Does the HIV-1 manipulate immune network via gp120 immunoglobulin-like domain involving V3 loop?

Vaccine, Vol. 13, No. 4, pp. 355-359, 1995 Copyright 0 1995 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0264-410xm $10.00 +o.oo

Does the HIV-1 manipulate immune network via. gp120 immunoglobulin-like domain involving V3 loop? Radmila MetlaS and Veljko Veljkovik* According to the multiple criteria used, the consensus sequences of HIV-I gp120 and immunoglobulin heavy chain variable segment, which is more than 40 amino acids long, show structural similarities. We assume that this gp120 sequence might encode idiotopes. If this is the case then the particular idiotope-bearing gp120, either soluble or expressed in multiple form on the surface of the infected cell, can influence the immune response in idiotype(Id)-anti-Id fashion. This might be the mechanism by which’ HIV induces immunological abnormalities and it should be taken into consideration in vaccine production as suggested by the authors previously. Keywords:

HIV-l;

gp120 V3 loop., immunoglobulin-like

domain

The mechanism associated with the activation of the immune system in HIV-infected individuals which leads to progressive immunodeficiency disorder is poorly understood’*‘. However, it has become clear that in addition to HIV-induced cytopathicity other mechanisms are required for the development of CD4 T-cell depletion and functional disregulation accompanied by increased B-cell activity. Autoimmune reactions might be provoked by HIV infection3 reflecting the chronic activation of multiple components of the immune system. The idiotypic network of interactions4 is involved in extrathymic tolerance induction to self antigens by the process of suppression or anergy and tolerance breakdown by allogeneic stimulation; immunization with anti-idiotype and cross-reacting antigen’ becomes an attractive basis for the formulation of models for immunopathogenesis of AIDS. In HIV-infected individuals autoimmune responses against several self antigens have been suggested where HLA6*7 and CD4 antigens” are indicated as the main targets. Molecular mimicry%’ ’ and structural/genetic similarities’2*‘3 between HIV and self antigens ,are recognized as potential autoimmunopathic factors. The disturbance of a series of cellular recognitions operating via immunoglobulin (Ig)-family members bearing combining sites and/or idiotypes that might be Iprovoked by HIV is mostly discussed in the context of the possible role of gp120 in allogeneic stimuli7*‘2-‘4. In the present study we extend our recently proposed’ 5 view of HIV gp120 involvement in immune network Laboratory for Multidisciplinary Research lW2,

Institute of Nuclear Sciences VINeA, PO Box 522, 11001 Beograd, Yugoslavia. *To whom correspondence should be addressed. (Received 10 February 1994; revised 1 July 1994; accepted 12 July 1994)

destabilization. Our model predicts that HIV gp120 may enter the immune network in a manner similar to the action of the immunoglobulin variable (V) domains bearing idiotypes. This comprises both gp120 processing and direct Id-anti-Id interaction between gp120 expressed on the surface of infected cells or free viral glycoprotein oligomers and the complementary antigen receptors of non-infected T and B cells.

IMMUNOLOGICAL

NETWORK

ldiotypes and anti-idiotypic antibodies were postulated by Jerne4 to form a regulatory network in the immune system. Since the network also includes T cells it is assumed that lymphocytes could exert control over the functions of other lymphocytes via Id-anti-Id interactions occurring between Ig (antibody) V regions on individual B cells and the specific MHC/antigen receptor on T cells (TCR). It is also possible to generate regulatory T-cell clones against other T cells16. An individual immune system recognizes the limited number of idiotopes on its own antibodies. This depends mostly on the B- and T-cell repertoire and individual genetic background. The Ids can be present in the germline V-domain genes, or they may be generated by the process of recombination and mutation involved in the production of functional V-region genes. Generation of the components of the immune system is temporally programmed by the order of both Ig17 and TCR” gene rearrangement so that the periphery is seeded with a discrete population of cells generated at different stages in development. Thus, T cells bearing TCR-y8 ’ 9 and B cells expressing the antigenrecognizing receptor with V, domains from the gene group III arise early in ontogeny. This selection may ensure both the development of a peripheral immune

