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.

Fig. 1

HIV evolution occurs on multiple spatial and temporal scales. a Multiple virions may infect a single cell, competing for cellular resources controlling viral replication. Budding virions may contain RNA, structural proteins, and enzymes from various genetic backgrounds. b During infection of a single individual, HIV diversifies into multiple strains that compete to infect CD4+ T cells and evade immune responses and drug treatment. c As HIV spreads through the human population it may adapt, becoming more or less virulent and accumulating mutations selected by immune responses or even widespread drug use. d HIV arose from a cross-species transmission of simian immunodeficiency virus (SIV), known to infect many primate groups. Primate phylogeny, from left to right: humans, chimpanzees, gorillas, orangutans, gibbons, old world monkeys, new world monkeys, prosimians

Fig. 2

Hypothetical evolutionary mechanism for HIV pathogenesis. Colors schematically represent diversity of viral strains. Bottlenecks during transmission lead to acute infection growing from approximately a single viral strain. Viral loads peak and decline rapidly during acute infection, with diversity remaining low. During asymptomatic infection, which may last from months to decades, viral loads remain near a lower set point. Diversity gradually increases, potentially as mutants that escape cytotoxic T cells are generated. At a certain point, helper (CD4⁺ T cells) reach a critically low level, due to direct and indirect effects of HIV, leading to a rapid rise in viral load and progression to the clinical symptoms of AIDS. Mathematical models suggest that crossing a diversity threshold could cause progression to disease. At the final stages of disease, diversity begins to decrease, possibly due to reduced selection pressure from a failing immune system. Figure adapted from [, –172]

Fig. 3

Drug-dependent fitness landscape for the antiretroviral drug efavirenz derived using measured pharamacodynamic and pharmacokinetic parameters for wild-type and the K103N drug-resistant strain. Viral growth rate is positive only when R ₀ >1 (above gray dotted line). a Fitness of wild-type and resistant strains follow dose–response curves, resulting in a mutant selection window where resistant strains are selected. We compare a single mutant (K103N) to two hypothetical double mutants by adding either a second equivalent resistant mutation (further increases IC₅₀ and decreases slope) or a compensatory mutation (changes fitness cost only). b Drug concentrations decay over time according to drug half-life. c Relative fitnesses of wild-type and resistant strains consequently change over time as drug decays. d In the CSF, reduced drug penetration results in concentrations reduced to 0.5 %, allowing viral replication at higher systemic drug levels. e Assuming about 10 % of cells are susceptible to direct cell-to-cell transmission, which typically occurs with around 100 virions and is sustainable with a single virion. f Combining the effects of (d) and (e). g At the maximum clinical drug concentration (immediately following a dose), only the doubly resistant mutant can grow. h At intermediate concentrations, the single resistant mutant can grow, facilitating evolution of the compensated mutation or the untreatable doubly resistant mutant. i Without treatment, the wild type is favored. While the doubly resistant mutant can stepwise revert to wild type, the compensated mutant is less likely to do so due to the presence of a fitness valley at either of the intermediate single mutants. See Appendix for methods