Highly active antiretroviral therapies (HAARTs) fail to eradicate the HIV-1 virus due to persistence of the virus in a long-lived pool of latently infected cells residing primarily in the resting memory CD4+ T-cells population, as well as monocyte-macrophages and hematopoietic progenitor cells. Eliminating the latent reservoir is particularly challenging since it is established early during infection and can be replenished during episodes of viremia or by homeostatic replacement of latently infected cells. Since intensification of antiviral regimens does not eradicate the latent pool from the infected host, there is a pressing need to develop entirely novel forms of therapy. One approach for attacking the latent reservoir is to induce transcription of the latent provirus while continuing treatment with antiviral drugs – a “shock and kill” strategy.
My research is concerned with both identifying new factors regulating HIV latency and defining the mechanism of action of drugs that induce latent proviruses. We have conducted detailed studies of the FDA-approved drug disulfiram, which was originally identified by the Siliciano laboratory as an inducer of latent HIV proviruses. We have shown that disulfiram is a potent activator of HIV in monocytic cells, but less efficient in T-cells. The drug appears to work primarily through activation of PKC-delta, which in turn leads to activation of NF-kB. In addition we will be looking at drug candidates identified in large screens conducted at Merck. We have found that none of the available drugs, alone or in combination, can re-activate the latent pool completely. This may be due to multiple restrictions imposed on latent proviruses that need to be overcome which suggest that proviral reactivation may not be achieved when only a single reactivation step is targeted, but will require both activation of the Tat-cofactor P-TEFb and removal- of epigenetic blocks leading to HIV silencing.
Unbiased identification of the positive and negative cellular regulatory factors controlling HIV latency is an important step for the identification of potential targets for therapeutic approaches. I am using genome-wide shRNA screens, based on next generation sequencing, to identify and validate the set of cellular gene products that are required to maintain HIV latency and/or play an essential role in HIV transcription. Our initial screens have shown that the polycomb silencing complex plays a central role in maintaining HIV latency. These screens will lay the groundwork for subsequent studies aimed at elucidated the mechanism of action of the most important of these cellular cofactors for HIV.
Das B, Young D, Vasanji A, Gupta S, Sarkar S, Sen S. (2010) Influence of p53 in the transition of myotrophin-induced cardiac hypertrophy to heart failure. Cardiovascular Research., 87(3):524-534.
Gupta A, Gupta S, Young D, Das B, McMahon J and Sen S. (2010) Impairment of ultrastructure and cytoskeleton during progression of cardiac hypertrophy to heart failure. Laboratory Investigation, 90(4):520-530.
Das B, Gupta S, Vasanji A, Xu Z, Misra S and Sen S. (2008). Nuclear co-translocation of myotrophin and p65 stimulates myocyte growth: regulation by myotrophin hairpin loops. J. Biol. Chem., 283(41): 27947-56.
Reddy KB, Fox JEB, Price MG, Kulkarni S, Gupta S, Das B and Smith DM. (2008). Nuclear Localization of Myomesin-1: possible functions. J. Muscle. Res. Cell. Motil., 29: 1-8.
Gupta S, Das B and Sen S. (2007). Cardiac hypertrophy: Mechanisms and Therapeutic opportunities. Antioxidant and Redox Signaling, 9(6): 623-652.
Das B, Roy S, Gangopadhyay G, Poddar R and Saha PK. (2006) Testa ultrastructures, water uptake pattern and seed germination of some medicinally important plants of Fabaceae. J. Bot. Soc. Bengal., 60(1): 50-64.