INFECTIOUS DISEASE

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HUMAN IMMUNODEFICIENCY VIRUS

ANTI-HIV CHEMOTHERAPY 

APPENDIX III

Dr Richard Hunt

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See also Virology Chapter 9
Chemotherapy

WEB RESOURCES

Anti-retroviral drugs used in the treatment of HIV infection

Approved therapies for the treatment of complications of HIV/AIDS

Approved anti-retroviral drugs for pediatric treatment of HIV infection

HIV/AIDS Treatment Investigations New Drugs (INDs) Allowed to Proceed

Current HIV treatment guidelines
 

Anti-HIV chemotherapy has made great strides in the past twenty years from the initial introduction, in 1987, of azidothymidine (AZT) monotherapy (which had little effect on longevity) to the triple drug cocktails that comprise highly active anti-retroviral therapy (HAART) in use today. Although HAART has resulted in major extensions of lifespan and suppression of symptoms in HIV-infected patients, it is not without major side effects. In addition, these drugs penetrate certain parts of the body (e.g. the brain) poorly, are toxic and can select for resistant mutants. Different resistant mutants can emerge in different parts of the body. These drugs target HIV replication and so have no effect on pre-integration complexes or integrated provirus in the latently infected T lymphocytes. As a result, although anti-viral chemotherapy has made HIV infection a tractable disease, it has not led to a cure and new approaches to treating HIV infection are very much needed.

 

POSSIBLE SITES FOR INTERVENTION IN THE HIV LIFE CYCLE  

When attempting to develop chemotherapeutic agents to combat viral infections, it is important that the life cycle of the virus be interrupted without killing the host cell. This is difficult because viruses use host cell metabolic process for most of their synthetic reactions. To achieve specificity, processes that are unique to the virus must be identified or, if the agent is toxic to the host cell, it is important that only virus-infected cells be killed. While HIV uses many cellular processes, there are vital functions that are unique to the virus and these have been successfully exploited in drug design. Several stages of the HIV replication cycle are possible targets for chemotherapy:

  • Binding to surface receptors

  • Fusion of viral and host cell membranes

  • Uncoating of the nucleocapsid

  • Reverse transcription of RNA to DNA

  • Integration of DNA provirus into the host genome

  • Replication (Host DNA polymerase)

  • Transcription (Host RNA polymerase II)

  • RNA splicing in the host cell nucleus (host and viral factors)

  • Translation of viral proteins

  • Proteolysis of viral polyproteins (Host protease in the Golgi Body processes gp160, Viral protease processes GAG,POL)

  • Glycosylation of gp160

  • Phosphorylation of viral proteins

  • Fatty acylation of GAG

  • Assembly of the virus at the host cell membrane

  • Budding

  • Maturation of the virus particle after budding

    The stages in italics are likely targets since they are specific to the virus

 

 

hivstage.gif (28491 bytes) Possible sites for chemotherapeutic intervention in the HIV life cycle

Until recent years, few drugs have shown sufficient activity against HIV at non-toxic concentrations to warrant further development. Effective agents must show activity against virus in T4 cells, macrophages, neural cells, epithelial cells etc. and thereby eliminate virus from the patient.

Most agents are virustatic rather than virucidal. This is, perhaps, all we can expect but there are some hopes that a chemotherapeutic approach could lead to the eventual eradication of HIV from the bodies of at least some individuals. However, there are  major doubts that eradication can ever be achieved because of the very slow clearance of HIV-infected resting memory T cells. 

At present, the chemotherapeutic approach that is most likely to eradicate the virus is the Highly Active Anti-Retroviral Therapy (HAART) or triple drug treatment (see below).

 

WEB RESOURCES

Classes of anti-HIV drugs
NSAID

 
 

INHIBITORS OF TRANSCRIPTION OF THE VIRAL GENOME 

The single strand HIV RNA genome is first transcribed to double strand DNA by reverse transcriptase, a retroviral-specific enzyme. Since reverse transcription is not a normal function of eukaryotic cells, this is likely to be an important target for anti-HIV chemotherapy and the first anti-HIV drug, azidothymidine (AZT) is such a compound.

