Receptors For Htlv

The cellular receptor(s) for HTLV-I and HTLV-II have not been identified. For years, one of the major goals in understanding HTLV biology has been the identification and characterization of its binding and/or fuso-genic receptors.31-33 The identification of the HTLV receptor is particularly important not only in understanding the viral replication, tropism, and pathogenesis of the virus, but also in generating therapeutic and prophylactic agents against HTLV. Several studies have reported that HTLV-I and HTLV-II share the same receptor.33-35 However, attempts to identify this receptor using various techniques such as syncytium formation inhibition, fluorescence-activated cell sorter (FACS) analysis, coprecipitation, and im-munoprecipitation have not been successful.

The task of identifying the HTLV receptor is further complicated by the fact that there may be more than one cellular receptor and possibly several cofactors and coreceptors involved in HTLV infection and cell fusion. For example, HTLV-I may have a cellular binding receptor and a separate fusion receptor. In addition, adhesion molecules could be also involved in infection of target cells by HTLV. Research on another retrovirus, HIV-1, has revealed that in addition to the specific cellular receptor CD4, coreceptors such as CXCR4 and CCR5 and other seven-transmembrane molecules36-38 are important for viral fusion and infection. In the case of HIV, the identification and understanding of these important coreceptors lagged years behind the discovery of the CD4 molecule as the primary receptor for HIV.

The first event in viral infection of the host cell is the binding of the viral protein to molecules expressed on the target cells. In retroviral infections, cell fusion and syncytium formation has been attributed to the interaction of viral envelope expressed on the surface of infected cells and the viral receptor on the surface of neighboring cells. In HTLV, syncytium formation is dependent on the interaction between gp46, the envelope glycoprotein expressed on the surface of infected cells, and cellular receptors on the membrane of target cells. Fusion of infected and uninfected target cells takes place following this interaction.

TABLE I

Cells That Have Ability to Form Syncytia with HTLV-I-Infected MT2 Cellsa

TABLE I

Cells That Have Ability to Form Syncytia with HTLV-I-Infected MT2 Cellsa

Syncytia formation

Cell

Type

with HTLV-I cells

BJAB-WH

Human Blymphosarcoma

++++

Jurkat

Human T-lymphosarcoma

+

SUPT-1

Non-Hodgkins human T-lymphosarcoma

+++

Molt4

Human T-lymphoblastoid

++

HUT78

Human cutaneous T-lymphoma, African green monkey

++

HOS

Human osteogenic TE85, clone F-5

+

HeLa

Human cervical carcinoma, cervix

++

MDBK

Bovine kidney cells

+

PBL

Peripheral blood lymphocytes, phytohemagglutin-activated

++

aThese data confirmed not only that HTLV receptor is present and biologically active on awide variety of cell lines, but also may be a common conserved biochemical structure in a wide variety of species.

aThese data confirmed not only that HTLV receptor is present and biologically active on awide variety of cell lines, but also may be a common conserved biochemical structure in a wide variety of species.

HTLV-I and HTLV-II have demonstrated a general T lymphocyte trop-ism,339-41 preferentially infecting human CD4+ T cells, although other cell populations such as B cells, fibroblasts, endothelial cells, and glial cells42-44 are known to be infected. Most interesting is the ability of HTLV to infect target cells of several species44 (Table I). These data suggest that the HTLV receptor is present and biologically active on a wide variety of cell lines and also may be a common conserved biochemical structure in a wide variety of species. Importantly, HTLV-I and HTLV-II infection in vitro generally requires contact between target and infected cells in order to transmit virus, since the cell-free transmission of HTLV is generally known to be inefficient. Therefore close contact between infected and target cells is very important for HTLV infection. Adhesion molecules expressed on the surface of target cells enhance this cell-cell contact.

Thus, in an attempt to identify and characterize the HTLV receptor, some investigators have focused on generating monoclonal antibodies that have the ability to inhibit the contact between target and infected cells that is necessary for HTLV-I-induced syncytium formation. One group generated and identified four monoclonal antibodies (mAbs) that inhibited syncytium formation in a culture of HTLV-I/MT2-infected cells and MolT-4, but not HOS or human PBMC target cells; however, these mAbs did not inhibit the binding of purified HTLV-I to target cells. Three of the four mAbs (C33, M101, and M104) recognized the same 28-kDa core protein and one mAb, M38, bound to a monomeric 28kDa protein. Molecular cloning of cDNA encoding C33 and M38 antigens determined that both molecules are members of the transmembrane-4 superfamily, which includes CD9, CD37, CD53, CD63, L6, C0-029, T11, Sm23, and TApA-1 .4546 Interestingly, the M38 antigen was identical to TAPA-1, and along with C33 antigen, was encoded by human chromosome 11. These data clearly indicate that these two membrane proteins do not represent an HTLV-I-binding receptor itself; however, it is likely that both of these antigens are indirectly involved in HTLV-I syncytia formation. In the following section, we will discuss in detail several molecules that could be important for HTLV-I infection and our attempts to characterize a specific adhesion molecule involved in HTLV-I-induced cell fusion.

Was this article helpful?

0 0

Post a comment