Macrophage- and CD4+ T cell-derived SIV differ in glycosylation, infectivity and neutralization sensitivity.

The human immunodeficiency virus (HIV) envelope protein (Env) mediates viral entry into host cells and is the primary target for the humoral immune response. Env is extensively glycosylated, and these glycans shield underlying epitopes from neutralizing antibodies. The glycosylation of Env is influenced by the type of host cell in which the virus is produced. Thus, HIV is distinctly glycosylated by CD4⁺ T cells, the major target cells, and macrophages. However, the specific differences in glycosylation between viruses produced in these cell types have not been explored at the molecular level. Moreover, it remains unclear whether the production of HIV in CD4⁺ T cells or macrophages affects the efficiency of viral spread and resistance to neutralization. To address these questions, we employed the simian immunodeficiency virus (SIV) model. Glycan analysis implied higher relative levels of oligomannose-type N-glycans in SIV from CD4⁺ T cells (T-SIV) compared to SIV from macrophages (M-SIV), and the complex-type N-glycans profiles seem to differ between the two viruses. Notably, M-SIV demonstrated greater infectivity than T-SIV, even when accounting for Env incorporation, suggesting that host cell-dependent factors influence infectivity. Further, M-SIV was more efficiently disseminated by HIV binding cellular lectins. We also evaluated the influence of cell type-dependent differences on SIV's vulnerability to carbohydrate binding agents (CBAs) and neutralizing antibodies. T-SIV demonstrated greater susceptibility to mannose-specific CBAs, possibly due to its elevated expression of oligomannose-type N-glycans. In contrast, M-SIV exhibited higher susceptibility to neutralizing sera in comparison to T-SIV. These findings underscore the importance of host cell-dependent attributes of SIV, such as glycosylation, in shaping both infectivity and the potential effectiveness of intervention strategies. Author summary: The human immunodeficiency virus (HIV) is the causative agent of the acquired immunodeficiency syndrome (AIDS), a lethal condition that necessitates life-long antiretroviral therapy for prevention. The envelope protein (Env) of HIV mediates the viral entry into host cells and is the sole target for the immune system on the surface of the virus. Env's extensive modification with sugars, so called N-glycans, shields crucial epitopes from neutralizing antibodies. Interestingly, key HIV producing cell types, such as CD4⁺ T cells and macrophages, modify Env with distinct N-glycosylation patterns. However, the specific molecular disparities in N-glycosylation between viruses from these cell types are unexplored, and whether the producer cell type impacts the viral spread and resistance to neutralization is incompletely understood. Utilizing the simian immunodeficiency virus (SIV) as a model for HIV, our study revealed differing N-glycan profiles between SIV Env produced in CD4⁺ T cells (T-SIV) and macrophages (M-SIV), with T-SIV incorporating more N-glycans of the oligomannose-type into Env than M-SIV. M-SIV displayed enhanced infectivity and transmissibility in in vitro studies. Additionally, M-SIV exhibited greater susceptibility to neutralizing sera compared to T-SIV, while T-SIV showed heightened susceptibility to mannose-specific carbohydrate-binding agents. These findings emphasize the critical role of host cell-dependent attributes in shaping N-glycosylation of Env as well as viral infectivity and spread. These findings have important implications for the development of new biomedical interventions against HIV. [ABSTRACT FROM AUTHOR]