HIV Life Cycle

Human CD4+ T lymphocytes, macrophages, microglial, dendritic and Langerhans cells, are believed to be targets for HIV-1 infection. The CD4 transmembrane protein along with one of several chemokine receptors are believed to be necessary for viral attachment and fusion to occur. The role of CD4 prompted considerable interest in the therapeutic use of soluble, truncated fractions of the CD4 protein as "receptor decoys" to block HIV-1 infection¹.

Problems with short biologic half-life and poor tissue penetration were addressed by covalent attachment of soluble CD4 to the Fc fragment of IgG². Unfortunately, however, most HIV+ patients at all stages of disease appear to already have a significant concentration of antibodies that block the HIV viral envelope-CD4 interaction³ and HIV clinical isolates appear to be resistant to soluble CD4⁴. These observations seriously undermined the rationale behind therapies based on CD4.

Small peptide derivatives (N-carbomethoxy-carbonyl-prolyl-phenylalanyl benzyl esters, or CPFs) have been found to interact with gp120 and appear to block HIV-1 binding to CD4 and post-binding events⁵. The effectiveness of such low molecular weight molecules offer the potential for the design of other small peptidyl derivatives to block gp120 CD4 interaction.

Anionic polysaccharides, such as dextran sulfate and pentosan polysuflate, have been found to impair the interaction of HIV-1 with CD4 in cultured cells. However, these compounds are poorly absorbed orally and no activity was noted when dextran sulfate was administered intravenously to p24 positive patients⁶. It has been reported that the binding of HIV-1 to CD4+ induces rapid phosphorylation of the CD4 receptors which involve protein kinase C (PKC)⁷. Some PKC inhibitors (e.g., glycyrrhizin ⁸) exhibit anti-HIV activity. However it is not known if the HIV inhibition by these compounds is mediated through blocking the CD4 receptor. The fusion process has also been inhibited by peptide analogs of the fusion domain of GP41⁹.

References

1.

Deen K.C.; McDougal J.S.; Inacker R.; Folena-Wasserman G.; Arthos J.; Rosenberg J.; Maddon P.J.; Axel R.; Sweet R.W., A soluble form of CD4 (T4) protein inhibits AIDS virus infection. Nature 1988 Jan 7;331(6151):82-84.

2. Capon, D.J. and R.H.R. Ward. Antiviral effects of CD4 derivatives. Current Opin. Immun 1990; 2:433-438

3. Callahan, L.N and Norcross M.A. Inhibition of soluble CD4 therapy by antibodies to HIV. Lancet 1989 734-735.

4. Daar, E.S., Li X.L. Moudgil T., and Ho D.D., High concentration of recombinant soluble CD4 are required to neutralize primary HIV isolates. Proc. Natl. Acad. Sci. 1990 87:6574-6578.

5. Finberg, R.W., Diamond, D.C., Mitchell, D.B., Rosenstein, Y., Soman, G., Norman, T.C., Schreiber, S.L., Burakoff, S.J. Prevention of HIV-1 infection and Preservation of CD4 Function of the Binding of CPFs to gp120. Science 1990 ; 249:287-291

6. Flexner, C., Barditch-Crovo, P., Kornhauser, D., Nerhood, L., Petty, B. and Leitman, P. Continuous Intravenous Dextran Sulfate in Patients with ARC and AIDS . Antiviral Res Supp l990 ; 1:116.

7. Fields, A.P., Bednarik, D.P., Hess, A., and May, W.S. Human immunodeficiency virus induces phosphorylation of its cell surface receptor . Nature (London) 1988 ; 333: 278-280.

8. Kazuhiro, H., Susamu, I., Hiroatsu, M., Takeo, M., Shoji, S., Masanori, B., Masahiko, I., Shiro, S., Hideki, N., and Yamamot, N. Antiviral Activiites of Glycyrrhizin and Its Modified Compounds against Human Immunodeficiency Virus Type 1 (HIV-1) and Herpes Simplex Virus Type 1 (HSV-1) in vitro. Chem Pharm Bull 1991 ; 39(1):112-115.

9. Owens, R.J., Tanner C.C., Mulligan M.J., Srinivas R.V., Compans R.W. Oligopeptide inhibitors of HIV-induced syncytium formation . AIDS Res. Human Retroviruses 1990 ; 6:1289-1296.