MODULATION OF CD4 LATERAL INTERACTION WITH LYMPHOCYTE SURFACE MOLECULES INDUCED BY HIV-1 GP120

CD4, a lymphocyte surface glycoprotein, serves as co-receptor for anti gen with the T cell receptor (TCR). It is also the lymphocyte receptor for HIV by binding the gp 120 viral envelope protein. Interaction of gp 120 with CD4 is crucial for viral infection, but is not sufficient to allow viral entry into cells. Recombinant gp120 alters CD4(+) T cel l responsiveness to activation stimuli. To express its co-receptor fun ction fully, CD4 must be laterally associated with the TCR and CD45 to form multi-receptor complexes competent to transduce potent activatio n signals. Here, we examine the possibility that gp120/CD4 binding alt ers lateral associations of CD4 with other lymphocyte surface molecule s, and that assembly of abnormal multi-molecular complexes is involved in the gp120-induced CD4(+) T cell dysfunction and in viral entry. In the absence of gp120, CD4 displayed high association with CD3, CD5, C D45RC, CD25, CD28, CD44, and CD53; weak association with CD2, CD38, CD 45RB, CD62L, and CD26; and no association with CD45RA, CD45RO, CD11b, CD11a, CD54, CD7, CD48, CD98, CD59, CD55, HLA class I and class II mol ecules. Treatment with gp120 significantly increased CD4 association w ith CD3, CD45RA, CD45RB, CD59, CD38, CD26, and HLA class I, and decrea sed that with CD45RC. Specificity of these results were assessed at va rious levels. First, gp120 did not influence lateral associations disp layed by other molecules, such as HLA class II. Second, the Leu3 mAb, which binds CD4 on a site overlapping the gp120 binding site, did not elicit the same CD4 lateral associations as gp120, and finally, a dire ct gp120/CD4 interaction was needed to induce the lateral associations , as shown by the observation that blocking the gp120/CD4 binding by t he Leu3 mAb inhibited the gp120-induced associations. These results ca n be interpreted in several ways. gp120/CD4 interaction could trigger an inside-out signal responsible for the associations, or gp120 could induce steric modifications of CD4 that increase its affinity for the associating molecules. Alternatively, these molecules may interact dir ectly with gp120, bridging them with CD4. It is also possible that the associations may be mediated by additional components, interacting wi th both gp 120 and the associating surface molecule. The last hypothes is is likely for CD59, whose gp120-induced association with CD4 requir ed the presence of serum in the co-capping assay. Since both CD59 and gp120 bind complement, the observed association could be mediated by c omplement components.