Krishna K. Murthy 

Scientist | Virology and Immunology and SNPRC
Phone: 210-258-9400

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Research Focus

“A major focus of our laboratory is to identify immune correlates of protection against infectious agents that cause acute or chronic diseases in humans, in order to develop better vaccines”

Exposure to infectious viral agents results in the stimulation of our immune system that responds vigorously to contain both the replication and dissemination of the virus from the portal of entry. The protective responses include both innate and adaptive arms of the immune system and our focus is on the adaptive immune responses that are elicited in response to infection or vaccination. Adaptive immune responses are primarily mediated by antibodies (neutralizing, ADCC, ACC) specific to viral antigens, and T cells
specific to immunodominant epitopes present on viral proteins. T cell responses include proliferative, cytotoxic, and production of various cytokines and chemokines that are required for further amplification of inflammatory and immune responses. Therefore, as one can see, eliciting a protective immune response to an infectious agent is a very complex biological phenomenon. It is dependent upon the inclusion of appropriate viral proteins/antigens in adequate concentration, with a suitable adjuvant to enhance the immunogenicity of the vaccine candidate. In addition, various prime and booster strategies should be considered to elicit a robust and long lasting immunity.

For the past several years, my team has been involved in designing and developing vaccines for prevention of infection with RSV, HIV, and HCV that cause disease in humans. Induction of broadly cross-reactive neutralizing antibodies, in high titers   against HIV has been difficult to achieve with the vaccine strategies tested so far. To overcome this bottle neck, we have taken an “outside the box” approach in designing and developing a novel vaccine strategy for prevention of infection with HIV. Under optimal experimental conditions, both passively administered or actively induced antibodies do prevent infection with HIV. Those studies have resulted in the identification of a monoclonal antibody that block the HIV- receptor complex on CD4+ target cells and prevent infection with HIV both in vitro and in vivo. Additional studies have led to the identification of conserved binding site of the antibodies in the receptor complex, its amino acid composition, and creation of synthetic peptide vaccines. In preliminary animal studies, the synthetic peptide vaccine has been shown to induce antibodies with similar biological activity as that of the monoclonal antibody. This vaccine approach is undergoing additional safety and immunogenicity studies in nonhuman primates to obtain permission from FDA for human trials. This approach is rather unconventional in the sense that all conventional vaccines target a viral protein or antigens whereas, our approach targets conserved sequences in the viral receptor complex on the target cell that is required by all genetic variants of HIV to establish infection.
Another novel vaccine strategy that we are pursuing is the use of an envelope protein from a virus known as GBV-C and unrelated to HIV, as a vaccine to induce both antibody and T cells responses to prevent infection with HIV. GBV-C is prevalent in approximately 1% of blood donor in the US and does not cause any disease in humans. In fact, retrospective studies have shown that co-exposure to both GBV-C and HIV results in protection of CD4 cell numbers, delayed progression to disease, and decreased mortality due to AIDS. Additional in vitro studies show that the protection is mediated by antibodies specific to the envelope protein of GBV-C. Such antibodies neutralize infection by genetic variants of HIV suggesting that the protection mediated by them is quite broad. Plans are underway to test this novel vaccine strategy in nonhuman primate models.

Hepatitis C virus (HCV) is a major cause of liver disease worldwide and approximately 200 million persons are chronically infected globally. Along with our collaborators at NIH, we are investigating a virus like particle (VLP) based vaccine for the prevention of infection. Our HCV-VLP construct contains E1, E2, and Core, the three structural genes of HCV and induced both antibody and T cell responses in mice and baboons. To test the efficacy of this vaccine, chimpanzees were immunized with four doses of the vaccine and then challenged with infectious HCV. All the vaccinated animals exhibited very transient and low level infection that was rapidly cleared. In contrast, all three control animals became infected with two of them developing persistent viremia and chronic infection. Although the vaccine strategy did not prevent infection all vaccinated animals were able to rapidly clear the infection. We are in the process of redesigning the VLP to include non-structural (NS) genes of HCV to enhance the immunogenicity as well as to enhance its potency that is likely to prevent infection.

Evaluation of potential immune response and in vivo survival of riboflavin-ultraviolet light-treated red blood cells in baboons.
Goodrich, R.P., Murthy, K.K., Doane, S.K., Fitzpatrick, C.N., Morrow, L.S., Arndt, P.A., Reddy, H.L., Buytaert-Hoefen, K.A., Garratty, G.
Transfusion 49 (1): 64-74, 2009
PubMed ID: 18954398

Nonhuman primate models for HIV/AIDS: An overview. In Research Issues in HIV and AIDS, The 7th Sir Dorabji Tata Symposium.
Murthy, K.K.
337-348, 2008

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