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system with an enormous repertoire and the rare autoimmune attack on autologous tissuess20. A central axiom of immunology is that an antigenspecific T cell is activated upon recognition of determinants on the processed antigen associated with class II molecules expressed on professional antigenpresenting cells (APC)“. However, accumulated evidence suggests that many cell types including B lymphocytes should present antigen**. The antigens presented by professional APC can both activate naive and restimulate memory T cells23 that subserve T-helper (TH) or suppressor (Ts) cell activities24. However, T cells differ in their responses to B cells being tolerogenic for naive T cells2s, which has an important role in immune network maintenance. An antigen-presenting B cell is associated with two types of Ids on its membrane. The surface immunoglobulin bears a native form of Id interacting with the antiidiotypic antibodies26 and a spontaneously processed form presented in the context of MHC molecules27. The processed peptides may derive either from germ-lineencoded or somatically mutated endogenous or exogenous immunoglobulins. It has been suggested that the latter form of B-cell Ids should be able to produce tolerance (anergy) in naive T cells, due to the absence of an additional co-stimulatory signal, but to restimulate memory or primed MHC-restricted anti-Id T cells2s,28. Thus, in T-cell mediated, Id-restricted regulation of B cells several mechanisms may be involved. In addition to spontaneous processing of endogenous immunoglobulin, ligation of surface immunoglobulins could induce or increase their processing as well as the processing and presentation of antigens or anti-idiotypic antibodies. These findings indicate that Id-bearing B cells could potentially communicate with antigens and anti-Id antibodies via their surface immunoglobulins and with MHC-restricted T cells via processed antigens or Ids presented by MHC. However, there is evidence that B cells are able to interact with T cells which express receptors recognizing Ids of the native surface B-cell immunoglobulins 29-31. These Id-specific T cells can selectively expand or suppress a B-cell population carrying common (dominant) Id expressed on antibodies of different epitope specificity appearing in the secondary response 32. It is of particular importance that the antibodies, of clonal dominance were found to be characteristic of the immune response to HIV antigens33-36. As antigen-specific T cells recognizing antigen in an MHC-restricted manner and Id-specific T cells that selectively expand or suppress all B-cell populations carrying the dominant Id often operate sequentially during an immune response, they are referred to as T,l and T,2 respectively. This leads to the conclusion that Id-specific T cells in many instances are not MHCrestricted. The possible explanation is that a high density of Id (IgG) on the B cell permits the T cell to interact with the B cell without MHC recognition, as has been demonstrated for Id-specific T-helper cells that directly bind to Id-positive antibodies without associated recognition of MHC29. According to current knowledge, the activation (proliferation and lymphokine secretion) of T and B cells can be achieved by at least two quite different stimuli: interaction with specific antigen and treatment with anti-TCR or anti-immunoglobulin antibodies (being

356 Vaccine 1995 Volume 13 Number 4

regulatory (Ab2a) or internal image anti-Id antibodies (Ab2B) bearing functional and structural characteristics of the antigen). The former requires the processing and presentation of the antigen by APC. It should be mentioned that the activation of T cells by the antibodies directed against Ig-idiotopes usually requires processing. The latter pathway for the activation of T and B cells comprises crosslinking of the membrane antigenreceptors by immobilized monoclonal antibodies or F(ab’), portions. Such interactions usually activate all cells that express the corresponding idiotope37,38. However, it is known that many of the physiological consequences of the T,-cell interaction with specificAPC, i.e. antigen, can be simulated by the direct T-cell interaction with anti-TCR antibodies specific for a clonotypic TCR determinant that can substitute the antigen/MHC signal at very low concentrations37939. While the significance of idiotypic interactions in normal physiology is debatable, the manipulation of the immune system via Ids by Ab2 is an accepted proposition 4o. We speculate that a similar strategy might be employed by HIV since gp120 contains an IgV,-like domain, which we suggest may make connections with complementary members of the Ig-family, similar to Id-bearing Igs.

DISCUSSION Proposal for the interaction between the IgV-like region of HIV-l gp120 and complementary lymphocyte antigen receptors Our idiotypic network model of HIV-induced immune disorders is based on the finding that the HIV gp120 consensus sequence shows a stretch of about 43 itim0 acids (encompassng the V3 loop and ten residues upstream) which is IgV-region-like, according to several criteria used. Thesq comprise: (i) sequence homology with the consensus sequence of the antibody heavy chain V domain (V,) of the group III gene products that involve FWl, CDRl and N-terminal of FW2 sharing with gp120 both variable and invariable residues”.41: (ii) similar sequence variability41; (iii) similarity in alpha propensity4*; and (iv) common recombination-like nucleotide motifs’3*41. Therefore, we have suggested that a particular gp120 may be a V,III counterpart expressing the idiotope involved in the interactions with complementary lymphocyte Id structures”. The fact that this portion of gp120 comprises the V3 loop, i.e. one of the hypervariable gp120 regions, increases the chance for gp120 to fit an Id. The results are summarized in Figure la, c and d. There are two main features of our model. The first is that during active production of the virus, the viral envelope protein gp120 is expressed on the surface of the infected cells in multiple form and that its V3 loop constitutes the principal neutralizing determinant which binds type-specific neutralizing antibodies43*44. The second point is that T cells recognizing the processed gp120 IgV-like domain encoding putative idiotopes may assist B cells in antibody production and/or react with Ids on other T cells (Figure2a, 6). The possibility that experienced T cells or virgin ones can recognize in an MHC-restricted manner the particular V3 loop idiotope on the surface of the B cell cannot be excluded (Figure 2a). We suggest that this process is related to the high

