| Summary: | Recent observations on the reduced susceptibility of HIV-1 cell-to-cell infection to inhibition by Reverse Transcriptase Inhibitors (RTIs) have raised questions on the bearing this mode of spread may have on the successful treatment of HIV-1, the maintenance of viral reservoirs and viral pathogenesis. This thesis presents a detailed assessment of the individual drug classes, which constitute first-line and second-line antiretroviral therapy, with regard to their ability to inhibit HIV-1 cell-to-cell infection in comparison to cell-free infection. Special emphases is given to the study of Protease Inhibitors (PIs), which have a mechanism of action different from RTIs, present a higher barrier to the selection of drug-resistant viruses, are highly potent and very important in both first-line and second-line treatment of HIV-1 infection. Also, PIs have not been studied before in the context of cell-to-cell spread of HIV-1. The results obtained show that different classes of antiretroviral drugs have different potencies against cell-to-cell spread of HIV-1. While PIs are equally effective at inhibiting cell-to-cell and cell-free spread of HIV-1, RTIs especially those of the Nucleoside Reverse Transcriptase Inhibitor (NRTI) class are ineffective inhibitors of cell-to-cell spread of the virus. This thesis also assesses the impact of combination antiretroviral therapy on these two modes of viral infection, using drug synergy analysis by the median effect principle. We show that combination antiretroviral therapy is effective against both cell-to-cell and cell-free HIV-1 infection. However in the context of antiretroviral drug resistance, cell-to-cell spread may contribute to a reduced efficiency of combination antiretroviral therapy in blocking the spread of infection. Overall, the study provides a better understanding of the impact of antiretroviral therapy on cell-to-cell spread of HIV-1 and within reason, bearing in mind the limitations of in vitro models, gives some insight on the possible clinical implications of these observations for current HIV-1 therapy.
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