Professor, Department of Microbiology & Immunology
Research in our laboratory is focused on three areas of HIV/AIDS: replication mechanisms, therapeutics and pathogenesis.
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 associated Dementia: The severe form of 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 such as 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 clade C Tat lacks the chemokine function of Clade B Tat that plays a crucial role in the increased brain infiltration of monocytic phagocytes in HAD. We study neuropathogenesis induced by the two HIV-1 clades using SCID mouse HIV encephalitis (SCID-HIVE) model, where it has been shown that introduction of clade B HIV into SCID mouse brain recapitulates the key features of the human HAD disease. We found that, 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.
Recent reports challenged the notion that clade C HIV-1 causes lower incidence of HAD by showing that South Africa and Botswana have a higher incidence of HAD (25-38%). Therefore, we examined whether Southern African HIV-1C is genetically distinct and investigated its neurovirulence. We focused our study on the variations seen in tat gene and its contribution to HIV associated neuropathogenesis. A phylogenetic analysis of tat sequences of Southern African HIV isolates with those from the geographically distant Southeast Asian (India and Bangladesh) isolates revealed that Southern African tat sequences are distinct from Southeast Asian isolates. The proportion of HIV − 1C variants with an intact dicysteine motif in Tat protein (C30C31) was significantly higher in the Southern African countries (20-25%) compared to Southeast Asia (2-3%) and broadly paralleled the incidence of HAD in these countries respectively. Neuropathogenic potential of a Southern African HIV-1C isolate (from Zambia; HIV-1C1084i), a HIV-1C isolate (HIV-1IndieC1) from Southeast Asia and a HIV-1B isolate (HIV-1ADA) from the US were tested using in vitro assays to measure neurovirulence and a SCID mouse HIV encephalitis model to measure cognitive deficits. In vitro assays revealed that the Southern African isolate, HIV-1C1084i exhibited increased monocyte chemotaxis and greater neurotoxicity compared to Southeast Asian HIV-1C. In neurocognitive tests, SCID mice injected with MDM infected with Southern African HIV-1C1084i showed greater cognitive dysfunction similar to HIV-1B but much higher than those exposed to Southeast Asian HIV − 1C.
Our results 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.
HIV-1 Replication Mechanisms
RNA aptamers targeted to HIV-1
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