Therapeutic antibodies to treat Pneumocystis pneumonia in a nonhuman primate model of HIV infection

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Despite tremendous efforts to develop a HIV vaccine, there is currently no vaccine for the prevention of HIV infection. With the advent of highly successful antiretroviral therapy, mortality and morbidity associated with HIV infection has been significantly reduced. Unfortunately, opportunistic infections are commonly observed among HIV-infected patients, and remain a problematic issue that must be urgently addressed. A frequently encountered HIV-associated opportunistic infection is Pneumocystis pneumonia (PCP), which is caused by the ubiquitous fungus Pneumocystis jirovecii. Although antiretroviral therapy has reduced the incidence of PCP, 30% of HIV- infected individuals will develop PCP, which can have unacceptable lethal outcomes despite current drug treatments. PCP is often a defining disease in infected patients who are unaware of their HIV infection. The goal of this K01 award is to support the transition of my research program to develop new therapeutics for opportunistic infections affecting HIV/AIDS patients, and to test these therapeutics in a nonhuman primate (NHP) model of HIV infection. My previous research has primarily focused on structural mechanisms of bacterial pathogenesis and antibody-mediated immunity to viral pathogens. Although I have been very successful in my previous training, I desire additional protected time to transition my research in an exciting and independent direction to study antibody-mediated immunity to opportunistic pathogens affecting HIV/AIDS patients, particularly incorporating NHPs, which represent the best model of HIV infection. To complete my training, I am leveraging the excellent resources at the University of Georgia NHP core, which my primary mentor Dr. Karen Norris recently established during her move to UGA. The proposed work in this application will focus on the development of therapeutic antibodies to treat PCP in a NHP model of HIV-infection. My overall hypothesis is that antibodies specific to the Pneumocystis kexin protease can effectively treat PCP. Dr. Norris has developed an excellent NHP model of HIV/PCP co-infection, and has identified a protein-based vaccine candidate (KEX1) based on the Pneumocystis kexin protease. The proposed work will combine my current expertise in antibody generation with new training in the HIV field under the guidance of Dr. Norris and my clinical mentor Dr. Alison Morris. In Specific Aim 1 I will determine if antibodies generated in response to KEX1 vaccination can effectively treat PCP. The KEX1 fragment of the Pneumocystis kexin protein was previously shown to protect against development of PCP. I will purify KEX1-specific antibodies and test the antibodies for treatment of PCP in a NHP model of HIV/PCP co-infection. In Specific Aim 2, I will leverage my expertise in human antibody generation to isolate novel human antibodies specific to the KEX1 protein. The antibodies will be characterized to identify the top candidate, and the top candidate will be tested for PCP treatment efficacy in the NHP model. I expect the top candidate will advance to clinical trials, and have high potential to serve as a therapeutic to treat PCP in HIV- infected individuals.