 

Nucleoside Reverse Transcriptase Inhibitors  

These are competitive inhibitors of reverse transcriptase since they bind to the enzyme's active site. In addition, they are DNA chain terminators, that is they are recognized by reverse transcriptase as nucleotides and incorporated into DNA; however, they usually lack the complete deoxyribose ring or a hydroxyl group at carbon 3 of the sugar and therefore their structure precludes the further addition of nucleotides to the nascent polynuceotide since a phosphodiester bond cannot be formed. The first of these competitive reverse transcriptase inhibitors was AZT. Compounds in this category can also be used in cell DNA synthesis leading to chain termination. This is not a problem for cells that are not dividing but is a problem in the replication of erythroid cells, spermatozoa, cell of the immune system and of the gut. Some specificity is achieved because AZT has a far higher affinity for reverse transcriptase that it does for the host cell DNA polymerase but it also inhibits cellular enzymes leading to severe side effects.

 

pcr.gif (4021 bytes)

Decline in the number of HIV particles in patients treated with a triple drug regimen (HAART). Clinically infected patients were treated with HAART. Plasma viremia declines in two phases: Within 2 weeks, it has declined by 99%. This is followed by a slower decline; by 8 weeks, HIV viral titers have declined below the limits of detection of the assay

Several reverse transcriptase inhibitors have been approved for use against HIV, none are without side-effects.

Approved Nucleoside Reverse Transcriptase Inhibitors
Drug Trade Names Link
AZT (3'-Azidothymidine)   Zidoudine, Retrovir  ZIDOVUDINE - AZT, ZDV (Retrovir)
DDI (2',3'-dideoxyinosine) Didanosine, Videx  DIDANOSINE - VIDEX
DDC (2',3'-didexoycytidine)  Zalcitabine, Hivid   ZALCITABINE (ddC, HIVID®)
d4T (Didehydrothymidine) Stavudine , Zerit STAVUDINE
3TC (2'-deoxy-3'-thiacytidine)  Lamivudine, Epivir  FDA Approves Epivir For Use In HIV Patients Three-Months Old And Up
Abacavir succinate      Ziagen Triple Therapy With Ziagen Effective For Up To 48 Weeks
Tenofovir disoproxil fumarate Viread

For more information go here

            

AZTn.gif (5101 bytes) AZT

From NIH-NIAID

Azidothymidine - AZT

Zidovudine, Retrovir®

AZT is the only nucleoside inhibitor that has been subjected to a placebo-controlled trial. When originally used as the first anti-HIV drug, it was administered when patient CD4 cells were <500 cells/mm3. It delays onset of AIDS-related opportunistic infections but in a controlled trial it was found that the use of AZT in asymptomatic HIV-infected patients resulted in no difference in survival at 3 years. 

Before the results of a major trial published in April 1993, AZT monotherapy was considered: "Mediocre---but better than nothing". After April 1993, the consensus was that AZT offers "no significant benefit to infected healthy people in slowing the disease or prolonging life" (Concorde trial France/UK. Lancet)

When non-syncytium-forming viruses convert to syncytium-forming, there is a change from clinical latency to a rapid decline. Unfortunately, AZT is minimally effective against syncytium-forming version of virus.

Nevertheless, AZT is extremely effective at preventing peri-natal transmission of HIV. As a result of the use of AZT monotherapy treatment  and similar interventions, the number of perinatally acquired AIDS cases in the United States dropped dramatically. The risk of mother-to-infant transmission of HIV has been found to range from 25% to 35% in an untreated individual. AZT treatment of the mother and her infant can reduce transmission risk  from 26% to 8% and AZT/3TC and triple therapy reduce that risk even further. Nevirapine is now the drug of choice for peri-natal treatment (see below).

Since AZT also interferes with host cell DNA synthesis, it causes severe side-effects among which are:

  • Anemia (because of inhibition of DNA synthesis in erythroid precursor cells)

  • Neutropenia (because of inhibition of DNA synthesis in neutrophil generation)

  • Myopathy (muscle pain)

AZT can also interfere with other drugs and should not be taken with d4T (stavudine, Zerit, d4T). Moreover, methadone can increase blood levels of AZT, leading to more pronounced side effects.

Resistance to AZT occurs rapidly when the drug is used in monotherapy.
 

ddin.gif (4805 bytes) From NIH-NIAID

Dideoxyinosine - DDI

Didanosine, Videx®

DDI is a potent inhibitor of reverse transcriptase but is not superior to AZT. It is approved for persons on AZT for > 4 months or who cannot tolerate AZT.