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recognized by MHC-restricted anti-Id-specific T cells, may play a role both in driving naive cells into the anergy state, i.e. tolerance induction to certain antigens, and in affecting activity of memory or primed T cells (Figure 2~). On the other hand, recognition of the multiple form of Id-bearing gpl20, similar to anti-immunoglobulins or F(ab’), fragments, can lead to crosslinking of all B- and T-cell receptors with the complementary determinants (Ids) (Figure 2~). This first step of B-cell activation (mostly polyclonal) will make them more sensitive to T-cell derived factors. However, aggregation of T-cell receptors may generate cytotoxic, suppressive and/or T,2 cell effects (Figure 24. Finally, clonotypic antibody-like gp120 may recognize T-cell idiotopes directly without the context of MHC molecules (Figure24 and generate antigen-specific T cells. The proposed pathways of gpl2Glymphocyte interactions could explain the impaired B- and T-cell activities observed in HIV-infected patients. The results obtained by others support our model by showing that (i) HIV envelope proteins may directly induce B-cell differentiation4$ (ii) Ig VJII gene products are natural ligands for gp1204’; (iii) immune response to HIV might be under idiotypic network contro133-36; (iv) sera of HIV-infected individuals contain crossreactive antibodies with gpl20-derived peptides which we suggest to be associated with altered network regulation4gs50. The current data extend our earlier finding that a particular gp120 V3 loop shows short sequence homology with human collagen and IgV regions (Figure Ib). Furthermore, affinity-purified antibodies from the sera of AIDS patients bind synthetic peptides

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CTRPNNNTRK!XHIGPGRAFY'ITGEIIGDIRQAHC comMS~Js"3SElzm4cKOFmv.I gp120 Figure 1 Comparison of the primary structures, variability and alpha propensity of the HIV-l gp120 encompassing the C terminus of the second conserved region and V3 loop and human lg V,III and human collagen I. The comparison of the primary structures of: (a) consensus sequences of human lg V,lll and HIV-l gp120, and (b) repeat motif from human collagen I, consensus motif of human lg V,K~’ and structural motif RGPGRA representing the chemical binding site for HIV-1 neutralizing antibodies. The sign (*) corresponds to identical residues in HIV-1 gp120 ,O of 222 HIV-1 isolates analysed by consensus (present in at least 750’ LaRosa et a/.“) and lg VHlll consens&‘. A dash (-) within the sequence denotes an insertion. The sign (+) above the residue position denotes an invariant residue in the lg V,,lll chain. A dot (.) within the sequence denotes insertion, which occurs nailurally in certain human lg V,lll. The sign (:) denotes homologies which occur between the consensus sequences of HIV-1 gp120 and some particular human lg VHIII. (c) The comparison of variability calculated1according to Ref. 54. The signs (0) and (m) correspond to the lg VJI and HIV- gp120. respectively. (d) Comparison of the alpha propensity%. The signs (0) and (m) correspond to the lg V,,lll and HIV-1 gp120. respectively

concentration of the gpi>i, expressed on the surtace of infected T cells. Such infected T cells in an Id-anti-Id fashion may crosslink and cluster antigen receptors of the B and T cells bearing complementary idiotopes. The interaction of putative gpl:20 Ids with B-cell receptors may induce or increase processing and presentation of the B-cell Ids as noticed after lymphocyte treatment with anti-immunoglobulins45. The processed Ids, when

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Figure 2 Possible pathways for the inductlon of an Immune response in HIV infection. In the pathway (a) and (b) the activated T cells could be helper/inducer, suppressor and some T,,2 cells. In the pathway (c) and (d) they are helper/inducer or cytotoxic/suppressor ones and mostly T,,2 cells. T cells (T): HIV infected, i, not-expressing gp120 or normal, n; macrophages (M); B cells (B)

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domain

on HIV-1 gp120:

R. MetlaS

and V. VeljkoviC

derived from the homologous proteins (results not presented). If, according to our postulate, the V3 loop may encode idiotopes, then by analogy with antibody Ids they could be associated with the combining site of the antibody (Ab2/?), being the internal image of an antigen epitope or crossreactive Ids (Ab2a). The homology between the collagen, i.e. putative antigen, Id-bearing V3 loop and the V portions of some antibodies might indicate to the epitope that it is under idiotypic regulation, inasmuch as anti-collagen antibodies are a common feature of AIDS”. Whether gp120 may affect the antigen-specific response by mimicking a native antigen epitope reactive with the antigen recognition site on the T cell without the context of MHC37*3g,52is under investigation. In conclusion, the mechanism that we are proposing may explain some of the observed immunological abnormalities leading to AIDS. The model explains: (i) tolerance induction to new antigens or memory cell reactivation as the result of affected Id presentation; (ii) increased or decreased production of some antibodies in direct interaction between the gp120 immunoglobulinlike domain and B cells or by triggering both Id-specific or antigen-specific T cells.

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