TAG to NIAID: Recommendations to Stimulate Research on HIV Persistence
Treatment Action Group’s response to the National Institute of Immunology and Infectious Diseases (NIAID) request for comments on the development of a research funding opportunity on HIV latency and persistence.
Treatment Action Group (TAG) strongly supports reinvigorating the research effort to cure HIV infection. As total eradication of HIV from the body would be essentially impossible to prove, at least with the current tools available, we believe that cure should be defined as the long-term absence of detectable HIV replication without the need for ongoing treatment. TAG encourages NIAID to request proposals for conducting goal-oriented, multidisciplinary research that aims to definitively answer key outstanding questions facing scientists attempting to maximize the chance for elimination of HIV from the human body.
It is possible to envision mutually complementary roles being played by academia, the private sector, and the government in this area of research. Academia has generated a number of lines of investigation and continues to do so, while pharmaceutical companies have the appropriate resources to screen compounds when investigators identify potential targets. The government needs to examine the process for approving translational research in humans, as the current process has been blamed for slowing clinical testing of promising leads and inhibiting progress in the field.
TAG is seriously concerned about the need to increase the funding available for the traditional, investigator-initiated (RO1) grant program. This mechanism has a rich history of supporting innovative, breakthrough research and—at least from the perspective of an organization outside of the NIH—it is disheartening to see large sums of money being used to support directed, multicenter research projects at the same time that young investigators are leaving the field due to ever-diminishing RO1 funding. It is vital that study sections responsible for reviewing RO1s be up to date on the importance and current status of research aiming to cure HIV infection, as increasing funding would be a Pyrrhic victory in the absence of mechanisms that can ensure that grant submissions in this area are appropriately reviewed and prioritized.
In terms of specific issues in the field, TAG previously noted the problems associated with relying excessively on highly artificial cell line models (“pristine, beautiful, irrelevant systems,” as they have been described), and this remains a significant problem in studies of HIV latency and persistence. The NIH should explicitly encourage the development of models involving primary human CD4 T cells (and other cells that support HIV infection) in order to recapitulate in vivo cell behavior as closely as possible. Another immediate priority should be ensuring that key assays and techniques are standardized in order to ensure that research results can be compared. Examples include assays for the measurement of integrated HIV proviral DNA and techniques for measuring HIV DNA and RNA in tissues. Imaging studies of CD4 T cells, antigenpresenting cells, and human host tissue dynamics in vivo are also a promising and underfunded research area of interest.
Animal models can play an important role in the study of HIV persistence, but NIAID should request that they be used strategically to address the specific questions for which they are best suited. For example, the current simian immunodeficiency virus (SIV) model is not ideal for studying antiretroviral therapy (ART), but can shed light on issues such as the in vivo tissue distribution of virus-infected cells. Priority should also be given to evaluating candidate simian/HIV hybrid viruses (SHIVs), such as those containing HIV reverse transcriptase, which may allow investigators to model suppressive ART in macaques. It would be an enormous benefit to the field if an appropriate SHIV could be developed and made available as a reagent.
Perhaps the holy grail of persistence research is the identification of unique markers that might allow cells containing transcriptionally silent HIV provirus to be identified and targeted. The search for such markers needs to be part of the research effort toward a cure, and comprehensive analyses of gene expression, protein production, and signaling pathways in latently infected versus uninfected cells are needed. Investigators in the burgeoning field of systems biology might be able to provide insights and should be considered for inclusion in multidisciplinary efforts to address HIV persistence.
Since several studies of treatment intensification are ongoing through both investigator-initiated efforts and the AIDS Clinical Trials Group (ACTG), the question of whether traditional ART can reduce HIV reservoirs is therefore being addressed and does not require an additional mechanism of support.