Since it is not specific to reverse transcriptase, this drug can also interfere with host cell DNA replication. Among its side effects are:

  • Peripheral neuropathy. This occurs in about one fifth of patients and is usually temporary if administration ceases. It can however become permanent if the patient continues on the drug.

  • Pancreatitis. This can be fatal and occurs in up to 7% of patients

  • Lactic acidosis
     

  Stavudine

D4T, Zerit®

Stavudine is another reverse transcriptase inhibitor. Again, it has side effects including:

It is used in combination therapy, particularly in advanced HIV disease.

 

ddcn.gif (4749 bytes) From NIH-NIAID

Didexoycytidine - DDC

Hivid®, zalcitabine

DDC is the most potent of the three original nucleoside inhibitors when used on infected cells in culture. It is approved for use with AZT in adults with <300 CD4 per mm3 who have significant deterioration. It is no longer manufactured.
 

abacavirn.gif (5613 bytes) From NIH-NIAID

Abacavir

Ziagen®

Abacavir sulfate (a synthetic carbocyclic nucleoside) is much less toxic than the above drugs with more mild side effects such as nausea and headaches

Tenofovir

Viread®, bis-POC PMPA

The main side effects of tenofovir are also nausea and headaches

 

Why do reverse transcriptase inhibitors not work completely?

None of the nucleoside analog reverse transcriptase inhibitors are now used as single drug monotherapy. Instead, they are combined with other drugs as part of HAART. Initially, they may reduce viral burden 50-90% but there is a failure to keep adequate drug levels over long periods of time. Subsequently, resistance develops after six months to one year and occurs more rapidly in patients that have been infected for longer time. This is because they have greater burden of more diverse forms of the virus. Resistance results from mutations in reverse transcriptase which quickly arise because of enormous proliferation rate of virus and the lack of a proof reading activity in host polymerase II. There is thus an enormous section pressure for resistant variants.

 

 


Non-Nucleoside Inhibitors  

The non-nucleoside reverse transcriptase inhibitors are non-competitive inhibitors of the enzyme, that is they bind elsewhere than the active site of the enzyme.

Because of the problems with AZT and the other nucleoside analogs in the treatment of HIV, interest  grew in another approach to inhibiting the same enzyme, reverse transcriptase. Alternative drugs might be useful in combination therapy since there is a limit to the number of mutations that reverse transcriptase can bear without losing function. Clearly, mutations resistant to a non-nucleoside non-competitive inhibitor of reverse transcriptase would be at a different site in the enzyme from the mutation that makes the enzyme resistant to a competitive nucleoside analog. Thus, although resistant virus strains are cross resistant to other non-nucleoside reverse transcriptase inhibitors, they are not to nucleoside analog inhibitors.

Not surprisingly, since these drugs target reverse transcriptase, resistant mutants rapidly emerge, even after only a few passages in cultured cells. In the clinic, resistant mutants also arise rapidly. They are therefore of little use in monotherapy.

These are the most potent and selective reverse transcriptase inhibitors that we have, working at nanomolar concentrations. Unlike nucleoside analogs, they have minimal toxicity in tests with cultured cells (anti-viral activity occurs at 10,000 to 100,000-fold lower concentration than the cytotoxic concentration) and they have been shown to work synergistically with nucleoside analogs such as AZT. There is some toxicity when used in humans.

These drugs work against nucleoside analog-resistant HIV. Thus, they have high therapeutic index and also show good bioavailablity so that anti-viral concentrations are readily achievable. 

There is now a collection of such agents that are chemically distinct. The three drugs of this type approved in the U.S. are nevirapine, delavirdine and efavirenz

 

 
nevirn.gif (5501 bytes)  From NIH-NIAID

Nevirapine

NVP, Viramune®, BIRG-587

In monotherapy, nevirapine gives an initial fall in HIV but resistance sets in and virus titers rise again to a high level. High concentrations that are achieved in the bloodstream may be of some use.  A pediatric suspension of nevirapine (Viramune) has been approved by the US Food and Drug Administration for the treatment of HIV-infected infants and children.

