Anti-retroviral drugs to block HTLV-1 transmission in vivo - PROJECT SUMMARY/ABSTRACT Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus which causes a highly aggressive CD4+ T-cell malignancy called adult T-cell leukemia/lymphoma (ATLL), the neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and other inflammatory disorders. Treatment of HTLV-1- associated diseases remain inadequate. Viral transmission occurs by sexual intercourse, infected blood products, and mother-to-child through breastfeeding. Proliferation of viral infection is first through viral replication and infectious transmission, followed by subsequent mitotic expansion of infected clones with periodic viral replication. Our group has shown that clinically approved human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and integrase (IN) inhibitors also effectively block HTLV-1 transmission in cells. Pre-exposure prophylaxis (PrEP) is the use of antiretrovirals for the prevention of HIV-1 in those people who have not yet been exposed to the virus. The effectiveness of PrEP for HIV-1 is through early inhibition of viral replication, before infection is established. Unlike HIV-1, antiviral therapies to treat existing HTLV-1 infections is lacking, placing a higher emphasis on transmission prevention. We hypothesize clinically approved PrEP antiretrovirals will effectively block HTLV-1 transmission in vivo. Currently, people on PrEP are either prescribed a combination of RT inhibitors (e.g. Truvada), or a long-acting injectable IN strand transfer inhibitor, cabotegravir (CAB-LA). HTLV- 1 RT has higher fidelity than HIV-1 RT. Together with the difference in replication dynamics, we hypothesize HTLV-1 will be less likely to develop resistance to antiretrovirals. To date however, this has not been tested. In this proposal, we will determine the efficacy of PrEP in blocking HTLV-1 transmission in vivo and investigate whether HTLV-1 will develop resistance upon prolonged exposure to antiretrovirals. The efficacy of PrEP will be examined in our well-established preclinical rabbit model. HTLV-1 infection of rabbits mimics early infection in humans and is used to study early viral infection events, persistence, and immune responses in vivo. Rabbits pre-treated with antiretrovirals (CAB-LA or Truvada) will be intravenously challenged with HTLV-1. Viral load and immune response against the virus will be measured at weekly time points. Rabbits with breakthrough infection will be identified and the integrated virus will be sequenced for mutations. The stimulated HTLV-1 immune response will also be examined. Resistance mutations will be identified and characterized in vitro using chimeric virus technology and IC50s for the indicated drugs will be determined. Finally, residues critical for drug resistance will be incorporated into an HTLV-1 molecular clone and subsequent viral fitness and EC50 for CAB-LA and Truvada will be determined by infectious virus release. The wide usage of PrEP has critical implications for HTLV-1 transmission. Data concerning the effect of antiretroviral activity against HTLV-1 transmission is severely lacking. Our study will be the first to test antiretroviral drugs in animal models with HTLV-1 transmission. This study will inform the efficacy of these clinically approved drugs and the types of resistance that may arise.
