The gp41 epitope, QARVLAVERY, is highly conserved and a potent inducer of IgA that neutralizes HIV-1 and inhibits viral transcytosis

Jain, Sumiti; Rosenthal, Kenneth L.

doi:10.1038/mi.2011.21

Cited by 19 publications

(22 citation statements)

References 109 publications

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“…This region has also been identified to be the target of various other antibody-mediated activities (42)(43)(44)(45)(46)(47)(48)(49)(50). Recent three-dimensional studies of gp140 trimers by crystallography and high-resolution cryo-electron microscopy show that this region lies in close proximity to the plasma membrane (28,29).…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…TZM-bl infection assay. The TZM-bl cells used in this study express CD4, CXCR4, and CCR5 as well as tat-responsive luciferase and ␤-galactosidase reporter genes (31,47,54,79). Cells (2.5 ϫ 10 4 cells per well) were seeded in a 96-well plate the day before.…”

Section: Study Participantsmentioning

confidence: 99%

“…The laboratory-adapted IIIB (X4-tropic) HIV-1 strain HIV-1 IIIB was prepared in peripheral blood mononuclear cells (PBMCs), and the ADA (R5-tropic) HIV-1 strain HIV-1 ADA was prepared in adherent macrophages purified from human PBMCs as described elsewhere (31). Supernatants of infected cells were collected, concentrated using 30-K Amicon filter tubes (Millipore, Billerica, MA), and assayed for p24 using an HIV-1-p24 ELISA kit according to the manufacturer's protocol.…”

Section: Study Participantsmentioning

confidence: 99%

“…Transcytosis of cell-free HIV-1 through the HEC-1A monolayer was performed as described before (31), with minor modifications. Briefly, HEC-1A cells were seeded at 1 ϫ 10 5 cells per insert and grown as a tight polarized monolayer on a permeable polycarbonate support (0.4-m-pore-diameter membrane tissue culture inserts; BD Falcon, Mississauga, Canada) for a minimum of 3 days, changing media every other day.…”

Section: Study Participantsmentioning

confidence: 99%

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Anti-HIV-1 Activity of Elafin Is More Potent than Its Precursor's, Trappin-2, in Genital Epithelial Cells

Drannik

Nag

Yao

et al. 2012

J Virol

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“…A few monoclonal antibodies (MAbs) display neutralizing properties, e.g., 2F5, 4E10, and Z13, which bind to the membrane-proximal external region (MPER) of gp41. Moreover, some antibodies were associated with HIV resistance in exposed but uninfected subjects; the corresponding targets were an epitope placed within the N-terminal alpha-helical region HR1 and another within MPER (10,24,25,45,51).…”

mentioning

confidence: 99%

Passively Transmitted gp41 Antibodies in Babies Born from HIV-1 Subtype C-Seropositive Women: Correlation between Fine Specificity and Protection

Diomede

Nyoka

Pastori

et al. 2012

J Virol

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e HIV-exposed, uninfected (EUN) babies born to HIV-infected mothers are examples of natural resistance to HIV infection. In this study, we evaluated the titer and neutralizing potential of gp41-specific maternal antibodies and their correlation with HIV transmission in HIV-infected mother-child pairs. Specific gp41-binding and -neutralizing antibodies were determined in a cohort of 74 first-time mother-child pairs, of whom 40 mothers were infected with HIV subtype C. Within the infected mother cohort, 16 babies were born infected and 24 were PCR negative and uninfected at birth (i.e., exposed but uninfected). Thirty-four HIV-uninfected and HIV-unexposed mother-child pairs were included as controls. All HIV-positive mothers and their newborns showed high IgG titers to linear epitopes within the HR1 region and to the membrane-proximal (MPER) domain of gp41; most sera also recognized the disulfide loop immunodominant epitope (IDE). Antibody titers to the gp41 epitopes were significantly lower in nontransmitting mothers (P < 0.01) and in the EUN babies (P < 0.005) than in HIV-positive mother-child pairs. Three domains of gp41, HR1, IDE, and MPER, elicited antibodies that were effectively transmitted to EUN babies. Moreover, in EUN babies, epitopes overlapping the 2F5 epitope (ELDKWAS), but not the 4E10 epitope, were neutralization targets in two out of four viruses tested. Our findings highlight important epitopes in gp41 that appear to be associated with exposure without infection and would be important to consider for vaccine design.

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The gp41 epitope, QARVLAVERY, is highly conserved and a potent inducer of IgA that neutralizes HIV-1 and inhibits viral transcytosis

Cited by 19 publications

References 109 publications

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

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

Anti-HIV-1 Activity of Elafin Is More Potent than Its Precursor's, Trappin-2, in Genital Epithelial Cells

Passively Transmitted gp41 Antibodies in Babies Born from HIV-1 Subtype C-Seropositive Women: Correlation between Fine Specificity and Protection

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