One side effect of nevirapine is skin rash. This occurs in about one quarter of patients. More serious and much rarer is the skin rash associated with Stevens-Johnson syndrome which can lead to death. In addition, this drug can result in liver damage which in some cases can be fatal.

 Nevirapine is  approved for combination therapy in adults. 

Chemotherapy and pediatric HIV infection in developing countries

Adverse reactions of nevirapine

 

WEB RESOURCES
NEVIRAPINE

Mother-to-Infant HIV Transmission Rate Less Than 2 Percent
in Phase III Perinatal Trial

 

Pyridinone derivatives

L-697,661

Trials in combination with AZT showed a delay in emergence of resistant virus with these drugs but resistance is NOT prevented. Disappointing results mean that these drugs have not been developed further.

 

rescripn.gif (6121 bytes) From NIH-NIAID

Delavirdine

Rescriptor®, Bis (heteroaryl) piperazine compounds, DLV

Delavirdine treatment leads to considerable increases in CD4+ cells in combination therapy (with AZT and 3TC). There have been promising results in patients with very low CD4+ cells that have prior treatment with AZT. In combination with AZT and 3TC, DLV may delay emergence of resistance to AZT. The drug is absorbed rapidly. This drug is used in combination with a nucleoside analog such as AZT and the protease inhibitors discussed below. 

Skin rash in about one quarter of patients is the major side effect.

Atervidine is a similar drug but is no longer in development.

 

WEB RESOURCES

Rescriptor With Indinavir At Lower Doses Decreases Viral Load

sustn.gif (5335 bytes) From NIH-NIAID

Efavirenz

DMP266, Sustiva®, Stocrin®

One of the more important treatment developments at the 12th World AIDS Conference was the report of new phase III data showing that Efavirenz (brand name Sustiva), used in combination with other treatment, may suppress viral load at least as well as the protease inhibitor Indinavir in the equivalent combination with nucleoside reverse transcriptase inhibitors. The most noteworthy result was a comparison of viral load reduction with Efavirenz plus AZT plus 3TC, vs. a standard-of-care control group treated with Indinavir plus AZT plus 3TC. The Efavirenz combination suppressed viral load to below 400 copies in a significantly higher proportion of the volunteers than the control arm, at all time points between week 2 and week 24.

Side effects include skin rash, nausea, dizziness, diarrhea, headache and insomnia. A small minority of patients develop serious psychiatric problems. In addition, this drug may cause major problems in pregnant women since it is teratogenic in rats. It should not be taken therefore during pregnancy and, especially, in the first trimester.

 

Approved Non-Nucleoside Inhibitors 
Drug - Generic Name Trade Names
Delavirdine, DLV Rescriptor
Efavirenz Sustiva
Nevirapine, BI-RG-587 Viramune

For more information go here

 

 
 

Combination Therapy Using Nucleoside Analogs  

Since the introduction of AZT and similar analogs, new avenues of anti-HIV chemotherapy have been explored since these drugs are clearly not sufficient as anti-HIV agents. This is because of their side effects and, more importantly because of:

  • their inability to reduce viral load over prolonged periods

  • their inability to prolong life

  • the high rate of evolution of resistant mutants in an infected patient 

AZT has no impact on survival. Combinations of nucleoside inhibitors are more effective in that they reduce plasma HIV RNA to about 10% of the initial value and maintain this for up to 2 years. This can slow development of disease but not prevent it.

Mutation rate

As always, there remains the problem of mutation of RNA viruses, a phenomenon that results in the rapid evolution of drug-resistant viral quasi species. In an HIV-infected person, about 10.3 x 109 virions are produced per day. These have a half life of 5.7 hours and a fixed mutation rate of 3 x 10-5 per base per replication cycle in an HIV genome of 104 base pairs. This means that at least one mutation may occur in each nucleotide of HIV in a day.

After a year from seroconversion, each infected individual establishes his/her own set point of steady state levels of plasma HIV RNA (102 to 107 copies per ml of blood). This level largely determines the rate at which T4 cells are lost. It appears that this level of viral load drives the rate of immune destruction and can predict the course of the disease. Reduction in viral load seems to account for most of the clinical benefits of any drug. Clearly, if viral load is reduced to negligible levels, we have a very important drug. If the negligible levels are achieved by suppression of replication, the evolution of resistant mutants may not be a problem since mutation requires replication.

