HIV-1 gp120 Binding to Dendritic Cell Receptors Mobilize the Virus to the Lymph Nodes, but the Induced IL-4 Synthesis by FcεRI⁺Hematopoietic Cells Damages the Adaptive Immunity – a Review, Hypothesis, and Implications

Abstract

HIV-1 is equipped with the envelope gp160 glycoprotein for interaction with Langerhans cells (LCs) and dendritic cells (DCs), the members of the innate immune system, which confront the virus at the portal of virus entry in the human body. These cells are equipped with receptors by which they bind and endocytose the virus. The gp120 glycoprotein is used for binding to CD4 receptor and CCR5 co-receptor of T helper 2 (Th2) cells and the virions shed gp120 is able to induce FcepsilonRI+ hematopoietic cells to produce IL-4, which inactivate the host adaptive immune response. The properties of gp120s various functional domains are analyzed together with the regulatory viral proteins, which are involved in the damage to T and B cells during HIV-1 replication. The interaction of HIV-1 virions through their gp120 with LCs and DCs at the portal of virus entry will be discussed. A hypothesis will be presented that the understanding of the role of the different functional domains of gp120 in the life cycle of the virus and during AIDS will help in the design of approaches to prevent and abrogate HIV-1 infection and AIDS.

A Point of View: HIV-1/AIDS is an Allergy but CpG ODN Treatments may Inhibit Virus Replication and Reactivate the Adaptive Immunity – Hypothesis and Implications

“…The reports on the presence of a superantigen domain in the gp120 molecules [17,18] and the ability of the viral gp120 to induce IL-4 release from IgE/FceRI + hematopoietic cells might have contributed to the failure of the gp120 vaccine trials in humans. The effectiveness of anti-HIV-1 antibodies in the neutralization of virions need to be reconsidered since the antigenic domains on gp120 are protected by the mannose-rich glycans and only 7-10 gp120 molecules associate with the virion [30].…”

“…This entire series of events, which is spurred on by increased levels of IL-4 and IgE, ultimately inhibits the patients' adaptive immune responses [17,18]. In the presence of IL-4, B cells stop synthesizing IgG antibodies and switch to the synthesis of IgE molecules, which are involved in the induction of IL-4 release from hematopoietic cells.…”

“…is based on the understanding of the mechanisms by which HIV-1 invades the lymph nodes, to establish foci of virus replication and its ability to cause AIDS and dementia [13,14,17,18,23]. The unique properties of the virions shed gp120 molecules that enable them to use the superantigen domain to bind to IgE bound to FceRI + hematopoietic cells, which respond with the release of large amounts of IL-4.…”

“…The innate immune system's Langerhans cells (LCs) and monocyte-derived dendritic cells (DCs) are instrumental to the transport of HIV-1 virions from the portal of entry to the lymph nodes and to the polarization of Th1 and Th2 cells, the latter of which are infected by the virus [18]. However, the Toll-like receptor (TLR) 9 + plasmacytoid DCs (pDCs) [19,20] can be triggered to synthesize and release large amounts of interferons (IFNs), while LCs and DCs serve as antigen-presenting cells that continue to function in infected patients.…”

CpG ODNs Treatments of HIV-1 Infected Patients May Cause the Decline of Transmission in High Risk Populations – A Review, Hypothesis and Implications

“…TLR9 is expressed by pDCs and on B cells [20] and serve as a receptor for unmethylated bacterial DNA and CpG ODNs. Takeshita et al [21] reported that the engagement of TLR9 by CpG ODNs is essential for the initiating of TLR9-mediated signaling.…”