Question

Diverse chemokine receptors are thought to be involved during HIV infection into T cells and macrophages. (1) How chemokines are acting to regulate the viral infection in these cells? (2) Would blocking the chemokine down-stream signaling pathways in the HIV target cells attenuate the progression to AIDS? (3) Why or why not

Answer 1

Solution

1. HIV infection leads to the proliferation of viral particles, death of the infected cells and destruction of host immune system. HIV carries a glycoprotein complex of gp160 which consists of gp120 (surface glycoprotein) and gp41 (transmembrane glycoprotein) on their outer envelope. The gp120 protein is responsible for binding to the CD4+ T- cells. The CD4 competent gp120 proteins interacts and binds to the CD4 receptors hosted on the outer surface of the T-cells. This binding leads to further folding and conformational rearrangement of gp120 to expose its co-receptor binding site. This co-receptor binding site is now capable of binding the CCR5/CXCR4 chemokine co-receptors present on the attacked T-cell membrane. This binding leads to further alterations in the structure of the glygoprotein complex which leads to the gp41 exposure and eventual insertion into the host cell membrane. This further leads to major structural changes in gp41which gradually brings the virus and host cell together leading to membrane fusion and release of the viral core into the cell cytoplasm. The viral replication can now start inside the host cell.

Chemokines, the cognate ligands for the chemokine receptors are low molecular weight proteins responsible for induction of immune cell-trafficking and migration. HIV infection elicits a 'cytokine storm' (immune hyperactivation) inside the host by abnormally upregulating cytokine and chemokine secretion. Any mutation in chemokine receptors or chemokine secretory signalling pathway proteins will either render the virus powerless or delay the effective onset of infection in host cells, respectively.

2. The blocking of chemokine downstream signalling pathways in HIV target cells will effectively attenuate the progression of AIDS.

3. HIV uses the mechanism of hyperactivation of chemokine secretory pathways to put the host immune system into overdrive. This condition is called AIDS. The over activation of immune system leads to cellular destructing and eventually the immunity of the host gets completely compromised. If the chemokine downstream signalling pathways were blocked the HIV will fail to elicit such an abnormally upregulated response. Even if the glycoproteins of HIV succeeds to establish membrane contact by binding the chemokine receptors and internalize its core particles into the host cell, still the additional effect of activation of chemokine signalling cascade would be blocked. The immune system will survive. The HIV infection will be delayed and the AIDS condition will be attenuated.