Other anti-HIV treatments aim to prevent HIV from gaining entry to its target cells. This is achieved by blocking the attachment of HIV to receptors on the cell surface, and by preventing the fusion of the cell membrane to HIV's outer envelope. Blocking either of these processes stops HIV from gaining entry to human cells.

Several HIV proteins and human cell receptors have been investigated as targets of attachment or fusion inhibitors. The gp120 and gp41 proteins on the outer surface of HIV, which HIV uses to attach to receptors on the outside of the human cell, are targets that have been exploited in the development of fusion inhibitors including the only licensed drug in this class, T-20 (enfuvirtide, Fuzeon).

To compare all antiretroviral drugs licensed in the European Union, see NAM's drug chart. The chart contains illustrations of the drugs, as well as information on drug doses, formulations, pill burdens, main side-effects and food restrictions.

The CD4 receptor and other 'co-receptors' on the surface of the human cells are possible targets for new anti-HIV therapies. These include inhibitors of the two main co-receptors, CCR5 and CXCR4, as well as drugs to interfere with the CD4 receptor.

Blocking CD4 receptors

It may be possible to block the CD4 receptor on human cells, thus preventing viral attachment. Experimental CD4 inhibitors include sulphated polysaccharides such as dextran sulphate as well as peptide T. A test tube study has also found that a molecule similar to DNA called (s⁴dU)₃₅ can inhibit HIV entry by binding to the CD4 receptor (Horvá´¨ 2005).

Another approach, abandoned some years ago but revived recently, is the targeting of specially designed monoclonal antibodies that target the CD4 receptor. TNX-355 targets domain 2 of the CD4 receptor, an area responsible for changes in the shape of the CD4 receptor that occur after binding to HIV's gp120 protein. Studies have shown that the drug is effective at reducing HIV viral load. For more information, see TNX-355 in Drugs used by people with HIV: Entry and fusion inhibitors.

Blocking gp120

One approach is to change the structure of gp120 and thus prevent it from fitting CD4 any longer. Researchers are trying to develop treatments called glycosylation inhibitors that prevent the normal formation of the sugars that make up the gp120 glycoprotein. In laboratory tests experimental treatments such as butyl DNJ and castanospermine have shown some promise in disrupting the assembly of gp120, but have significant side-effects. Researchers are working on modified versions of both of these drugs.

An alternative approach is to block gp120 using experimental treatments such as artificial versions of CD4 produced through genetic engineering. Researchers tried using artificial CD4 molecules to target poisons to HIV-infected cells, although this approach has now been abandoned.

Bristol-Myers Squibb is pursuing the development of small molecules that will prevent attachment of HIVs gp120 molecule to the CD4 receptor. The attachment inhibitors are designed to prevent viral infection of CD4 cells. The current drug under development is BMS-488043. A dosing study found viral load fell by over 1 log₁₀ after just seven days of monotherapy (Hanna 2004). Other molecules under investigation that bind to gp120 include NBD-556 and NBD-557, although these have only been investigated in the test tube, as well as a protein called griffithsin that is derived from an alga (Mori 2005; Zhao 2005).

HIV-infected cells usually carry the gp120 protein on their cell membrane and this can also dock with receptors on uninfected cells, resulting in useless clumps of large numbers of CD4 cells called syncytia. Blocking gp120 may also help to minimise the formation of these syncytia.

Blocking gp41

HIV's gp41 protein is exposed after gp120 has become attached to the CD4 receptor. When gp41 is exposed, it interacts with the cell surface to allow fusion to take place. Blocking the activity of crucial sites within gp41 limits the capacity for fusion to take place.

T-20 is the first fusion inhibitor to be approved for use as an anti-HIV drug. It acts by binding to the gp41 protein and preventing the fusion of HIV's envelope to the cell membrane. Developed by Trimeris in collaboration with Roche, T-20 has strong antiviral effects and may be taken in combination with other classes of antiretroviral drugs by people with few treatment options. It is not currently approved as first-line therapy. T-20 is injected twice daily and injection site reaction is the most common side-effect. See T-20 - overview in Drugs used by people with HIV: Entry and fusion inhibitors for more information.

Another fusion inhibitor, T-1249, also showed promising suppression of HIV in animal and laboratory studies, although development was suspended due to formulation problems in 2004. For further information see T-1249 in Drugs used by people with HIV: Entry and fusion inhibitors.

Other experimental compounds that block gp41 include ADS-J1 and D-peptides. The D-peptides block a portion of the gp41 protein called the 'pocket'. This creates the potential for a new class of drugs known as pocket inhibitors (Eckert 1999). Experiments have also suggested that it may be possible to make CD4 T-cells produce fusion inhibitors using gene therapy (Perez 2005).

