Herpes drug has direct anti-HIV effect, could offer cheap addition to antiretroviral therapy for developing world

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Aciclovir, a drug commonly used in the treatment of genital herpes, also suppresses HIV activity in cells already infected with herpes viruses, researchers from the US National Institutes of Health report in the journal Cell Host and Microbe.

The findings may partially explain the effect of anti-herpes treatment on HIV shedding in people infected with HIV, and could also point the way to a new type of nucleoside analogue reverse transcriptase inhibitor (NRTI) based on aciclovir, they say.

HSV-2, the virus that causes genital herpes, has been shown to increase HIV replication and to increase the risk of HIV transmission to sexual partners of those who are infected with both viruses. Even where genital herpes lesions are not present, HSV-2 may cause micro-lesions that are associated with increased shedding of both HSV-2 and HIV in people with HIV infection.

Glossary

replication

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

herpes simplex virus (HSV)

A viral infection which may cause sores around the mouth or genitals.

first-line therapy

The regimen used when starting treatment for the first time.

herpes viruses

Family of viruses which can cause disease in advanced HIV infection, e.g. cytomegalovirus, varicella-zoster, herpes simplex and Epstein-Barr virus.

shedding

Viral shedding refers to the expulsion and release of virus progeny (offspring such as competent particles, virions, etc.) following replication. In HIV this process occurs in the semen, the vaginal secretions and other bodily fluids, making those fluids more infectious.

Aciclovir and its pro-drug valaciclovir have been tested in a number of studies to determine their effect on HIV shedding in genital fluids in people coinfected with HIV and HSV-2. The studies have produced contradictory results:

In all cases, study investigators have assumed that aciclovir or valaciclovir reduce HIV levels in genital fluids and blood by suppressing HSV-2 replication, leading to less activation of HIV replication.

However, in the study published this week, researchers from the US National Institutes of Health and Emory University, Atlanta, found that aciclovir only reduces HIV activity in cells infected with herpes viruses.

Using small blocks of human tonsil tissue in the laboratory and cell cultures, the researchers found that even when HSV-2 was not present, aciclovir reduced HIV replication substantially in the tissues. But in sterile cell lines, aciclovir had no effect on HIV replication.

Examination of the tissues showed that they were infected with a range of human herpes viruses (HHV-4,-5,-6 and -7), with HHV-6 present in 96% of cases (HHV-6 is present in most adults and is usually acquired in childhood). In sterile tissue where HHV-6 was not present, aciclovir did not suppress HIV replication.

"HHV has a unique ability to phosphorylate aciclovir to activate it, making the drug quite specific for HHV and, for the same reason, relatively non-active against other viruses, including HIV," said senior study author Dr. Leonid Margolis from the National Institutes of Health.

By altering the way in which a version of aciclovir called a pro-drug was processed, the researchers found they could bypass the need for the phosphorylation of aciclovir by herpes viruses, but still suppress HIV in cells.

"This discovery by our research team that activated aciclovir can suppress HIV paves the way for additional research on the possible uses of this drug and holds promise for the development of new treatments, combining aciclovir with other antiretroviral therapies," said Dr Raymond Schinazi, professor of paediatrics at Emory University School of Medicine, a co-author of the study.

In the early 1990s there was considerable interest in the use of aciclovir in combination with AZT, based on the observation of improved survival in cohort analysis, but further investigation of aciclovir was superceded by the arrival of combination antiretroviral therapy in 1994.

The researchers also observed that a strain of HIV that is highly resistant to AZT remained fully sensitive to aciclovir. This observation is likely to encourage further investigation into antiretroviral drugs based on aciclovir, since high-level resistance to AZT may potentially reduce the effectiveness of all drugs in the nucleoside analogue class.

However they also observed that resistance to 3TC resulted in a fourfold loss of sensitivity to aciclovir.

“Exceptionally low toxicity and the low cost of aciclovir and related drugs that have been safely used in humans for more than 30 years…make them potentially applicable for HIV treatment, possibly in combination with other drugs,” the investigators conclude.

The investigators say that further studies will be needed to determine whether aciclovir itself is a useful antiretroviral drug, and whether the drug concentrations used in this study can be replicated using aciclovir or valaciclovir in humans. Aciclovir activity, for example, was found to be directly proportional to HHV-6 viral load in the tissue studied. In immunocompetent humans HHV-6 replication is largely restricted to the intestines and the vagina.

The contradictory results of the studies outlined above suggest that there is still a lot to learn about the potential antiretroviral properties of aciclovir before it could even enter large randomised studies.

Investigation of aciclovir or valaciclovir for use in second-line therapy in the developing world could be of particular importance, since a cheap drug that is active against viruses resistant to AZT or d4T could be needed by millions of people currently taking first-line therapy if that regimen fails to control viral replication (first-line therapy based on AZT or d4T has been associated with high-level resistance to most nucleoside analogues in around 30 to 50% of people failing treatment, according to diverse reports from Asia and Africa). However, the reduction in HIV sensitivity to aciclovir caused by 3TC resistance could be problematic, and may require the testing of considerably higher doses of aciclovir and valaciclovir than those currently in use to prove effectiveness in second-line treatment.

References

Lisco A et al. Acyclovir is activated into HIV-1 reverse transcriptase inhibitor in herpesvirus-infected human tissues. Cell Host & Microbe 4: 1-11, 2008.