 

 

Protease inhibitors  

With the advent of protease inhibitors, there has been optimism that HIV might become a tractable disease since now we have the promise of a drug regimen that can suppress indefinitely the progress of disease. If, as seems to be the case, viral load is the key to the progression from infection to the clinical manifestations of the disease, combination therapy may make HIV infection manageable.

Many aspartyl protease inhibitors are being developed but at present, only a few are approved. They are all substrate analogs, that is they mimic a peptide that can bind to the active site of the viral protease. The latter is a dimeric aspartyl protease (has catalytic aspartates at its active site). When used individually, protease inhibitors can drive down viral load to between one 30th and one 100th of initial value but sub-optimal doses of these inhibitors when used alone can result in loss of suppression after several weeks or months and an accumulation of multiple mutations in the protease gene giving a high level of drug resistance. However, patients with sustained suppression do not develop the resistant mutations. This is because replication must be maintained for the development of such mutations under the selective pressure of the drug. 
 

 
saqn.gif (7110 bytes) From NIH-NIAID

Saquinavir

SQ, Invirase® (there was also a version called Fortovase®) - Made by Hoffman-La Roche

This is a hydroxyethylamine transition-state analog of the HIV protease cleavage site. It is the least bio-available of the present protease inhibitors and is the least effective. It is used in combination therapy (HAART). In clinical trials, SQ + AZT + ddC reduced viremia with a rise in T4 cells in individuals with a T4 cell count of 50 - 300/mm3. SQ plus ddC versus any drug alone in individuals with prior AZT treatment showed significant benefit. 

There are a few side effects in a minority of patients. These are mild: nausea, diarrhea, upset stomach, and heartburn.
 

ritonn.gif (6469 bytes) From NIH-NIAID

Ritonavir

Norvir® - Made by Abbot Labs.

Alone Ritonavir reduces AIDS-defining events and death by 58% compared to placebo.

This drug is now rarely used alone because of side effects that make it difficult tolerate but it is often used to increase blood levels of other protease inhibitors. This dose much smaller lower than that used in monotherapy or as a single protease inhibitor in HAART and thus causes fewer side effects. Ritonavir causes nausea in 25% of patients. It also causes diarrhea, oral numbness and problems with tasting food.

indinn.gif (6271 bytes)   From NIH-NIAID

Indinavir

Crixivan® - Made by Merke

Indinavir is a frequent component of HAART. It plus two anti-reverse transcriptase drugs (AZT and 3TC) reduces HIV to such an extent that PCR cannot detect the virus in 85% of patients. Initial levels in the patients tested were 20,000 to 11,000,000 RNA copies per cu mm of blood (The threshold for detection by PCR is now in the area of 20 copies per ml). This suppression lasted several years in greater than 90% of patients. 

Indinavir should not be used by pediatric patients or pregnant women. Side effects include kidney stones and anemia.

WEB RESOURCES

INDINAVIR (Crixivan®)

Crixivan In Triple Therapy Kept HIV Below Detection In Most Patients After Three Years

Anti-HIV Combo Of Ziagen+Combivir Equivalent To Crixivan+Combivir At 24 Weeks


 

HIGHLY ACTIVE ANTI-RETROVIRAL THERAPY (HAART)

HAART consists of triple drug therapy. Usually, two nucleoside reverse transcriptase inhibitors are combined with one non-nucleoside reverse transcriptase inhibitor or with one protease inhibitor. For example, one such HAART cocktail consists of zidovudine (AZT) , lamivudine (3TC), both nucleoside analog reverse transcriptase inhibitors, and Indinavir, a protease inhibitor. Another triple drug combination consists of two nucleoside analog reverse transcriptase inhibitors (tenofovir, (R)-9-(2-Phosphonylmethoxypropyl)adenine) and emtricitabine (2',3'-Dideoxy-5-fluoro-3'-thiacytidine) plus the non-nucleoside inhibitors of reverse transcriptase, Efavirenz (Sustiva).

