Increase in live infected cell number with drug and generation of a quasispecies are consequences of multiply HIV infected cells.
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Date
2018
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Abstract
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.
Description
Doctoral Degree. University of KwaZulu-Natal, Durban.