different microarray platforms and have revealed a large diversity of antiglycan antibody repertoires, including antibodies specific for cellulose and monosaccharides (Schwarz et al, 2003). Individual serum has been tested from healthy individuals (Muthana and Gildersleeve, 2016) as well as in HIV positive individuals (Scheepers et al, 2017) from the array platforms generated by Gildersleeve's group (see discussion in section Other Approaches in Glycan Microarray Generation). We have also surveyed the anti-carbohydrate antibody repertoire (ACAR) of 105 healthy donors, ranging from 20 to 60+ years old on the NCFGv1 array (Luetscher et al in review).…”

Abnormal antibodies to self-carbohydrates in SARS-CoV-2 infected patients

“…67 In these cases, antibodies to self-glycans were present in fewer patients and for fewer glycans than what we observed in COVID-19 patients. In prior studies, we found that serum IgG and IgM levels to nearly all glycans on our array are stable over time frames of up to 3 years, 66,68 indicating that high signals in certain patients are not simply due to high variability or random fluctuations over time. Lastly, our prior studies on healthy subjects of varying age indicate that these high antibody populations are not merely due to increasing age.…”

“…For example, we did not observed high antibodies to these glycans in ~100 cancer patients prior to or after vaccination with a live-attenuated poxvirus-based vaccine (PROSTVAC-VF), 64,65 indicating that they are not due to a general effect of disease or a non-specific effect of viral infection. Some instances where we have observed high antibodies to some of the glycans are HIV infected patients (antibodies to Man9, GT2, and GT3) 66 and cancer patients immunized with a whole cell cancer vaccine (antibodies to GM2, GM3, Gb5, and sialyl Lewis X). 67 In these cases, antibodies to self-glycans were present in fewer patients and for fewer glycans than what we observed in COVID-19 patients.…”

“…We have investigated anti-glycan antibody repertoires in numerous human serum samples previously, including over 200 healthy subjects and over 100 cancer patients before and after treatment with various cancer vaccines. 56,[64][65][66][67][68] Based on our prior work, abnormally high antibodies to human gangliosides, N-linked glycans, and other self-glycans are uncommon. For example, we did not observed high antibodies to these glycans in ~100 cancer patients prior to or after vaccination with a live-attenuated poxvirus-based vaccine (PROSTVAC-VF), 64,65 indicating that they are not due to a general effect of disease or a non-specific effect of viral infection.…”