The levels of HIV in HAART-treated patients fall to below those in the blood of long term non-progressors who have remained clinically stable and shown no loss of T4 cells for over a decade. It was hoped that HAART treatment might lead to the possibility of purging the patient of the virus as infected cells eventually died. (This would have to occur in the absence of reinfection by released virus particles which would be the case if cells only harbored the proviral form of HIV). It is now known that latent, persistently infected CD4+ cells remain in the body for long periods. These cells contain the proviral form of the virus but can reinitiate synthesis of viral particles when reactivated on contact with antigen.
 

Could HAART be a cure for HIV infection?

It was formerly the practice to add one additional drug to the treatment as the patient deteriorated. However, this will result in selection of resistant virus and preclude the benefits of combination therapy. If eradication becomes possible, aggressive early treatment is indicated.

Although the use of the HAART regimen of drugs can lead to undetectable levels of HIV in the bloodstream, there may still be HIV in genital secretions. Thus these persons are still infective. Recently, patients have been appearing who have clearly been  infected by a person who harbors protease inhibitor-resistant virus. This means that patients on the  HAART regimen are again having unprotected sex with their partners.

 

Continued impact of HAART on AIDS mortality
in some Western European countries: 1998–2002.
Source: HIV/AIDS surveillance in Europe (2002). End-of-year report. Data compiled by the European Centre for theEpidemiological Monitoring of AIDS.

At present these drugs must be taken three times a day, every day.. forever, unless they prove to eradicate the virus from the patient. When taken separately, they must be taken under different conditions (empty stomach or after food), making compliance a problem in some patients. Atripla is a combination of three drugs in one pill allowing the HAART regimen as one pill once a day. It contains two nucleoside reverse transcriptase inhibitors, Tenofovir and Emtrictabine ((−)-β-L-3′-thia-2′,3′-dideoxy-5-fluorocytidine) and the non-nucleoside reverse transcriptase inhibitor Efavirenz. It does not contain AZT.

Currently protease inhibitors cost about $7000 per year. The cost of zidovudine/lamivudine/protease inhibitor regimen is $12,000 per year. However, HAART is cost effectiveness  when compared to the cost of treating a sick AIDS patient. These drugs are, however, no answer to the worldwide AIDS epidemic. In 2001, Cipla, an Indian pharmaceutical company, offered HAART for US$350 per person per year

 

Guidelines for HAART treatment of treatment-naive patients

How much does HIV treatment cost and how long does the patient on HAART survive?


 

 
Approved Protease Inhibitors
Drug Brand Name
Saquinavir Fortonase
Saquinavir mesylate, SQV Invirase
Ritonavir, ABT-538 Norvir
lopinavir and Ritonavir Kaletra
Indinavir, IDV, MK-639 Crixivan
Nelfinavir mesylate, NFV Viracept
Amprenavir Agenerase
Fosamprenavir Calcium Lexiva
Tipranavir Aptivus
Atazanavir sulfate Reyataz
 
 


Side effects of HAART

Despite the spectacular results achieved using HAART, these combination therapies are not without side effects. The protease inhibitors, for example, can lead to abnormal redistribution of body fat, called lipodystrophy (40-60% of patients) which may be quite disfiguring. Lipodystrophy results in loss of sub-cutaneous fat. There is increased abdominal girth, enlargement of the dorsocervical fat pad ("buffalo hump"), enlargement of the breasts and fat accumulation around various organs (visceral fat). Some protease inhibitors also lead to red blood cell destruction (hemolytic anemia) and hemorrhaging.

More on lipodystrophy

 

 

OTHER ANTI-HIV DRUGS  

Although HAART combination therapy has proved highly effective in suppressing viral loads in infected patients, other avenues of treatment are being explored since HAART is not effective in all patients and because of the high costs of this drug combination. Moreover, virus strains that are resistant to HAART have emerged.

Drugs that target the initial attachment of HIV to the cell surface  

It would be clearly logical to target the receptors for HIV on the cell surface since this is the initial stage of infection and is also the rate-limiting step in infection. The first stage in entry is adhesion probably to a charged molecule such as heparan sulfate proteoglycan but it should be noted that the actual mechanism of initial attachment may depend on the cell type. Little progress has been made here.

 


Cyanovirin-N

Drugs that inhibit uptake of the virus  

The uptake of the virus involves the CD4 antigen, the receptor, and chemokine receptor co-receptors. Blocking the interaction of HIV gp120 with either of these could potentially inhibit infection. Antibodies or antibody derivatives that bind to either receptor or gp120 might be useful but none of these agents below can be taken orally. Similarly, receptor or receptor derivatives could act as decoys that bind to HIV gp120, thereby preventing binding to CD4 antigen or co-receptors on the cell surface.

