Leukemia (1999) 13, Suppl. 1, S99–S105 1999 Stockton Press All rights reserved 0887-6924/99 $12.00 http://www.stockton-press.co.uk/leu Modulation of cell surface protein expression by infection with HIV-1 C Speth and MP Dierich Institute for Hygiene and Ludwig-Boltzmann-Institute for AIDS Research, Innsbruck. Austria Keywords: HIV; protein expression; costimulation; complement; The modulation of several cell surface molecules by HIV-1 adhesion; apoptosis as described in the literature is summarized in Table 1. The list includes: (1) certain molecules involved in immune acti- vation eg B7, CD7, MHC class I and II and CD4; (2) comp- Introduction lement-related proteins like complement receptors and nega- tive regulators of complement activation; (3) various cell The infection of several cell types by the human immunodefi- adhesion molecules; (4) Fas and FasL as apoptosis-related pro- ciency virus (HIV-1) has profound effects on the surface pro- teins; and (5) receptors for important immune regulatory cyto- tein pattern of the host cell. Expression of a variety of cell kines. For some of these surface molecules the viral effector surface molecules is modulated by infection, the most promi- protein responsible for modulatory effect is already known nent being CD4, the coreceptor for MHC class II on helper including the surface molecules gp120 and gp41 and the T cells. regulatory molecules Nef, Tat and Vpu. In this review we will This phenomenon might be biologically relevant in provide a more detailed discussion about some selected several aspects: examples of each group with possible effects of modulated (1) Since HIV-1 is known to acquire a lot of host cell surface expression on HIV-induced pathogenesis and, if known, the molecules during the budding process, upregulation of viral proteins responsible for the modulation. their cell surface expression results in an increased occur- rence on the viral surface. Host cell-derived molecules have at least partly been shown to retain their biological Decreased expression of costimulatory molecules CD28 function on the viral surface and to be involved in pro- and B7 cesses like adhesion of viral particles to potential host cells (eg ICAM-1) or protection of virions against attack by the A complete T cell activation requires both T cell receptor complement system (eg CD55, a negative regulator of (TCR) stimulation and costimulation by accessory molecules. complement activation). Consequently, a high cellular expression of certain membrane molecules is advan- tageous for the progenitor virions budding from this cell. Table 1 Examples for the modulation of cell surface molecules by (2) Alteration of the cell surface protein expression can also infection with HIV-1 modulate functionality of host cells. Important cellular processes of immune cells like migration or lymphocyte Protein family Protein Regulatory HIV Ref. homing depend on the presence of special receptors on protein the cell surface, eg adhesion molecules for blood vessel endothelial cells. Modulation of receptor expression, General HLA-DR gp41; not gp 1,2 therefore, influences viral spreading throughout the body. 120 or p24 CD4 gp120—Nef, 3–7 (3) Modulation of the expression of cellular surface receptors Vpu, Tat may alter susceptibility of the host cells towards cytokines CD7 not gp120 or 2 or intercellular counter-receptors, thereby modulating p24 parameters like cell proliferation, differentiation and, via MHC 1 Vpu, Nef, gp41 8–12 cell activation, viral replication. B7 (CD80, 13 (4) Since an altered cytokine synthesis is involved in HIV- CD86) CD16 13 induced pathogenesis several therapy attempts aim to CD3 14 restore the normal cytokine level by an external addition CD28 15,16 of cytokines. Many therapeutical approaches include Complement-related CR1 17,18 external addition of interleukine 2 (IL-2) to re-activate the proteins immune response against viral infection. Altered levels of CR2 19,20 cytokine receptors is one possible reason for therapy fail- CR3 21 C5aR 22 ure in some cases. CD55 (Daf) 21,23 (5) Downmodulation of host cell surface receptors (eg CD28, Adhesion molecules LFA-1 (CD1 not gp120, p24 2 MHC class I) might reduce immune cell activation as a la/CD18) protection mechanism for viral particles and virus-infected VLA-5 Tat 24 cells, thereby contributing to the disturbed immune status CD62L 25 of the organism and the occurrence of secondary infec- CR3 21 Apoptosis-related Fas Tat, gp120 26–28 tions in the late stage of disease. proteins (6) Alteration of the cell surface protein expression could also FasL 29–31 alter the sensitivity of virus-infected cells towards apop- Cytokine receptors IL-2R Tat, gp120, nef 32–34 totic signals and support or inhibit the elimination of virus- TNF receptor Tat 