Professor, Department of Microbiology & Immunology
Research in our laboratory is focused on three areas of HIV/AIDS: HIV associated neurocognitive disorders (HAND), HIV replication mechanisms and RNA aptamers targeted to HIV.
HIV associated Neurocognitive Disorders (HAND): The severe form of HAND, the HIV associated dementia (HAD), is common among clade-B HIV-infected individuals in the US, but less common among individuals infected with clade-C HIV-1 in India, suggesting that there are clade-specific differences in neuropathogenicity. Understanding clade-specific determinants of neuropathogenesis may shed light on the disease mechanism and help develop targeted drugs for HAD. We previously showed that due to a C31S polymorphism, clade C Tat lacks the chemokine function of Clade B Tat that plays a crucial role in an increased brain infiltration of monocytic phagocytes in HAD. We studied neuropathogenesis induced by these two HIV-1 clades using SCID mouse HIV encephalitis (SCID-HIVE) model and reported that while the introduction of clade B HIV-1ADA into SCID mouse brain recapitulates the key features of human HAD disease, mice exposed to similar inputs of HIVIndie-C1 (clade C) made fewer memory errors than those exposed to HIV-1ADA (clade B). HIV-1ADA also caused greater astrogliosis and loss of neuronal network integrity.
We have more recently generated evidence that clade C HIV-1 isolates in different geographic regions can differ from each other in their neuropathogenic potential. We hypothesize that such variation is due to polymorphism in the neuropathogenesis determinants in Tat or gp120, the two major neurotoxicity determinants of HAND. With respect to Tat, we observed that the percentage of HIV isolates with dicysteine motif in Tat is 2-3% on the Indian subcontinent while in the Southern African countries, they ranged from 19-26%. These data broadly correlate with the HAD frequencies reported from India, South Africa and Botswana (3-4%, 25% and 38% respectively). This finding has been corroborated using a Zambian HIV-1C isolate that displays a C31 residue and thus an intact dicysteine motif. Our in vitro and SCID-HIVE results clearly indicate that Tat dicysteine motif determines neurovirulence. If confirmed in population studies, it may be possible to predict neurocognitive outcomes of individuals infected with HIV-1C by genotyping Tat.
In addition to Tat, our more recent findings indicate that gp120 can also display region-specific differences. For example, the Southern African HIV isolates appear to contain more robust neurovirulence determinants than those in the Indian isolates. Thus, two different viral genes in India appear to show determinants of low neurotoxicity.
HIV Replication Mechanisms: We have a long-standing interest in elucidating the mechanistic basis of key steps in HIV-1 replication. In earlier work, we delineated the determinants of fidelity of DNA synthesis by RT. We are currently focused on the interaction between the cellular factors and viral proteins that are crucial for HIV-1 replication.
RNA aptamers targeting HIV: For over a decade, we are developing and testing the efficacy of novel, anti-HIV-1 RNA aptamers to inhibit HIV-1 replication in cell culture. Aptamers are sequences isolated by the iterative process of SELEX and are highly specific to their targets. The most efficacious aptamers identified in our laboratory as well as combinations of them could be tested in nonhuman primates (macaques). We will introduce such aptamers into hematopoeitic stem cells, which will then be used in bone marrow transplantation followed by challenge with chimeric, pathogenic SHIVs. In earlier work, we have done considerable amount of work on anti-RT aptamers. We have now generated new aptamers to other viral targets including structural, catalytic and accessory proteins of HIV (Gag, Protease and Nef). Perturbation of HIV-1 Gag and viral RNA interaction using anti-Gag aptamers has provided new insights showing that preventing Gag-RNA binding causes down-modulation of viral RNA thus inhibiting virus production. We are currently characterizing the Nef aptamers to understand the specific Nef functions in HIV replication that are affected by each aptamer.
HIV-1 Replication Mechanisms
RNA aptamers targeted to HIV-1
11. Ramalingam, D, Duclair, S., Datta, S., Ellington, A.D., Rein, A. and Prasad, V. R. (2010) RNA aptamers directed to HIV-1 Gag bind to the matrix and nucleocapsid domains and inhibit virus production. J. Virol. 85:305-314.
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Albert Einstein College of Medicine
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