Soluble CD4 
A preparation of the region of the CD4 molecule that binds to gp120, would clearly block attachment to CD4 on the cell surface and soluble CD4 blocks infection in culture. Unfortunately, it has little effect clinically. This may not be a practical approach since the protein gets broken down rapidly. In addition, it can exacerbate infectivity as it promotes binding of HIV to chemokine receptors. 

CD4-Ig2 (PRO542)
PRO 542 is a tetrameric form of soluble CD4 antigen genetically fused to an immunoglobulin. This CD4-immunoglobulin fusion protein comprises the D1 and D2 domains of human CD4 and the heavy and light chain constant regions of human IgG2. It has a high affinity for gp120.

CD4-PEG (Pseudomonas aeruginosa endotoxin A) 
This drug synergizes with AZT but may have too great a non-specific toxicity 

Antibodies that bind to CD4 antigen

Antibodies that bind to CD4 antigen are likely to block virus attachment but may be immunosuppressive because they will lead to depletion of CD4 cells. 

 

amd3100n.gif (6162 bytes) AMD3100   From NIAID

Agents that block interaction of gp120 with co-receptors

The involvement of co-receptors was discovered when some chemokines were shown to block infection. CCR5 is a co-receptor for HIV and CCR5 deletions make the infected patients resistant to HIV. Persons with this deletion appear normal and healthy. This suggested that targeting CCR5 might block HIV in patients without any severe effect on the immune system. RANTES is a chemokine that binds to CCR5 and a RANTES analog (n-nonanoyl (NNY)-RANTES) has been shown to block HIV infection without triggering any measurable intracellular signal from the receptor. However, although CCR5 co-receptor antagonists are effective in inhibiting non-syncytium-inducing HIV replication, they provide a selective pressure for the outgrowth of syncytium-inducing (X4) virus strains which are resistant to the RANTES analog and can use the CXCR4 co-receptor. Moreover, chemokine derivatives are proteins (or at least peptides) and so will not be orally available and will probably have short half lives in vivo. Monoclonal antibodies against the co-receptor might be better and work well to block infection in vitro but they will also not be available orally.

Maraviroc
Chemical name: 4,4-difluoro-N-{(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclohexanecarboxamide.
Maraviroc (brand-named Selzentry, or Celsentri outside the U.S.) was approved for use in HIV-infected patients in August 2007. It is a small molecule that blocks the interaction between CCR5 and HIV gp120. Because HIV can also use another co-receptor, CXCR4, an HIV tropism test is performed to determine if the drug will be effective. In a study comparing Maraviroc plus the conventional HAART triple combination of drugs with the standard of care HAART alone, use of HAART plus Maraviroc gave twice as many patients with HIV levels of fewer than 50 copies/ml compared to standard HAART.

AMD3100
Because of their charge, small molecule antagonists of the co-receptors have very low oral bioavailability but AMD3100 is undergoing clinical trials in which it is administered by injection. It appears to bind to CXCR4 (fusin) and block the interaction between CXCR4 and the V3 loop.

 

t22n.gif (4369 bytes) T20   From NIAID

Agents that block fusion by interacting with gp41

Fuzeon

Peptides derived from gp41 can inhibit infection, probably by blocking the interaction of gp41 with cell membrane proteins during fusion or by stopping the conformational change that results from the association of two gp41 molecules and which is necessary for fusion. T-20 (Fuzeon)  blocks this conformational change. In clinical trials, a nearly two log reduction in plasma viral levels was achieved. This drug was approved in 2003 but recent reports suggest low bioavailability and the emergence of resistant mutants.

There is a cavity in gp41 that could hold a small molecule inhibitor. Peptides containing D-amino acids that would fit this cavity have been identified and inhibit fusion

Approved Fusion Inhibitors

Drug

Brand Name

Enfuvirtide, EFV, T-20

Fuzeon

 

Cyanovirin
Cyanovirin-N (CV-N) is a protein from the cyanobacterium (blue-green algaa) Nostoc ellipsosporum and acts as an HIV fusion inhibitor with activity against both HIV-1 and HIV-2 in vitro and in animals.

