At the IAS conference last July, Victor Garcia described results obtained in the humanized mouse model with a strategy that targets HIV-infected cells for elimination. The study was published in PLoS Pathogens last week, drawing considerable media coverage. The strategy involves the use of an “immunotoxin” – a combination of an antibody fragment that recognizes a relatively conserved part of the HIV-1 envelope protein and a cell-killing toxin derived from Pseudomonas bacteria. Prior studies have shown that the immunotoxin is capable of recognizing and killing HIV-infected cells in a lab dish. Garcia’s study demonstrated that the addition of the immunotoxin to antiretroviral therapy (ART) led to more extensive depletion of HIV-infected cells in multiple tissues in humanized mice compared to ART alone (over about two months of follow-up).
The researchers conclude that the results provide proof-of-concept that targeted killing of HIV-infected cells is possible. Although the approach cannot target latently HIV-infected cells because these cells are not producing the viral envelope protein, they note that it should be possible to combine immunotoxins with compounds that aim to induce latent HIV to express viral proteins. The news stories about the paper have mostly been diligent about including this key caveat, which is gratifying. Last year there were many news stories about a similar approach developed by Ekaterina Dadachova that uses targeted radiation to deal the deathblow to infected cells (also using an antibody to the HIV envelope protein for the targeting), but in that case it was often misleadingly implied that this could be curative and the caveat about latently infected cells was rarely mentioned.
In terms of translating their strategy for human use, the researchers point out that combinations of different targeted immunotoxins will likely be needed because there is the potential for immune responses to develop against each individual construct, thereby curtailing its activity. HIV is also likely to develop resistance to any single immunotoxin. Another possiblity is combining immunotoxins with other complementary approaches, such as Dadachova’s radioimmunotherapy or conjugates of HIV-specific antibodies and cytotoxic drugs. While efforts to activate latent HIV are still in their infancy, it is encouraging to know that there are many candidates for delivering the coup de grace to infected cells should these efforts ultimately prove successful.
PLoS Pathog. 2014 Jan;10(1):e1003872. doi: 10.1371/journal.ppat.1003872. Epub 2014 Jan 9.
Denton PW, Long JM, Wietgrefe SW, Sykes C, Spagnuolo RA, Snyder OD, Perkey K, Archin NM, Choudhary SK, Yang K, Hudgens MG, Pastan I, Haase AT, Kashuba AD, Berger EA, Margolis DM, Garcia JV.
Antiretroviral therapy (ART) can reduce HIV levels in plasma to undetectable levels, but rather little is known about the effects of ART outside of the peripheral blood regarding persistent virus production in tissue reservoirs. Understanding the dynamics of ART-induced reductions in viral RNA (vRNA) levels throughout the body is important for the development of strategies to eradicate infectious HIV from patients. Essential to a successful eradication therapy is a component capable of killing persisting HIV infected cells during ART. Therefore, we determined the in vivo efficacy of a targeted cytotoxic therapy to kill infected cells that persist despite long-term ART. For this purpose, we first characterized the impact of ART on HIV RNA levels in multiple organs of bone marrow-liver-thymus (BLT) humanized mice and found that antiretroviral drug penetration and activity was sufficient to reduce, but not eliminate, HIV production in each tissue tested. For targeted cytotoxic killing of these persistent vRNA(+) cells, we treated BLT mice undergoing ART with an HIV-specific immunotoxin. We found that compared to ART alone, this agent profoundly depleted productively infected cells systemically. These results offer proof-of-concept that targeted cytotoxic therapies can be effective components of HIV eradication strategies.