Saturday, April 18, 2009

AIDS and HIV Entry Inhibitors’ Target Action

Acquired immunodeficiency Syndrome or AIDS is caused by human immunodeficiency virus (HIV). HIV is an enveloped virus that contains two copies of genomic ribonucleic acid (RNA). There is a glycoprotein of 120 kD molecular weight commonly known as gp120, through which the virus binds to the cellular receptors at the surface of T-helper lymphocytes or CD4+ cells. The binding of virus to the CD4 receptor in association with chemokine co-receptor causes a dynamic change in gp120 and further activates trans-membrane protein gp41. These changes cause fusion of HIV envelope to the cell membrane of CD4+ cell and further make way for the entry of virus into the cytoplasm of CD4+ cell. The virus entry inhibitors sabotage the ability of gp41 to mediate fusion of viral and cellular envelopes. HIV entry inhibitor drugs are of first choice after exposure to virus and are newer drugs in the scenario of HIV therapy. Currently, most regimens of HIV therapy are combinations of inhibitors of two viral enzymes: reverse transcriptase and protease. HIV entry inhibitors are of great interest because of their activity against multi-drug resistant viruses.

The brief mechanism of HIV entry into T-helper lymphocytes or CD4+ cells has been cited above. The main receptors used by HIV-1 are chemokine receptors CCR5 and CXCR4. It has been resolved through the assessment of amino acid sequences of different HIV-1 strains that there are five variable (V1-V5) and four constant (C1-C4) regions in gp120. The expression of CCR5 or CXCR4 on the surface of CD4+ target cells (T-helper lymphocytes) defines their susceptibility to infection by corresponding HIV-1 strain. The use of specific receptors by viruses for infecting the target cells determines the virus cell tropism. The dual tropic viral strains can use both the receptors at the surface of CD4+ target cells. The HIV entry inhibitor compounds could be targeting the inhibition at different stages of virus entry such as:


  1. The attachment inhibitor: Sulfated polysaccharides or polyanions such as dextran sulfate (dextran-2-sulfate or D2S) and heparin have been shown to inhibit binding of V3 loop antibodies to HIV-1 gp120 in-vitro.

  2. Inhibitors of gp120-CD4 interaction: The currently available inhibitors of gp120-CD4 interaction are PRI 542 (CD4 - IgG2), TNX 355, and BMS 488043 antibodies/molecules. PRI 542 (CD4 - IgG2) is a tetravalent antibody and has passed clinical trials. TNX 355 is a monoclonal antibody (humanized) against the domain-2 of human CD4. BMS 488043 is a small molecule and blocks the entry of virus by preventing the binding of gp120 to CD4 receptors on CD4+ target cells.

  3. Co-receptor Antagonists: Some new molecules have been tried as antagonists to CXCR4 and CCR5 but abandoned due to cardiac abnormalities and heart conduction abnormalities like prolonged QT intervals. CCR5 is the co-receptor mainly used by HIV for its transmission; so many drugs have been enlisted for targeting CCR5.

It is well established now that R5 viruses remain present in approximately 50-60% of individuals who progress to AIDS, whereas remaining 40-50% of individuals switch to X4 viruses with the progression of the disease and show a decline in the count of CD4+ target cells. The mutations in viruses confer them resistance to CCR5 treatment in the absence of co-receptor switch. HIV entry inhibitor compounds have been gaining importance as therapeutic agents for the treatment and post exposure prophylaxis against HIV.

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