In addition to drugs that target HIV's components, several drugs that block the activity of components of infected human cells have also been tested. While none of these are currently licensed for use in HIV infection, interest in this approach continues and future anti-HIV strategies may include these types of drug.

However, despite encouraging results in some trials, the potential for drugs targeting human cellular factors to cause side-effects is greater than for those targeting viral factors, as they may interrupt normal cell functions.

Ribonucleotide reductase inhibitors

The process of reverse transcription, which involves the 'translation' of HIV's RNA into DNA within the human cell can be blocked not only by reverse transcriptase inhibitors, but also by reducing the activity of the cellular enzyme ribonucleotide reductase. This enzyme is used to produce the nucleotide building blocks of viral DNA.

By blocking ribonucleotide reductase, the drug hydroxycarbamide (Hydrea), previously known as hydroxyurea, depletes the pool of nucleotides, thus hindering HIV reproduction. The drawback of using hydroxycarbamide is that it inhibits the bone marrow, suppressing the production of blood cells.

For more information, see Hydroxycarbamide - overview in Drugs used by people with HIV: Other types of experimental anti-HIV therapy.

Phosphorylation enhancers

Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs and NtRTIs) must undergo conversion within the human cell to become active, a process known as phosphorylation. This involves the addition of chemicals called phosphate groups to the drug molecules. The availability of phosphate groups in the human cell determines the rate at which the drug is processed, and hence the drug's anti-viral potency.

A number of substances can improve the phosphorylation of the NRTIs and NtRTIs, thereby increasing their activity:

• Hydroxycarbamide has been shown to improve the phosphorylation of d4T (stavudine, Zerit) in the cells of people who had been exposed to AZT or other NRTIs for long periods. This may counteract the reduced capacity for d4T phosphorylation in patients with extensive prior NRTI treatment.

• The anti-cancer drug 5-fluorouracil has been shown to enhance the activity of AZT and d4T against drug resistant viruses in the test tube.

• 3-deazauridine, another anti-cancer drug, has been shown to enhance the activity of 3TC (lamivudine, Epivir) against 3TC-resistant viruses in the test tube, and also improves the effect of ddC.

• Animal studies suggest that two other compounds, didox and trimidox, might have a similar effect, enhancing the activity of abacavir (Ziagen), tenofovir (Viread) and ddI.

Trim5-alpha

A vital step between the entry of HIV into a human cell and the conversion of its RNA into DNA is the removal, or uncoating, of the protective shell surrounding the viruss genetic material. This coat, called the capsid, must be removed before HIV can insert its genetic material into a human cell and make copies of itself.

Scientists have discovered a new protein called Trim5-alpha that specifically targets HIVs capsid. It is not known exactly how Trim5-alpha works, but investigators believe that the protein chops up HIVs capsid, preventing the orderly uncoating the virus must undergo before it replicates.

Two possible therapeutic options have been opened up by the discovery. Research could focus on enhancing the ability of human Trim5-alpha to block HIV. Another approach would be finding a way to alter the human protein so that it resembles the monkey version, which protects cells against HIV infection. Recent studies have shown that the human and monkey versions of Trim5-alpha differ by only one amino acid building block (Stremlau 2004, 2005; Yap 2005). However, while theoretically possible, it is unlikely that the gene therapy required to alter human genes in this way will become a practical possibility for HIV treatment for many years.

Cyclophilin A inhibitors

Cyclophilin A is a chemical present in all cells which interacts with HIV virions when they enter a cell. It has a number of functions, including releasing HIV's genetic material from the capsid, allowing the virus' genes to be accessed by reverse transcriptase. Cyclophilin A also has the unusual property of being taken up by HIV-1 during the manufacture of new virions and must be present within virus particles to allow infection of new human cells.

Cyclophilin A levels can be reduced by ciclosporin (Neoral / Sandimmun), an immunosuppressive drug normally used to prevent the rejection of transplanted organs and tissue grafts. If cyclophilin A is inhibited, researchers have proposed that HIV's capacity to infect new cells could be reduced.

Deoxyhypusine hydroxylase and synthase inhibitors

Deferiprone is a drug that inhibits the formation of the amino acid hypusine by blocking the activity of the enzyme deoxyhypusine hydroxylase (DOHH). Hypusine is a component of only one human enzyme, called eukaryotic translation initiation factor 5A (eIF5A). This enzyme is required for HIV multiplication, as well as preventing the human cell from committing suicide or 'apoptosis'.

Inhibiting DOHH by the use of deferiprone in the test tube was found to trigger cell death in HIV-infected, but not in normal cells or cells infected with human papilloma virus. It is possible that the novel strategy of cycled, high-dose pulse therapy of deferiprone may achieve the selective killing of HIV-infected cells (Hanauske-Abel 2004).

Another enzyme that is crucial for the production of hypusine is deoxyhypusine synthase. The experimental drug CNI-1493 has been shown to block this enzyme and suppress HIV replication in the test tube, including HIV strains that were resistant to currently available HIV drugs. CNI-1493 is currently undergoing phase II trials for the treatment of Crohn's disease (Hauber 2005).

Cyclin-dependent kinase inhibitors

Cyclin-dependent kinases are enzymes that co-ordinate the human cell's life-cycle, determining when the cell produces new proteins, when it copies its DNA and when it divides. One research group has shown that blocking one of these enzymes called cdk2 prevents the cell from producing new viral proteins in the test tube. This drug, called R-roscovitine (CYC202), may therefore be a promising future target as an anti-HIV drug (Agbottah 2004).

CD4 receptor down-regulation

One of the functions of the HIV proteins Nef and Vpu is to reduce the number of CD4 receptors on the cell surface to allow the production of infectious HIV particles. While this may seem counter-intuitive, it seems that this down-regulation gives the HIV particles enough space to escape from the cell membrane and that failure to reduce the number of CD4 receptors results in the production of HIV particles that cannot infect new human cells.

To inhibit the down-regulation of CD4 receptors, one research group used gene therapy techniques to deliver triuncated CD4 receptor genes to cells in the test tube. The CD4 receptors produced from these truncated genes were insusceptible to the down-regulation normally caused by the actions of Nef and Vpu, resulting in the release of viral particles that were 1000 times less infectious than normal HIV. This approach may eventually provide the basis for new anti-HIV strategies (Pham 2005).

References

Agbottah E et al. Antiviral activity of CYC202 in HIV-1-infected cells. J Biol Chem 280: 3029-2042, 2004.

Hanauske-Abel HM et al. Selective ablation of HIV-infected lymphocytes by inhibitors of hypusine formation: the mature eukaryotic translation initiation factor 5A is pivotal for retroviral suppression of apoptosis. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 542, 2004.

Hauber I et al. Identification of cellular deoxyhypusine synthase as a novel target for antiretroviral therapy. J Clin Invest 155: 76-85, 2005.

Pham HM et al. Lentiviral vectors interfering with virus-induced CD4 down-modulation potently block human immunodeficiency virus type 1 replication in primary lymphocytes. J Virol 78: 13072-13081, 2005.

Stremlau M et al. The cytoplasmic body component TRIM5-alpha restricts HIV-1 infection in old world monkeys. Nature 427: 848-853, 2004.

Stremlau M et al. Species-specific variation in the B30.2 (SPRY) domain of TRIM5alpha determines the potency of human immunodeficiency virus restriction. J Virol 79: 3139-3145, 2005.

Yap MW et al. A single amino acid change in the SPRY domain of human Trim5alpha leads to HIV-1 restriction. Curr Biol 15: 73-78, 2005.