Humoral Immune Responses Against gp41

From the beginning of the AIDS epidemic the preponderance of studies concerning the HIV-1 envelope have focused on antibodies against the surface gp120 component. Over the past several years, however, investigations have now shifted to include studies that demonstrate the importance of the transmembrane gp41 structure.

With regard to gp41, antigenic epitopes are clustered in two regions. Cluster I antibodies are directed to an immunodominant region that can potentially form a disulfide loop; cluster II antibodies map to a region that includes a distal helix on the gp41 ectodomain.

Neutralizing as well as nonneutralizing and in vitro enhancing anti bodies directed against a series of overlapping epitopes within the immunodominant domain of gp41 (cluster I) are produced in human sera in response to HIV-1 infection.

Immunoreactive regions of HIV type 1 gp41 have been finely mapped by reacting (polyclonal) HIV-1 antibody-positive human sera with sequential overlapping synthetic peptides which covered the transmembrane protein.21 Immunoreactive regions of gp41 have been reported by Horal et al.22 Within cluster I, three immunoreactive domains were identified, and five different and partially overlapping epitopes recognized by HIV-1-positive human sera were found within one immunodominant region, DQQLLGIWGCSGKLIC-TTAVPWN. The five different and partially overlapping epitopes were delineated as LLGIWG, WGCSGK, GKLICT, ICTTAV, and TAVPWN. It is important to note that no single serum sample demonstrated reactivity to all individual epitopes.

Human sera fractionated to obtain anti-HIV-1 antibodies and human monoclonal antibodies derived from immortalized B cells obtained from HIV-1-infected individuals have demonstrated binding to cluster I and cluster II within the transmembrane gp41.2324

Antigenic epitopes within gp41 have been characterized using human monoclonal antibodies generated from individuals with high-titer HIV-1-seropositive serum.

Immunological binding to the immunodominant region of HIV-1 transmembrane gp41 (579RILAVERYLKDQQLLGIWGCSGKLICHTT606Myers) and biological reactivity against HIV-1 are presented in Table I.

The human monoclonal antibody, clone 3 antibody, which specifically binds to the gp41-conserved linear epitope LIC within the immunodomi-nant region (cluster I), has been demonstrated to bind to both oligomer as well as monomeric transmembrane glycoprotein. In addition, the clone 3 antibody has been demonstrated to have neutralizing capacity against lab-adapted strains.2526 Also, clone 3 antibody has been demonstrated to have broad neutralizing capacity against primary HIV isolates in clades B, E, and F.27

Clone 3 antibody is the only human monoclonal antibody in Table I that specifically binds within the represented gp41 immunodominant region (cluster I) and also possesses neutralization activity against HIV-1. All other human monoclonal antibodies which have been produced against this region either possesses HIV-1-enhancing activity or no biological activity at all.

With regard to the cluster II region of gp41, the human monoclonal antibody 2F5 has been demonstrated to bind to the gp41 oligomeric structure and has been reported to have broad neutralizing capacity for lab as well as clinical HIV-1 isolates.28 2F5 binds to the epitope ELDKWA, a con-

TABLEI

Human Monoclonal Antibody Immunological Binding to the Immunodominant Region of HlV-1 Transmembrane gp41 (™RILAVERYLKDQQLLGIWGCSGKLICTT«»™i«>) and Biological Reactivity Against HIV-1

TABLEI

Human Monoclonal Antibody Immunological Binding to the Immunodominant Region of HlV-1 Transmembrane gp41 (™RILAVERYLKDQQLLGIWGCSGKLICTT«»™i«>) and Biological Reactivity Against HIV-1

Human mAb

Class

Amino acid sequence (epitope)

Biological activity

References

V10-9

IgG1k

RILAVERYLKDQQLLGIW

Enhancing

71, 72

86

IgG1k

RILAVERYLKDQQLLGIW

Enhancing

71, 72

50-69

IgG2k

QQLLGIWG

Enhancing

24

246-D

IgG1k

QQLLGIWG

Enhancing

24

181-D

IgG2k

QLLGIWG

None

24

240-D

IgG1k

LLGIWGCSG

Enhancing

24

2F11

IgG1

DQQLLGIWGCSG

Enhancing

73

41-7

IgG1k

GCSGKLIC

None

74

F240

IgG1k

LLGIWGCSGKLICT

None/

75

enhancing

Clone 3

IgG1

GCSGKLICTT

Neutralizing

25

served peptide sequence near the transmembrane segment. Moreover and importantly, when combined with 2F5, clone 3 antibody has been shown to produce a synergistic neutralizing effect against clades B, E, and F.27

Investigations to characterize specifically which of the many antibodies induced after HIV-1 infection can actually provide a neutralizing function continue to be the intense focus for many research groups. Results from the Antibody Serological Project (ASP) suggest that the functional activity of HIV-specific antibodies most likely to predict therapeutic efficacy is the capacity to neutralize primary isolates.29 Additionally, since a large proportion of primary isolates replicate only in peripheral blood mononuclear cells (PBMC), a PBMC neutralization assay appears essential to characterize the neutralizing ability of anti-HIV-1 monoclonal antibodies.

Early in vitro assays demonstrated that HIV-1 lab strains passaged in T cell lines were extremely sensitive to neutralization by the following: sera from HIV-1-infected individuals or sera from individuals who were vaccinees immunized with gp120, and reagents including soluble CD4, and monoclonal antibodies.30-32

Currently, PBMC-based neutralization assays utilizing low passaged primary HIV-1 isolates have identified four human monoclonal antibodies with the capability of neutralizing a broad range of field isolates.252729

The four human monoclonal anti-HIV-1 antibodies with broad neutralizing effect against clinical isolates are listed along with immunological

TABLE II

The Four Human Monoclonal Anti-HIV-1 Antibodies with Broad Neutralizing Activity Against Clinical HIV-1 Isolates"

Neutralization Core epitope _

TABLE II

The Four Human Monoclonal Anti-HIV-1 Antibodies with Broad Neutralizing Activity Against Clinical HIV-1 Isolates"

Neutralization Core epitope _

Antibodies

recognized

TCLA strains

Primary strains

References

b12

gp120

Yes

Yes

29, 76, 77

(IgGll)

(CD4bd/V2 loop)

Conformational

2G12

gp120

Yes

Yes

78, 79

(IgGlk)

(C2/C3/V4)

Conformational

2F5

gP41

Yes

Yes

28, 79, 80

(IgG3k)

cluster II

Linear

elDKWA aa = 662-667

Clone 3

gP41

Yes

Yes

25-27

(IgG1)

Cluster I

Linear

gcsgkLICtt aa = 597-606

'TCLA, T cell-line-adapted; CD4bd, CD4-binding domain; aa, amino acids.

'TCLA, T cell-line-adapted; CD4bd, CD4-binding domain; aa, amino acids.

characteristics in Table II. The production and characterization of these human monoclonal antibodies directed against surface envelope components and other data provide evidence that virions as well as HIV-1-infected cells can induce a humoral immune response with a neutralizing capacity.

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