The role of co-receptors

In addition to the CD4 receptor, HIV uses other 'co-receptors' to gain entry to its target cells. These co-receptors are present on immune cells as they detect the presence of immune system messenger chemicals called chemokines. By blocking these co-receptors, HIV is unable to gain entry to CD4 T-cells and macrophages.

Interest in co-receptors stemmed from studies showing that people with a naturally-occurring mutant form of the chemokine receptor CCR5, and to a lesser extent CCR2 and SDF-1, have a slower rate of HIV disease progression than those who do not. Approximately 35% of long-term non-progressors have at least one of these mutant chemokines.

Consequently, CCR5 has been identified by drug developers as the most promising drug target. In addition, it is the co-receptor that most strains of HIV use as their co-receptor. In contrast, HIV that uses the CXCR4 co-receptor is much less common until very advanced stages of disease.

For further information on co-receptors, see Receptors, co-receptors and immunity to HIV in The immune system and HIV: How HIV damages the immune system.

Co-receptor inhibitors in development

Several inhibitors of CCR5 and other co-receptors are currently being tested. The three compounds whose development is most advanced are CCR5 blockers: aplavriroc, maraviroc and vicriviroc.

• GlaxoSmithKline is developing a product discovered by the Japanese company Ono Pharmaceuticals known as aplaviroc, which partially blocks CCR5 co-receptors. Studies have already shown that this drug can reduce viral loads in HIV-positive patients, and is currently entering trials in combination with other anti-HIV drugs (Lalezari 2004). However, concerns have arisen over a link between the drug and liver toxicity. For further information, see Aplaviroc in Drugs used by people with HIV: Entry and fusion inhibitors.

• Under development by Pfizer, maraviroc has also shown promising potency and tolerability in phase I trials. Three further trials are underway, assessing the compound in combination with other anti-HIV drugs. See Maraviroc in Drugs used by people with HIV: Entry and fusion inhibitors for further details.

• Following the discontinuation of a related compound, Schering-Plough's CCR5 blocker vicriviroc has produced significant falls in viral loads when given to HIV-positive patients. It is now being tested alongside other anti-HIV drugs in two trials. A preliminary dosing study found that viral load fell by between 1.0 and 1.5 log₁₀ over ten days with the greatest reduction occurring among people who took the top dosage. However, a phase II trial of this drug in treatment-naive patients was halted due to early viral load rebound, casting doubt on the future of this drug. For further information, see Vicriviroc in Drugs used by people with HIV: Entry and fusion inhibitors.

The Aaron Diamond Centre and Progenics Pharmaceuticals are investigating the potential of a number of monoclonal antibodies to inhibit receptor and co-receptor binding and cell entry. Research to date shows that monoclonal antibodies called PRO 140 (also known as PA14) and 2D7 are the most promising inhibitors of cell fusion and entry but have not yet been tested in humans (Olson 2000a,b).

PRO 140 works by binding to a particular site on the CCR5 co-receptor which, in turn, inhibits HIV. Test-tube data indicated that resistance to this compound does not develop readily. However, following a single injection study in mice, it was found that HIV may escape inhibition by switching to CXCR4, suggesting that coreceptor usage should be closely monitored. PRO 140 is now entering phase I human studies (Cormier 2003; Franti 2004).

Other co-receptor blockers under development include Fuji ImmunoPharmaceutical's FP-21399, which has had encouraging results in HIV-infected individuals. For further information see FP-21399 in Drugs used by people with HIV: Entry and fusion inhibitors. Another experimental CCR5 inhibitor is TAK-779. Test tube studies have found it is a highly potent inhibitor of CCR5 but that it does not affect other chemokine receptors including CXCR4.

A class of anti-HIV drugs called bicyclams have shown potent anti-HIV effects. The first of these to be investigated was AMD3100, but development of this compound has now been abandoned due to toxicities (Schols 2000). However, the Canadian biotech company AnorMED has reported in vitro anti-HIV activity of a CCR5 antagonist, AMD887, and a CXCR4 antagonist, AMD070, singly and together (Schols 2004). A related compound called AMD3451 has recently been shown to inhibit binding of HIV-1 and HIV-2 to both CCR5 and CXCR4 (Princen 2004).

Japanese researchers have reported that a peptide therapy called T22 inhibits replication of the T-tropic HIV by blocking the CXCR4 co-receptor (Murakami 1999). Similarly, Japans Kureha Chemical Industry Co. has reported that their CXCR4 inhibitor KRH-2731 has both potent and selective anti-X4 HIV-1 activity in vitro and in rats and dogs (Murakami 2004).

