Vinayaka R. Prasad, Ph.D.

Research in our laboratory is focused on three areas of HIV: Biology, therapeutics and pathogenesis.

HIV Biology: We have a long-standing interest in in the early events of HIV-1 replication. In earlier work, we outlined the role of residues in the polymerase domain that determine the fidelity of DNA synthesis by RT. We are currently focused on cellular proteins that influence the viral reverse transcription process upon viral entry into a susceptible cell during 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. The most efficacious aptamers identified in our laboratory as well as combinations of them will then be tested in nonhuman primates (macaque). 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. We have shown that perturbing HIV-1 Gag and viral RNA interaction using anti-Gag aptamers can lead to downmodulation of viral RNA metabolism thus inhibiting virus production.

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-1_ADA) or clade C (HIV_Indie-C1) HIV-infected macrophages were injected intracranially into SCID mice. In cognitive tests, mice exposed to similar inputs of HIV_Indie-C1 made fewer memory errors than those exposed to HIV-1_ADA. Mice exposed to HIV-1_ADA 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-1_Indie-C1-infected macrophages recruited monocytes poorly in vitro compared to HIV-1_ADA-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.

In ongoing work, we are identifying the genetic basis underlying some subtype C countries showing high incidence of HAD. In addition, we are also interested in understanding the mechanisms underlying the damage to blood-brain barrier caused by exposure to HIV infected cell supernatants in vitro.