 

 

 

Drugs that inhibit uncoating of the nucleocapsid  

The process of uncoating is not well understood but appears to involve a cell protein called cyclophilin A which appears to be needed for a productive infection by HIV. This cell protein is actually packaged in the viral capsid. However, in vitro studies show that mutants can evolve that no longer require cyclophilin A.


Isentress (Raltegravir)
 


L-chicoric acid


Dicaffeoylquinic acid

Drugs that inhibit integrase activity

Integration of the viral DNA into the host cell chromosome is essential for the production of new virus particles and this would be an excellent target for a specific anti-viral agent since there is no homologous enzyme in humans. A new class of anti-retroviral drugs targets the integration enzyme, the integrase.

Isentress  (Raltegravir, MK-0518)
Isentress was approved for use in adults by the USFDA in October, 2007. It can be used as part of a HAART regimen when the patient is resistant to other drugs such as protease inhibitors. It was comparable to Sustiva (standard of care) in HAART over a period of 24 weeks. More than 80 percent of those who took the drug showed a drop in the blood level of virus to barely detectable levels. It is not approved for HIV-infected children.

Zintevir (AR177)  is a 17-base oligonucleotide containing two deoxyguanosine quartets and was thought ot be an integrase inhibitor. It has undergone phase I and II clinical trials.

L-Chicoric acid prevents HIV-1 replication through the inhibition of HIV-1 integrase. 3,5-DCQA, a dicaffeoylquinic acid, isolated from Baccharis genistelloides, is also a potent inhibitor of the HIV-1 integrase and binds to the active site of the enzyme.
 

A note on Zintevir

Isentress integrase inhibitor

 

 

Drugs that block post-translational modifications  

The matrix protein is myristoylated and the surface glycoprotein is glycosylated. The addition of these post-translational modifications offers a potential target for drug therapy.

Blockers of myristoylation 
Analogs of myristic acid that block myristoyl coA:Myristoyl transferase such as 4-oxatetradecanoic acid are non-toxic and work well in culture. Clinical efficacy is unknown. 

Blockers of glycosylation

Castanospermine, a naturally occurring alkaloid and inhibitor of glucosidase-I has some effect against HIV in vitro. This has led to the development of analogs such as N-Butyl deoxynojirimycin(butyl-DNJ) and 6-butyl-castanospermine which have more potent activity against HIV

 

 

Nucleic acid based strategies  

Several possibilities are being investigated. These include:

  • Anti-sense RNAs that bind to HIV mRNAS and block their translation

  • Catalytic RNAs (ribozymes)

  • Oligonucleotides that target the nucleic acid-binding control proteins of HIV such as TAT and REV.

 However, all have delivery problems.

 

WEB RESOURCES

Links to other new chemotherapeutic approaches to treating HIV infection

HIV therapy tricks cell into suicide

Thiol-based reagents  

N-acetyl cysteine and procysteine can inactivate HIV in latently infected cells where they raise intracellular GSH. 1,2-dithiole-3-thiones raise GSH and also irreversibly inhibit reverse transcriptase. 

   
 

Return to the HIV lecture notes

Return to the Virology section of Microbiology and Immunology On-line

 

This page copyright 2008, The Board of Trustees of the University of South Carolina
This page last changed on Tuesday, May 05, 2009
Page maintained by
Richard Hunt

Please report any problems to
rhunt@uscmed.sc.edu
 


OTHER HIV SECTIONS

PART I HUMAN IMMUNODEFICIENCY VIRUS AND AIDS

PART II HIV AND AIDS, THE DISEASE

PART III COURSE OF THE DISEASE

PART IV PROGRESSION AND COFACTORS

PART V STATISTICS

PART VI  SUBTYPES AND CO-RECEPTORS

PART VII  COMPONENTS AND LIFE CYCLE OF HIV

PART VIII  LATENCY OF HIV

PART IX GENOME OF HIV

PART X  LOSS OF CD4 CELLS

PART XI  OTHER CELLS INFECTED BY HIV AND POPULATION POLYMORPHISM

APPENDIX I  ANTI-HIV VACCINES

APPENDIX II  DOES HIV CAUSE AIDS?

APPENDIX III  ANTI-HIV CHEMOTHERAPY