Frontline Science: Plasma and immunoglobulin G galactosylation associate with HIV persistence during antiretroviral therapy

Abstract

Global antibody glycosylation is dynamic and plays critical roles in shaping different immunological outcomes and direct antibody functionality during HIV infection. However, the relevance of global antibody or plasma glycosylation patterns to HIV persistence after antiretroviral therapy (ART) has not been characterized. First, we compared glycomes of total plasma and isolated immunoglobulin G (IgG) from HIV+ ART-suppressed, HIV+ viremic, and HIV-negative individuals. Second, in ART-suppressed individuals, we examined the associations between glycomes and (1) levels of cell-associated HIV DNA and RNA in PBMCs and isolated CD4+ T cells, (2) CD4 count and CD4%, and (3) expression of CD4+ T-cell activation markers. HIV infection is associated with persistent alterations in the IgG glycome including decreased levels of disialylated glycans, which is associated with a lower anti-inflammatory activity, and increased levels of fucosylated glycans, which is associated with lower antibody-dependent cell-mediated cytotoxicity (ADCC). We also show that levels of certain mono- and digalactosylated nonfucosylated glycomic traits (A2G1, A2G2, and A2BG2), which have been reported to be associated with higher ADCC and higher anti-inflammatory activities, exhibit significant negative correlations with levels of cell-associated total HIV DNA and HIV RNA in ART-suppressed individuals. Finally, levels of certain circulating anti-inflammatory glycans are associated with higher levels of CD4 T cells and lower levels of T-cell activation. Our findings represent the first proof-of-concept evidence that glycomic alterations, known to be associated with differential states of inflammation and ADCC activities, are also associated with levels of HIV persistence in the setting of ART suppression.

Sialylation and fucosylation modulate inflammasome-activating eIF2 Signaling and microbial translocation during HIV infection

“…We recently showed that HIV infection is associated with alterations, including hypo-sialylation, in the plasma circulating glycome; these changes were associated with markers of inflammation and levels of PBMCs-derived CD4+ T cell-associated HIV DNA and RNA. 71 This HIV-associated hyposialylation is not completely reversed by ART. 71 In the general population, hypo-sialylation on circulating glycoproteins drives inflammation and is associated with premature aging.…”

Glycomic alterations in HIV infection: one galactose or two?

“…One such example is the association between changes in Ab glycosylation and their ability to control HIV infection. 2 In particular, there is an observed increase in agalactosylated Abs in spontaneous HIV controllers. An increase in bisected Abs in HIV-infected individuals compared to healthy controls has also been reported, 8…”

“…Although ART has dramatically decreased morbidity and mortality in HIV‐infected individuals, persistent infection is associated with chronic immune activation and inflammation leading to damage across multiple organ systems, ultimately contributing to the size of the HIV reservoir and decreased quality and quantity of life . Although the failure of Ab therapy to be curative in HIV infection has long been appreciated, up to the publication in the current issue by Vadrevu et al, there have been no reports on the impact of Ab glycosylation on the HIV reservoir. The authors hypothesized and then went on to show that differences in Ab glycosylation between HIV‐naïve individuals, HIV‐infected viremic individuals, and HIV‐infected ART‐suppressed individuals are associated with virus reservoir, immune activation, and CD4 count.…”

“…It then follows that changes to the IgG glycome can affect how Abs interact with pathogens. One such example is the association between changes in Ab glycosylation and their ability to control HIV infection . In particular, there is an observed increase in agalactosylated Abs in spontaneous HIV controllers.…”

“…In this issue of JLB, Vadrevu et al . identify modifications in the plasma and IgG glycomes that were persistent across distinct HIV‐noninfected and HIV‐positive sample population.…”