Acyclovir: a new use for an old drug.
OBJECTIVE
Epidemiological studies have demonstrated that HIV-1 and herpes simplex virus-2 (HSV-2) are responsible for two epidemics and that, by overlapping in risk populations, they reinforce the spreading of both HIV-1 disease and genital herpes. Randomized controlled trials have investigated whether acyclovir (ACV), a synthetic drug designed to suppress herpes viruses, might provide an inexpensive and safe way to drastically reduce HIV-1 spreading around the world. The controversial results of these trials are reviewed below in light of the recent discovery of the direct suppression of HIV-1 by ACV.


RESULTS
Recent studies have shown that although ACV therapy does not prevent HIV-1 transmission, it decreases plasma, genital, rectal, and seminal HIV-1 RNA levels. The decrease of HIV-1 load has been believed to be the result of an indirect mechanism and explained by reduction of HSV-2-mediated inflammation. The discovery of the direct inhibitory activity of ACV on HIV-1 reverse transcriptase brings new insights into the interpretation of these results. Also, it is important to understand why HSV-2-suppressive therapy with ACV did not reduce HIV-1 acquisition/transmission.


CONCLUSIONS
The direct suppression of HIV-1 by ACV activated by coinfecting HSV-2 may in part explain the ACV-induced decrease of HIV load reported in several clinical trials. If this is the case, other herpes viruses capable of ACV activation may contribute to this effect. New basic studies and new targeted clinical trials are needed to understand whether ACV therapy can also be beneficial for HSV-2-negative patients. These studies will show whether ACV therapy should be included in HIV-1 treatment as well as whether ACV-based drugs specifically targeting HIV-1 can be developed.
Vanpouille
Christophe
C
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Lisco
Andrea
A
Margolis
Leonid
L
D000212:Acyclovir / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy* / Q000635:transmission; D054303:HIV Reverse Transcriptase / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006561:Herpes Simplex / Q000188:drug therapy; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D019562:Viral Load / Q000187:drug effects
D000998:Antiviral Agents; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D000212:Acyclovir