Repository logo

Doctoral Degrees (Medicine)

Permanent URI for this collectionhttps://hdl.handle.net/10413/8104

Browse

Browsing Doctoral Degrees (Medicine) by Subject "Antiretroviral drugs."

Filter results by typing the first few letters
Now showing 1 - 1 of 1
  • Thumbnail Image
    Item
    Increase in live infected cell number with drug and generation of a quasispecies are consequences of multiply HIV infected cells.
    (2018) Jackson, Laurelle.; Sigal, Alexander.
    HIV may form reservoirs in anatomical compartments and evolve a quasispecies in order to survive under selective pressures such as antiretroviral drugs. Lymph nodes and lymphoid tissue - critical sites for reservoir formation - are environments conducive to cell-to-cell spread, an efficient mode of HIV transmission. Cell-to-cell spread can lead to multiple infections per cell which in turn profoundly changes how the virus responds to selective pressure. In this thesis, my goal was to understand the consequences of multiple infections per cell on how the infection responds to and evolves in the face of inhibitors. The specific aims were to: (1) model and experimentally examine the effect of attenuating cell-to-cell spread by using antiretrovirals (ARVs) on infected cell viability; (2) test whether a stable quasispecies can be formed and maintained by complementation– a process where virions derived from different HIV genotypes infecting the same cell share components; (3) test the feasibility of new single-cell RNA-Seq methodology that can be applied to quantify the frequency of multiply infected cells in vivo. These studies showed that: (1) partially attenuating infection involving multiple virions per cell with drug resulted in an increase in the number of live infected cells in both cell line and lymph nodes at suboptimal drug strengths. The increase in live infected cells was a result of fewer HIV DNA copies per cell, relative to no drug; (2) under the selective pressure of efavirenz (EFV), when drug-resistant and drug sensitive HIV co-infect the same cell during drug resistant evolution, complementation takes place, driving the formation and maintenance of a quasispecies; (3) Novel single-cell RNA-Seq approaches are feasible to quantify the number of cells that are multiply infected in vivo. Inhibiting mechanisms such as cell-to-cell spread may therefore reduce infection in the face of ARVs and limit viral diversity and hence the ability of HIV to evolve resistance.