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Slow turnover of HIV-1 receptors on quiescent CD4+ T cells causes prolonged surface retention of gp120 immune complexes in vivo.

ABSTRACT: Peripheral blood CD4(+) T cells in HIV-1(+) patients are coated with Ig. However, the causes and consequences of the presence of Ig(+) CD4(+) T cells remain unknown. Previous studies have demonstrated the rapid turnover of viral receptors (VRs) on lymphoma and tumor cells. The present study investigates the turnover of VRs on peripheral quiescent CD4(+) T cells (qCD4s), which are the most abundant peripheral blood CD4(+) T cells. Utilizing pharmacological and immunological approaches, we found that the turnover of VRs on qCD4s is extremely slow. As a result, exposure to gp120 or HIV-1 virions in vitro causes gp120 to remain on the surface for a long period of time. It requires approximately three days for cell-bound gp120 on the surface to be reduced by 50%. In the presence of patient serum, gp120 forms surface immune complexes (ICs) that are also retained for a long time. Indeed, when examining the percentages of Ig(+) CD4(+) T cells at different stages of HIV-1 infection, approximately 70% of peripheral resting CD4(+) T cells (rCD4s) were coated with surface VRs bound to slow-turnover gp120-Ig. The levels of circulating ICs in patient serum were insufficient to form surface ICs on qCD4s, suggesting that surface ICs on qCD4s require much higher concentrations of HIV-1 exposure such as might be found in lymph nodes. In the presence of macrophages, Ig(+) CD4(+) T cells generated in vitro or directly isolated from HIV-1(+) patients were ultimately phagocytosed. Similarly, the frequencies and percentages of Ig(+) rCD4s were significantly increased in an HIV-1(+) patient after splenectomy, indicating that Ig(+) rCD4s might be removed from circulation and that non-neutralizing anti-envelope antibodies could play a detrimental role in HIV-1 pathogenesis. These findings provide novel insights for vaccine development and a rationale for using Ig(+) rCD4 levels as an independent clinical marker.

SUBMITTER: Suzuki Y

PROVIDER: S-EPMC3916329 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Slow turnover of HIV-1 receptors on quiescent CD4+ T cells causes prolonged surface retention of gp120 immune complexes in vivo.

Suzuki Yasuhiro Y Gatanaga Hiroyuki H Tachikawa Natsuo N Oka Shinichi S

PloS one 20140206 2

Peripheral blood CD4(+) T cells in HIV-1(+) patients are coated with Ig. However, the causes and consequences of the presence of Ig(+) CD4(+) T cells remain unknown. Previous studies have demonstrated the rapid turnover of viral receptors (VRs) on lymphoma and tumor cells. The present study investigates the turnover of VRs on peripheral quiescent CD4(+) T cells (qCD4s), which are the most abundant peripheral blood CD4(+) T cells. Utilizing pharmacological and immunological approaches, we found t ...[more]

PMID: 24516533

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Project description:Cyanovirin-N (CV-N), an 11-kDa protein isolated from the cyanobacterium Nostoc ellipsosporum, potently inactivates diverse strains of human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus. While it has been well established that the viral surface envelope glycoprotein gp120 is a molecular target of CV-N, the detailed mechanism of action is of further interest. We compared matched native and CV-N-treated virus preparations in a panel of assays that measure viral replication, assessing successive stages of the viral life cycle. CV-N-treated virions failed to infect cells as detected by p24 production and quantitative PCR for HIV-1 reverse transcription products, whereas treatment of the target cells did not block infection, confirming that CV-N acts at the level of the virus, not the target cell, to abort the initial infection process. Compared to native HIV-1 preparations, CV-N-treated HIV-1 virions showed impaired CD4-dependent binding to CD4(+) T cells and did not mediate "fusion from without" of CD4(+) target cells. CV-N also blocked HIV envelope glycoprotein Env-induced, CD4-dependent cell-cell fusion. Mapping studies with monoclonal antibodies (MAbs) to defined epitopes on the HIV-1 envelope glycoprotein indicated that CV-N binds to gp120 in a manner that does not occlude or alter the CD4 binding site or V3 loop or other domains on gp120 recognized by defined MAbs and does not interfere with soluble CD4-induced conformational changes in gp120. Binding of CV-N to soluble gp120 or virions inhibited subsequent binding of the unique neutralizing MAb 2G12, which recognizes a glycosylation-dependent epitope. However, prior binding of 2G12 MAb to gp120 did not block subsequent binding by CV-N. These results help clarify the mechanism of action of CV-N and suggest that the compound may act in part by preventing essential interactions between the envelope glycoprotein and target cell receptors. This proposed mechanism is consistent with the extensive activity profile of CV-N against numerous isolates of HIV-1 and other lentiviruses and supports the potential broad utility of this protein as a microbicide to prevent the sexual transmission of HIV.

Dataset Information

Slow turnover of HIV-1 receptors on quiescent CD4+ T cells causes prolonged surface retention of gp120 immune complexes in vivo.

Publications

Slow turnover of HIV-1 receptors on quiescent CD4+ T cells causes prolonged surface retention of gp120 immune complexes in vivo.

Similar Datasets

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