Grant: Travel Awards - Institute Community Support

Although antiretroviral therapy (ARV) has been lifesaving for many HIV-positive individuals, drug resistance threatens its long-term efficacy. IN is a HIV protein that is essential for the integration of viral DNA into the host's genome, which is a crucial step in the HIV lifecycle. Though HIV has been able to develop resistance to the first-generation IN inhibitors RAL and EVG, it has yet to do so to the newly developed DTG in ARV-naive patients. However, we have been able to artificially make the virus resistant to DTG through the R263K mutation. This mutation impairs the activity of the IN, as do the primary resistance mutations identified for RAL and EVG. I investigated the possibility of combining the novel R263K mutation with primary resistance mutations that emerge in response to RAL and/or EVG therapy, and found that the combination of N155H with R263K caused increases in fitness and resistance to both DTG and EVG. However these increases were relatively small, which led me to question whether secondary mutations specific to N155H, which are known to be compensatory, might further enhance this resistant virus. To test this hypothesis, I generated multiple versions of IN with N155H and R263K in combination with known secondary mutations. Three of these mutations, T97A, E157Q, and G163R, had positive effects on the enzymatic activity of IN. I will next generate HIV virus with the same mutations and analyze the ability of the viruses to infect human cells. The outcomes of this research will have a direct effect on patient care for HIV-positive individuals as DTG has been approved for use in RAL/EVG-experienced patients; the combination of resistance mutations is not arbitrary but a reflection of clinical reality and the difficulties facing both patients and their healthcare providers.