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Research in Dr. Prasad's laboratory is focused on three areas of HIV: Biology, therapeutics and pathogenesis:
HIV Biology: Our long-standing interest in HIV lies in the early events of HIV-1 replication. However, recently we have expanded investigations into other aspects of HIV replication including assembly and exit. Our main interests are in the structure-function of HIV-1 reverse transcriptase. Our recent work has outlined the role of a critical residue (K65) in the polymerase domain that increases the propensity of HIV-1 RT to make errors during DNA synthesis. We are also interested in understanding the role of functional interactions of HIV-1 RT with other viral proteins such as Integrase. Efforts are also under way to delineate the role of cellular proteins with a view to generating a better picture of the overall intracellular setting in which reverse transcription proceeds upon infection.
Aptamer therapeutics: 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 that are highly specific to their targets. We have shown that anti-HIV-1 RT aptamers, when expressed in human cells, prevent the infection of HIV-1 even at very high inputs of virus. These aptamers could also inhibit several clades of HIV-1 tested and drug resistant forms of clade B HIV-1, the most prevalent virus in the US. Efficacious aptamers thus identified in our laboratory will then 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 addition to published reports on anti-RT aptamers, we have now generated new aptamers to other viral targets including structural, catalytic and accessory proteins of HIV.
HIV associated Dementia: The severe form of HIV associated dementia (HAD) is common among clade-B HIV-infected individuals in the US and Western Europe, 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. Therefore, we are investigating neuropathogenesis induced by the two HIV-1 clades using SCID mouse HIV encephalitis model. It has previously been shown that introduction of clade B HIV into SCID mouse brain recapitulates the key features of the human HAD disease. In our studies, clade B (HIV-1ADA) or clade C (HIVIndie-C1) HIV-infected macrophages were injected intracranially into SCID mice. In cognitive tests, mice exposed to similar inputs of HIVIndie-C1 made fewer memory errors than those exposed to HIV-1ADA. Mice exposed to HIV-1ADA exhibited greater astrogliosis and loss of neuronal network integrity. In vitro differences were noted in another key characteristic of HIV-1 that influences HAD, the increased monocyte recruitment. HIV-1Indie-C1-infected macrophages recruited monocytes poorly in vitro compared to HIV-1ADA-infected macrophages. Monocyte recruitment was HIV-1 Tat-dependent. These results are in agreement with our striking observation previously that the Tat protein from clade C HIV-1 is a defective chemokine. This is the first demonstration, since HIV neuropathogenesis was first recognized, that genetic differences in different HIV-1 clades can affect disease severity. We are currently examining other clades as well as exploiting clade differences to identify viral determinants of HAD.