Evolutionary dynamics of HIV at multiple spatial and temporal scales

Abstract

Infectious diseases remain a formidable challenge to human health, and understanding pathogen evolution is crucial to designing effective therapeutics and control strategies. Here, we review important evolutionary aspects of HIV infection, highlighting the concept of selection at multiple spatial and temporal scales. At the smallest scale, a single cell may be infected by multiple virions competing for intracellular resources. Recombination and phenotypic mixing introduce novel evolutionary dynamics. As the virus spreads between cells in an infected individual, it continually evolves to circumvent the immune system. We discuss evolutionary mechanisms of HIV pathogenesis and progression to AIDS. Viral spread throughout the human population can lead to changes in virulence and the transmission of immune-evading variation. HIV emerged as a human pathogen due to selection occurring between different species, adapting from related viruses of primates. HIV also evolves resistance to antiretroviral drugs within a single infected host, and we explore the possibility for the spread of these strains between hosts, leading to a drug-resistant epidemic. We investigate the role of latency, drug-protected compartments, and direct cell-to-cell transmission on viral evolution. The introduction of an HIV vaccine may select for viral variants that escape vaccine control, both within an individual and throughout the population. Due to the strong selective pressure exerted by HIV-induced morbidity and mortality in many parts of the world, the human population itself may be co-evolving in response to the HIV pandemic. Throughout the paper, we focus on trade-offs between costs and benefits that constrain viral evolution and accentuate how selection pressures differ at different levels of selection.

Evolutionary scalpels for dissecting tumor ecosystems

“…Acquired drug resistance, on the other hand, proceeds by replacement of a population of drug-sensitive cells – which succumb to therapy – with a separate population of drug-resistant cells. The difference between intrinsic and acquired resistance can be understood in terms of the fitness costs and benefits of drug resistance 39-42 . If a mutation that occurs within a growing untreated tumor confers drug resistance without incurring a fitness cost (Fig.…”

“…1F). In the setting of antimicrobial drug resistance, this concept has been explored extensively, resulting in definition of a “mutant selection window,” or concentration of drug in which a drug-resistant clone both outperforms the sensitive wild type (is relatively fit) and still manages to grow (positive absolute fitness) 39-42 . To optimize therapy, drug concentrations within this window should be avoided.…”

Genetic Variation and HIV-Associated Neurologic Disease

“…Moreover, the dynamics of antiretroviral drugs also determine the path of HIV evolution and play a role in therapy outcome. Mathematical simulation studies have established that simulation of clinical trials with new and untested HIV treatment protocols could be used as a potent tool in selecting novel antiretroviral combinations (Hill, Rosenbloom, & Nowak, 2012; Rosenbloom, Hill, Rabi, Siliciano, & Nowak, 2012). Although this simulation approach may have biases toward success and may be limited with respect to the incorporation of all possible sequence variants that would render the compound combination inferior in clinical trials, the simulation can still be used as a preliminary step to strengthen a proposed antiretroviral combination prior to testing in preliminary efficacy analyses.…”

The evolution of evolutionary molecular medicine

“…Improved understanding of evolutionary biology will provide new hypotheses and new lessons for NCDs, as well as how to better deal with infectious agents [11,12]. Early stimulation of the immune defense systems, as was the norm for our ancestors, and more intelligent use of antibiotics to avoid the evolution of drug resistant bacteria are just two practical applications of evolutionary concepts in medicine and public health [13,14].…”