Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Doctor of Philosophy

Program

Applied Mathematics

Supervisor

Lindi Wahl

2nd Supervisor

Art Poon

Abstract

HIV-1 is a rapidly replicating retrovirus that faces two distinct fitness landscapes: within-host HIV-1 faces viral competition for host cells and for escape from the immune system, and between hosts HIV-1 faces a transmission bottleneck in which the majority of new infections are started by a single virus strain. Possibly as a result of these conflicting selective pressures, the rate of evolution of HIV-1 tends to be greater within-host than between hosts.

A current hypothesis for this difference in evolutionary rates is that the HIV-1 latent reservoir acts to archive virus for later transmission. We offer a related but complimentary hypothesis: while some of the viruses’ life history traits are under selective pressure within-host, traits that are responsible for the efficiency of transmission to a new host are not under direct selection within-host and thus are subject to drift. Combined with the necessity of transmission through an extremely severe, competitive bottleneck, this results in the preferential transmission of founder-like viral lineages.

As further evidence of the conflict between transmission fitness and within-host fitness, experimental evidence demonstrates that subtypes A and D are 100-fold more fit than subtype C in in vitro fitness competitions, yet subtype C dominates the global spread of new infections. It is unclear whether this discrepancy is caused by differences in within- and between-host fitness, or primarily reflects differences in in vitro versus in vivo fitness measures. To address this question, data from a four-year, 8000 participant study in Uganda and Zimbabwe were analysed for evidence of in vivo fitness differences between subtypes A, C and D. Analyzing this dataset along with simulated participant data, we conclude that either more frequent data sampling, or an even larger study, would be necessary to capture the early within-host dynamics sufficiently for a comparison across subtypes.

Similar to subtypes A and D, subtype B is estimated to have an eight- to ten-fold in vitro fitness advantage over subtype C. Since frequent data collection over the early course of infection is necessary to quantify in vivo viral fitness, another approach to this question is to use data collected for simian/human immunodeficiency virus (SHIV). We develop a non-linear mixed-effects model for a meta-analysis of 143 non-human primates from over 20 sources to study in vivo fitness differences between SHIV subtypes B and C. Results suggest that subtype C has a lower replicative fitness but higher burst size than subtype B.

Summary for Lay Audience

Human immunodeficiency virus (HIV) is a rapidly evolving virus that faces two distinct environments. Within a single infected individual (``within host''), HIV is engaged in a race with the immune system, evolving to avoid the host defences. When transmitted from one infected individual to another (``between hosts''), HIV faces an extreme transmission bottleneck. A faster evolutionary rate is observed within-host than between-hosts. We hypothesize that the ability of the virus to transmit across the extreme transmission bottleneck is an important factor for this difference in the evolutionary rates, and that when a virus mutates within-host the ability for the virus to transmit is usually reduced. This leads to the transmission of viruses that are more like the virus that established the infection than the average virus within-host at the time of a transmission.

Further evidence of this conflict between the virus' ability to out compete other viral strains within-host and the ability of the virus to transmit is seen in the discrepancy between laboratory experiments, where HIV subtypes A and D replicate more quickly than subtype C, and the global epidemic, which is increasingly dominated by HIV subtype C. To address this conflict we consider data from a four year, 8000 participant study in Uganda and Zimbabwe where differences between subtypes in the study participants were considered. To detect the ability of one viral subtype to out-compete another subtype, samples from early in a participant's infection are required. By simulating participant's appointment timing and infection time courses, we were able to determine that the data-set did not contain the information needed to detect differences in within-host replication rates between subtypes.

In order to detect possible differences between HIV subtypes we consider the constructed virus, simian/human immunodeficiency virus (SHIV), which infects macaques and shares the subtype differences of HIV. Developing a statistical model and gathering data from over 143 non-human primates infected with SHIV from over 20 previous studies, we were able to detect distinct replication advantages for both subtype C and D. Subtype C has a lower ability to infect new cells, within-host, but generates more new virus from each cell it infects than subtype D.

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