HIV Viral Entry

HIV enters macrophages and CD4+ T cells by the adsorption of glycoproteins on its surface to receptors on the target cell followed by fusion of the viral envelope with the cell membrane and the release of the HIV capsid into the cell.

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Entry to the cell begins through interaction of the trimeric envelope complex (gp160 spike) and both CD4 and a chemokine receptor (generally either CCR5 or CXCR4, but others are known to interact) on the cell surface. gp120 binds to integrin α4β7 activating LFA-1 the central integrin involved in the establishment of virological synapses, which facilitate efficient cell-to-cell spreading of HIV-1. The gp160 spike contains binding domains for both CD4 and chemokine receptors. The first step in fusion involves the high-affinity attachment of the CD4 binding domains of gp120 to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine binding domains of gp120 and allowing them to interact with the target chemokine receptor. This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane. Repeat sequences in gp41, HR1 and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin. This loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.

Once HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease and protease, are injected into the cell. During the microtubule based transport to the nucleus, the viral single strand RNA genome is transcribed into double strand DNA, which is then integrated into a host chromosome.

HIV can infect dendritic cells (DCs) by this CD4-CCR5 route, but another route using mannose-specific C-type lectin receptors such as DC-SIGN can also be used.DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T cells once the virus has been captured in the mucosa by DCs.

Cancer Metastasis: CXCR4

CXCR4, also called fusin, is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12), a molecule endowed with potent chemotactic activity for lymphocytes.

Metastasis shares many similarities with leukocyte trafficking. Among those chemokine receptors thought to be involved in hemopoietic cell homing, stromal cell-derived factor-1 and its receptor CXC chemokine receptor-4 (CXCR4) have received considerable attention. Like hemopoietic cell homing, levels of stromal cell-derived factor-1 are high at sites of breast cancer metastasis including lymph node, lung, liver, and the marrow. Moreover, CXCR4 expression is low in normal breast tissues and high in malignant tumors, suggesting that a blockade of CXCR4 might limit tumor metastasis investigating the role of a synthetic antagonist 14-mer peptide (TN14003) in inhibiting metastasis in an animal model. Not only was TN14003 effective in limiting metastasis of breast cancer by inhibiting migration, but it may also prove useful as a diagnostic tool to identify CXCR4 receptor-positive tumor cells in culture and tumors in paraffin-embedded clinical samples.

CXC chemokine receptor 4 (CXCR4) has been shown to play a critical role in chemotaxis and homing, which are key steps in cancer metastasis. There is also increasing evidence that links this receptor to angiogenesis; however, its molecular basis remains elusive. Vascular endothelial growth factor (VEGF), one of the major angiogenic factors, promotes the formation of leaky tumor vasculatures that are the hallmarks of tumor progression. On investigating whether CXCR4 induces the expression of VEGF through the PI3K/Akt pathway. Results showed that CXCR4/CXCL12 induced Akt phosphorylation, which resulted in upregulation of VEGF at both the mRNA and protein levels. Conversely, blocking the activation of Akt signaling led to a decrease in VEGF protein levels; blocking CXCR4/CXCL12 interaction with a CXCR4 antagonist suppressed tumor angiogenesis and growth in vivo. Furthermore, VEGF mRNA levels correlated well with CXCR4 mRNA levels in patient tumor samples. In summary, our study demonstrates that the CXCR4/CXCL12 signaling axis can induce angiogenesis and progression of tumors by increasing expression of VEGF through the activation of PI3K/Akt pathway. Findings suggest that targeting CXCR4 could provide a potential new anti-angiogenic therapy to suppress the formation of both primary and metastatic tumors.

Treatment for HIV

At present treatment for HIV infection involves using a combination of drugs. One type of drug inhibits nucleic acid replication, for example, when AZT is incorporated into DNA by reverse trasncriptase, no additional nucleotides can be added.

A second class of drugs inhibits a protease involved in cleaving large polyproteins into functional segments. When the protease is inhibited, virus particles cannot be produced Use of a combination of drugs directed at different targets reduces the likelihood of the development of resistance by mutation.

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Research is underway to develop new treatments for HIV. Chemicals called chemokines appear to inhibit HIV infection by binding to and blocking the CXCR4 and CCR5 co receptors on the host cells.

A search is in progress to apply such chemicals in HIV treatment,Some individuals who are HIV positive, but did not develop AIDS have a mutation in the CCR5 receptor that makes it defective.

Research is in progress to determine whether disabling the CCR5 receptor might beeffective in controlling AIDS in infected patients.An antiviral factor called CAF is found in CD8 cells.Research is in progress to determine if this substance could be used to block replication of HIV.

There is currently no approved vaccine against HIV infection. One problem is that HIVsurface proteins such as gp120 mutate at a high rate.Scientist may be able to construct a vaccine using an HIV with a defective form of the viral gene nef.

Viruses with the defective nef gene seem to have reduced reproductive capability, allowing the immune system to keep the virus in check.