Watters, SA; (2016) Dynamics of HIV-1 viral populations in individuals undergoing chemotherapy. Doctoral thesis , UCL (University College London).

Abstract

The success of ART has led to HIV infected individuals having normal life expectancies compared to the general population. However ART can only control the virus and not cure it and HIV persistence in long-lived cells represents one of the major barriers to HIV eradication. Moreover, an aging infected population shows an increase in cancer incidence. The classical successful strategy to treat cancer is chemotherapy by agents that can be either cytotoxic or immunomodulatory (IMiDs) to immune cells. Cytotoxic agents kill immune cells and therefore have the potential to constrict or shift the viral population via the activation of a new pool of latently infected CD4+ T-cells. IMiDs cause cellular activation and have the potential to clonally expand or shift the viral population. Using quantification of viral nucleic acids and single genome sequencing of longitudinally obtained samples from HIV infected individuals with comorbid neoplasms we demonstrate the effect of chemotherapy on HIV population dynamics. In individuals not on ART a change to viral population size and structure was seen in 1) a single case of Tcell ablation and disruption of viral control followed by a tropism switch and rebound of CCR5 using virus in an elite controller following myeloablative chemotherapy, and 2) a shift in viral population in an individual undergoing intensive chemotherapy. In individuals on suppressive ART we demonstrate that in the absence of strong effects on T-cells no change to HIV population size or structure was detected in 1) individuals undergoing treatment with a single cytotoxic agent, or 2) a cohort undergoing treatment with the IMiD pomalidomide. These results are important in the context of longer survival of HIV infected individuals, and therefore subsequent increased cancer risk and exposure to cancer drugs. This work shows that in the absence of ART chemotherapy agents with a detectable effect on CD4+ and CD8+ T- cells can alter the viral reservoir structure, reinforcing the need for ART alongside chemotherapy in the context cancer. This work demonstrates that these agents are unlikely to be of benefit in cure strategies but offer a new insight into a potential utility of CCR5 antagonists during future functional cure protocols.

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