Human tissues, where critical events of HIV disease occur, are not sterile. Unlike cell cultures used in the laboratories, human tissues are coinfected with other microbes, in particular viruses which interact with HIV-1 and affect HIV infection. Exploiting them may reveal new anti-HIV strategies. Towards this goal, we study HIV interactions with human herpesvirus (HHV) in coinfected human lymphoid, rectal, and cervico-vaginal tissues ex vivo. We infected tissues ex vivo with HIV and various HHVs, including highly pathogenic HSV-2 and low pathogenic HHV-6 and HHV-7, and found that in coinfected tissues these viruses interact with each other.
Moreover, it is possible to establish a new mode of HIV-1 interaction with HHVs by administrating acyclovir, a common antiherpetic drug. This drug, upon phosphorylation, inhibits both HHV and HHV-1, suppressing HIV reverse transcriptase (RT). We developed monophosphorylated acyclovir derivatives that do not require activation by HHVs and inhibit HIV-1 in HHV-free systems. Activated acyclovir and its monophosphorylated derivatives suppress replication of both R5 and X4 HIV-1 variants, including variants that are resistant to other NTRIs. Although an ACV-resistant HIV variant with a dominant V751 RT mutation has been identified in ex vivo tissues, there is no evidence that this mutation evolves in HIV-infected patients treated with acyclovir.
Interactions between HIV and other viruses, particularly HHVs, largely determine the course of HIV disease and can be exploited and mimicked to develop new anti-HIV-1 strategies.