Problems with inhibiting co-receptors

Some researchers are concerned that, over time, use of agents which block the CCR5 co-receptor will favour the emergence of more lethal viruses that use the CXCR4 receptor. Viruses that favour the CXCR4 receptor are known to infect and kill CD4 T-cells much more rapidly than CCR5 viruses.

There is some evidence to support this theory. In the study of vicriviroc described above, one patient with a viral load reduction of greater than 1.5 log₁₀ had evidence of a transient switch to CXCR4 virus after treatment. A phase I / II study of maraviroc showed that one patient with a mixed population of CCR5 and CXCR4-tropic viruses experienced no viral load reduction after 10 days of monotherapy. Instead, the population of X4-tropic viruses increased tenfold, suggesting that a CCR5 inhibitor will select for CXCR4 variants (Pozniak 2003). There is also some evidence from animal studies that blocking one receptor will select for virus which prefers other receptors (Mosier 1999; Zhang 2000), and that viral tropism may differ between the blood and the cerebrospinal fluid that surrounds the brain and spinal cord (Spudich 2005).

However, other researchers have not found a similar switch in virus isolates from humans. Virus with an R5 phenotype was exposed to a CCR5 antagonist in the test tube, but did not lose the ability to infect and replicate in CCR5 cell lines, and remained sensitive to some CCR5 inhibitors. The researchers concluded that the development of resistance to one CCR5 antagonist did not necessarily indicate a switch to a X4 phenotype (Moore 2001).

Although they are lagging behind CCR5 blockers in development, it is possible that the concomitant use of a CXCR4 blocker may be useful in preventing the switch from R5- to X4-using HIV. A phase I/II study of the CXCR4 antagonist AMD3100 found that three people treated with the drug switched from a mixed X4/R5 phenotype, suggesting that intermittent treatment with a CXCR4 antagonist might prevent the switch to an X4 phenotype (Fransen 2004). This study also found that the virus population in the three individuals had consisted of a mixture of R5, X4 and dual tropic virus at baseline. The use of compounds that block both co-receptors, such as AMD3451, may also prove to be a useful strategy to prevent the switch in co-receptor use, although further trials are required to examine whether this drug can be used in humans (Princen 2004).

CCR5 is often the co-receptor used by HIV during early infection, and some researchers have suggested that a CCR5 blocker may be most effective when someone has a relatively high CD4 count, because the virus will have less ability to exploit a wide range of chemokine receptors. Two cohort studies have investigated the distribution of R5 and X4 strains of HIV and found that X4 viruses became more common as CD4 cell counts decline.

In the British Columbia cohort individuals with CD4 cell counts below 200 cells/mm³ had a five to seven fold higher risk of carrying virus that used the X4 receptor when compared with people with CD4 cell counts above 500 cells/mm³ (Harrigan 2004). In the Chelsea and Westminster, London, cohort the prevalence of a mixed R5 / X4 population, or phenotype, ranged from 7% in those with CD4 cell counts above 300 to 46% in those with CD4 cell counts below 100 cells/mm³ (Moyle 2004). In both cohorts viral phenotype was predicted by CD4 cell count, not viral load. However, as even patients with low CD4 cell counts may still have R5-tropic HIV, baseline testing may be of use in determining whether a patient will benefit from a CCR5 blocker.

Another contention which supports the use of CCR5 inhibitors is that HIV's ability to use other co-receptors may not be as significant as once thought. Researchers at the Aaron Diamond Centre have found that although HIV certainly can use other co-receptors to enter cells, the virus does not replicate in cells where the CCR5 co-receptor is missing or blocked. They argue that CCR5 and CXCR4 should remain the key target of co-receptor research (Zhang 1999).

Another potential question with this approach to treatment is whether all the cells which HIV infects can be protected by blocking the same chemokine receptors. Little is known about the distribution of different chemokine receptors amongst different types of immune cells, nor how important various receptors might be.

Furthermore, genetic variation affects the expression and activity of co-receptors. This means that there may be substantial variation in the effectiveness of chemokine antagonists due to these natural polymorphisms (Mosier 2000).

The pharmacokinetic aspects of chemokine inhibition are still poorly understood. In particular, it is unclear whether the peak or trough level will prove more important in determining efficacy. If the key requirement for efficacy is that all receptors are blocked, peak levels will be more important because saturation of the co-receptors will be key. On the other hand, some researchers think that trough levels may be more important, because HIV needs to engage with multiple CCR5 receptors to gain entry to a cell, and even if all receptors are not blocked, viral entry could be substantially limited.

