Correlates of HIV-Associated Immune Response Modulation (CHARM)
Heads: Guido Poli and Paola Cinque
After the discovery of HIV as the cause of AIDS (1983-1984), CD4 was soon identified as the primary receptor utilized by the virus to infect T lymphocytes and mononuclear phagocytes. However, 10 years passed before the identification of the second co-receptor required for viral entry in the molecule known as CCR5. Genetic variants of CCR5 include a deletion of 32 base pairs leading to misfolding of the protein and lack of surface expression. Individuals who are homozygotes for such a mutation are naturally resistant to HIV-1 infection, whereas heterozygotes are frequently “long-term nonprogressors”, thus underscoring the importance of this receptor in the natural history of HIV-1 infection. CCR5 binds to 3 natural CC chemokines and these observations have led to the rapid discovery of small molecules antagonizing HIV infection at the entry step. CCR5 antagonists are indeed the first drugs approved for the therapy of HIV infection that are targeting a host rather than a viral protein. The specific clinical use of CCR5 antagonists in the context of potent cART targeting both the viral reverse transcriptase (RT) or protease, might be significantly enhanced by their potential “immunomodulatory/anti-inflammatory” effect resulting from the interference with the chemokine receptor. If proven, this activity could be exploited in other conditions where reduction of the inflammatory cellular influx by interference with CCR5 could be desirable.
General goals of CHARM are the investigation and exploitation of the role of CCR5 and its natural or chemical ligands in HIV infection and in infection-related inflammation. The program stems from the recognition of a critical mass of basic and applied investigators already ongoing in this Division and in the Department of Infectious and Tropical Diseases on the role of CCR5 and its ligands in HIV infection and related clinical entities. The projects and their individual leaders have already proven their validity and vitality in terms of dedicated scientific publications, grants and patents. However, they have never been coordinated as an internal network or program up to date. Therefore, CHARM has the general goal to create and foster such a network of knowledge and mutual exchange of information, and collaborations by promoting their synergy, avoid duplicating efforts, and seeking for additional funding and support both to individual projects and, hopefully, to the Program as a whole.
Main achievements (updated 2012)
Implementation of CHARM during the least year has been made possible by the awarding of individual grants to CHARM participants for projects related to CCR5, including new grants from the National AIDS Program (2010-2011) and other source (NIH-Lombardy Region).
The following clinical trials are currently being performed as part of CHARM:
- VEMAN: Maraviroc/PI in ART-naive patients (phase II);
- MAIN: Maraviroc/ART in primary HIV-1 infection (phase II);
- MOTIVATE1: Maraviroc/OBT in experienced patients (continuation of registrative trial);
- MERIT: Maraviroc/Combivir in naive patients (continuation of registrative trial);
- POEM: Maraviroc in ART-experienced patients (observational).