35 infected cells, thereby being an important parameter for IL-4R Tat 36 viral pathogenesis. Abstracts S100 The CD28 receptor on CD4+ and CD8+ T cells interacts with and/or C4b. CR1 on erythrocytes enables these cells to trans- B7 molecules on antigen-presenting cells (APC) to generate port opsonized immune complexes to phagocytic cells in liver those essential costimulatory signals. B7 includes two func- and spleen, where the immune complexes are removed from tionally related costimulatory molecules, B7–1 (CD80) and the erythrocytic surface and engulfed by the phagocytes.42 B7–2 (CD86). Costimulation results in cytokine production, T Moreover, CR1 is a negative regulatory protein of complement cell proliferation and activation of cytotoxicity. cascade activation with cofactor activity for factor I-mediated During the progression of AIDS disease CD28 expression is cleavage of C3b and C4b into inactive fragments. CR1 also lost on CD4+ and CD8+ T cells.37 This loss is correlated with has decay-accelerating activity for the C3 convertase of both reduced responsiveness to costimulation suggesting that dys- the classical and the alternative complement activation regulation of normal T cell function associated with HIV-1 pathway.43,44 infection may partly result from the loss of CD28 expression. B cells isolated from HIV-infected persons express signifi- On CD8+ T cells from HIV+ subjects the disease stage-related cantly reduced levels of surface CR1 when compared with B reduction in CD28 expression was rather strong and associa- cells derived from control donors.18 This down-modulation of ted with significantly reduced proliferative response to complement receptor I may have some effects on the ability costimulation with cell-bound anti-CD3 and B7. CD4+ T cells of B cells to capture and engulf opsonized antigens for presen- from the patients showed a slighter but nevertheless significant tation to T cells. The decrease in complement receptor level CD28 down-regulation and were also hyporesponsive to B7 in late stages of disease could thus be one factor adding to co-stimulation.38 the immune dysfunction of T cells. In addition, lack of the Not only CD28 but also the ligand B7 shows an altered negative regulator molecule CR1 of the complement system expression after HIV infection. Patient-derived macrophages may contribute to increased complement activation observed express B7 molecules in a lower density than macrophages in HIV patients. derived from healthy donors.13 Monocytes that express consti- On erythrocytes the number of CR1 surface molecules is tutively B7 lose this marker after HIV-1 infection and become also significantly decreased in symptomatic HIV-infected indi- refractory to inducers of B7 synthesis.39 This down-modu- viduals correlating with increasing levels of circulating lation is an indirect effect mediated by an altered IL-10 pro- immune complexes and with the clinical severity of dis- duction since B7 expression can be normalized by the incu- ease.45,46 Since reduced CR1 expression on erythrocytes has bation of patient macrophages with anti-IL-10 monoclonal been associated with autoimmune diseases HIV-mediated antibodies.13 The decreased expression of CD28 and B7 mol- down-modulation of CR1 on erythrocytes in HIV patients ecules on T lymphocytes and macrophages is a critical para- could also contribute to the increase of autoantibody presence meter for immune dysfunction and disease progression. noticed in infected individuals.46 Since costimulation is crucial for immune activation also Additional studies on erythrocytes indicated that modu- novel vaccination protocols have been developed to induce lation of CR1 expression on those infected cells is achieved HIV-1 antigen-specific immune responses by DNA vacci- by enhanced proteolytic cleavage of the surface receptor.17 nation. Coimmunization of CD86 and CD80 expression plas- The CR1 molecule is sensitive against proteolytic attack and mids along with plasmid DNA harboring the genes for HIV-1 CR1 fragments are found on normal erythrocytes as well. The antigen induced a dramatic increase in cytotoxic T lympho- relative amount of these fragments is increased on erythro- cyte induction and CD4+ proliferation when compared with cytes derived from AIDS patients. The mechanism for CR1 HIV antigen immunization alone.40 This stimulating effect is decrease on B cells is as yet unknown as well as the mech- mediated mainly by CD86 expression and can be decreased anism of protease activation by viral infection. by combination with an inhibitor of B7/CD28 costimu- 40,41 lation. The approach represents a new immunization strat- The complement receptor type 2 (CR2) agy to achieve a significant enhancement of the antigen- specific cellular immune response. Complement