Another pharmacokinetic problem already identified by Pfizer in the development of its CCR5 inhibitor is the difficulty of achieving adequate drug levels when the compound is taken with food.

Potential immunological side-effects are also uncertain. Could interference with particular chemokines induce other unwelcome immunological effects in the long-term? So far, studies of chemokine inhibitors have taken place only for short periods and there has been no evidence of immunological toxicity.

It is hoped that blocking certain chemokine receptors will not affect other immune functions because the chemokines in question can utilise several other receptors. However, chemokines are necessary for certain inflammatory reactions, and blocking particular receptors may lead to adverse consequences. A review of immune responses in mice genetically engineered to be CCR5 deficient by Schering-Plough found an impaired response to opportunistic infections such as leishmaniasis, cryptococcus and listeria (Huffnagle 1999; Zhou 2005). The potential for reduced immune responses will clearly require further research to prove that CCR5 antagonists are safe for use in HIV infection, especially in individuals with a prior history of opportunistic infections.

Blocking CCR5 co-receptors may produce a similar immunological profile to that seen in individuals with the CCR5 delta 32 deletion. Although this variety of the CCR5 co-receptor provides long-term protection against acquisition of HIV and most people with this polymorphism come to no long-term harm, there is evidence that it can impair immune function. For example, it has been linked to:

• Reduced incidence and severity of rheumatoid arthritis (Gomez-Reino 1999; Zapico 2000).

• Increased survival in transplant recipients (Fischereder 2001).

• Elevated aspartate aminotransferase (AST) levels, indicating liver toxicity (Laurence 2002).

• Inhibited antibody response to herpes-zoster (Wiencke 2001).

People with the CCR5 delta 32 deletion can also experience more severe cases of lupus, have poorer prognosis in certain types of breast cancer and may be less likely to clear hepatitis C virus (HCV) following infection (Aguilar 2003; Favorova 2002; Manes 2003; Woitas 2002). Conversely, the 32 deletion may be very protective against heart attacks (Gonzalez 2001). Nevertheless, researchers will need to consider the subtle and profound long-term effects of inhibiting CCR5 receptors, particularly in patients co-infected with HIV and HCV.

Modulation of CXCR4 expression may have wider consequences. CXCR4 abnormalities proved lethal in mice, and it may prove more important for humans than CCR5 due to its role in the maturation of white blood cells called B-cells and the production of blood cells. It may also be important for embryonic developmental processes such as the formation of organs and blood vessels (Murdoch 2000).

These subtle and serious effects may not be seen in the short-term, and might take over five or six years to develop. Furthermore, they are unlikely to be detected in short-term clinical trials.

Combining fusion inhibitors and co-receptor antagonists

Combining different types of fusion inhibitors and co-receptor antagonists is being investigated as a treatment strategy. Laboratory studies have provided some encouraging evidence that combinations of fusion inhibitors may significantly reduce HIV cell fusion and entry.

Researchers from Progenics have tested a combination of T-20, PRO 542 and PRO 140 individually and in combination against test tube samples of HIV to see whether the drugs could boost each others effects (synergy). T-20 and PRO 542 were found to be synergistic, to such an extent that when used together, concentrations of the drugs required to inhibit HIV replication could be reduced 30-fold in comparison with the concentrations required when used individually. PRO 140 was not synergistic, but in a separate test tube study, it was shown to be a potent inhibitor of HIV activity not only in lymphocytes, but also in macrophages, an important reservoir of HIV infection. PRO 542 is in advanced human studies, but PRO 140 has not yet been tested in humans.

Combining bicyclams (CXCR4 antagonists) with fusion blockers such as T-20 is also a developing area of research. Such a combination would target several sites of fusion, potentially creating a potent anti-HIV treatment. Strong synergy between AMD3100 and T-20 was observed in test-tube studies, but AMD3100 has now been discontinued due to cardiac toxicity.

The use of CCR5 antagonists in combination with drugs that block gp41 is particularly attractive because researchers have found that reducing the amount of CCR5 expression on a CD4 T-cell increases the amount of time that HIVs gp41 region remains exposed. Multiple linkages between HIV and CCR5 are needed for swift fusion to occur, so blocking CCR5 may increase the time during which gp41 inhibitors like T-20 or T-1249 could act against the virus.

Potential for cross-resistance

Preliminary test-tube studies suggest that common mutations in the env gene of HIV may cause some level of cross-resistance amongst the fusion inhibitors. Furthermore, the bicyclam AMD3100 generates alterations in gp120 that seem to cause cross-resistance to drugs that target the co-receptors, suggesting there may be cross-class resistance (Este 1999).

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