Human immunodeficiency virus-infected T cells and monocytes are killed by monoclonal human anti-gp41 antibodies coupled to ricin A chain.

Till, Mark; Zolla‐Pazner, Susan; Gorny, M. K.; Patton, John S.; Uhr, Jonathan W.; Vitetta, Ellen S.

doi:10.1073/pnas.86.6.1987

Cited by 58 publications

(30 citation statements)

References 31 publications

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“…Preliminary studies suggest that they neither neutralize nor enhance virus infectivity (E. Robinson, W. Mitchell, M.K.G., and S.Z.-P., unpublished data). However, when coupled to deglycosylated ricin A chain, at least two of the Abs, 50-69 and 98-6, specifically kill HIV-infected cells (41). Thus, the Abs have sufficiently high affinity to bind to antigen immobilized on various matrices and to bind to antigen on the Immunology: Gorny et al…”

Section: Resultsmentioning

confidence: 99%

Generation of human monoclonal antibodies to human immunodeficiency virus.

Górny

Gianakakos

Sharpe

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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170

127

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Section: Resultsmentioning

confidence: 99%

Generation of human monoclonal antibodies to human immunodeficiency virus.

Górny

Gianakakos

Sharpe

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

170

127

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“…The addition of sCD4 destabilizes the gp120-gp41 interaction, resulting in greater exposure of this otherwise partially obscured epitope. Others have also targeted this region (11,19). A different group of investigators has focused on the CD4-binding site (CD4bs) as the target of choice (10,14,15,17,18,20).…”

Section: Importancementioning

confidence: 99%

“…Most studies with anti-HIV monoclonal antibodies (MAbs) have examined the neutralization of cell-free virus (1)(2)(3)(4) or the prevention of intercel-lular transmission (5). In reality, MAbs likely exert anti-HIV effects in multiple ways, including by prevention of cellular infection; targeting of infected cells, including FcR-positive cells or complement, for destruction by Fc-mediated effects (6)(7)(8)(9); or delivery of a toxic payload to cells in the form of immunoconjugates (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). It is often assumed that the same MAbs that prevent the transmission of infection are also the most effective in eliminating persistently infected cells (21,22), despite evidence to the contrary (6,13,16,19).…”

Section: Importancementioning

confidence: 99%

Identification of Human Anti-HIV gp160 Monoclonal Antibodies That Make Effective Immunotoxins

Pincus

Song

Maresh

et al. 2017

J Virol

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The envelope (Env) glycoprotein of HIV is the only intact viral protein expressed on the surface of both virions and infected cells. Env is the target of neutralizing antibodies (Abs) and has been the subject of intense study in efforts to produce HIV vaccines. Therapeutic anti-Env Abs can also exert antiviral effects via Fcmediated effector mechanisms or as cytotoxic immunoconjugates, such as immunotoxins (ITs). In the course of screening monoclonal antibodies (MAbs) for their ability to deliver cytotoxic agents to infected or Env-transfected cells, we noted disparities in their functional activities. Different MAbs showed diverse functions that did not correlate with each other. For example, MAbs against the external loop region of gp41 made the most effective ITs against infected cells but did not neutralize virus and bound only moderately to the same cells that they killed so effectively when they were used in ITs. There were also differences in IT-mediated killing among transfected and infected cell lines that were unrelated to the binding of the MAb to the target cells. Our studies of a well-characterized antigen demonstrate that MAbs against different epitopes have different functional activities and that the binding of one MAb can influence the interaction of other MAbs that bind elsewhere on the antigen. These results have implications for the use of MAbs and ITs to kill HIVinfected cells and eradicate persistent reservoirs of HIV infection.IMPORTANCE There is increased interest in using antibodies to treat and cure HIV infection. Antibodies can neutralize free virus and kill cells already carrying the virus. The virus envelope (Env) is the only HIV protein expressed on the surfaces of virions and infected cells. In this study, we examined a panel of human anti-Env antibodies for their ability to deliver cell-killing toxins to HIV-infected cells and to perform other antiviral functions. The ability of an antibody to make an effective immunotoxin could not be predicted from its other functional characteristics, such as its neutralizing activity. Anti-HIV immunotoxins could be used to eliminate virus reservoirs that persist despite effective antiretroviral therapy.

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“…They may be targeted either to cell types known to be sites of HIV replication (1)(2)(3) or to actively infected cells expressing the HIV envelope protein(s) gp160, gp120, and gp41 on the cell surface. These anti-HIV ITs may be targeted with either CD4 (4 -6) or with mAbs (7)(8)(9)(10). In vitro studies have shown that anti-HIV ITs are among the most effective antiviral agents tested (11,12), with efficacy against multiple cell types, including macrophages (13), and against a variety of HIV isolates (10,14).…”

mentioning

confidence: 99%

In Vivo Efficacy of Anti-Glycoprotein 41, But Not Anti-Glycoprotein 120, Immunotoxins in a Mouse Model of HIV Infection

Pincus

Fang

Wilkinson

et al. 2003

The Journal of Immunology

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Immunotoxins (ITs) targeting the HIV envelope protein are among the most efficacious antiviral therapies when tested in vitro. Yet a first-generation IT targeted to gp120, CD4-PE40 (chimeric immunotoxin using CD4 and the translocation and enzymatic domains of Pseudomonas exotoxin A), showed limited promise in initial clinical testing, highlighting the need for improved ITs. We have used a new mouse model of HIV infection to test the comparative efficacy of anti-HIV ITs targeted to gp120 or to gp41. Irradiated SCID/nonobese diabetic mice are injected with a tumor of human CD4+ cells susceptible to infection and at a separate site persistently HIV-infected cells. The spread of infection from infected to susceptible tumor is monitored by plasma p24 and the presence of HIV-infected cells in the spleen. Anti-gp41 ITs in combination with tetrameric CD4-human Ig fusion protein have pronounced anti-HIV effects. Little if any anti-HIV efficacy was found with either CD4-PE40 or an Ab-targeted anti-gp120 IT. These data support continued exploration of the utility of ITs for HIV infection, particularly the use of anti-gp41 ITs in combination with soluble CD4 derivatives.

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Human immunodeficiency virus-infected T cells and monocytes are killed by monoclonal human anti-gp41 antibodies coupled to ricin A chain.

Cited by 58 publications

References 31 publications

Generation of human monoclonal antibodies to human immunodeficiency virus.

Generation of human monoclonal antibodies to human immunodeficiency virus.

Identification of Human Anti-HIV gp160 Monoclonal Antibodies That Make Effective Immunotoxins

In Vivo Efficacy of Anti-Glycoprotein 41, But Not Anti-Glycoprotein 120, Immunotoxins in a Mouse Model of HIV Infection

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