Drastic Fitness Loss in Human Immunodeficiency Virus Type 1 upon Serial Bottleneck Events

Abstract

Muller’s ratchet predicts fitness losses in small populations of asexual organisms because of the irreversible accumulation of deleterious mutations and genetic drift. This effect should be enhanced if population bottlenecks intervene and fixation of mutations is not compensated by recombination. To study whether Muller’s ratchet could operate in a retrovirus, 10 biological clones were derived from a human immunodeficiency virus type 1 (HIV-1) field isolate by MT-4 plaque assay. Each clone was subjected to 15 plaque-to-plaque passages. Surprisingly, genetic deterioration of viral clones was very drastic, and only 4 of the 10 initial clones were able to produce viable progeny after the serial plaque transfers. Two of the initial clones stopped forming plaques at passage 7, two others stopped at passage 13, and only four of the remaining six clones yielded infectious virus. Of these four, three displayed important fitness losses. Thus, despite virions carrying two copies of genomic RNA and the system displaying frequent recombination, HIV-1 manifested a drastic fitness loss as a result of an accentuation of Muller’s ratchet effect.

Viral evolution

“…Extinctions of infectivity were not observed, neither with VSV, nor with MS2. This contrasts to the sensitivity of HIV-1 [136], where in a comparable experiment 6 out of 10 clones could not produce viable progeny after only 15 plaque-to-plaque transfers. This observation might reflect a different internal time scale in different virus, in the sense that different viruses employ different time lengths in a replication cycle, or in the killing of a cell.…”

Is HIV-1 evolving to a less virulent form in humans?

“…Red Queen dynamics (in which the interaction between a parasite and its host leads to a constant evolutionary process of adaptation and counter-adaptation) predict that increasing replicative fitness must be associated with a continual expansion of the genetic breadth and size of a population 97,98 . Any strong selective pressure can result in the contraction of population size, the appearance of deleterious mutations and decreasing fitness [99][100][101] . Interestingly, the introduction of ARVs as a strong selective pressure during asymptomatic disease resulted in a dramatic decrease in HIV-1 load, genetic diversity and replicative fitness, even in the absence of drug resistance mutations 29 .…”

Virus population dynamics examined with experimental model systems

“…The operation of Muller's ratchet appears as rather general in viruses since, in addition to bacteriophage 46 and the animal virus VSV (studies summarized in Section 6.5), other viral systems have documented fitness loss associated with serial bottlenecks (de la Iglesia and Elena, 2007;Escarmís et al, 1996;Jaramillo et al, 2013;Yuste et al, 1999). The studies by C. Escarmís and colleagues with FMDV contributed decisively to define the molecular basis of fitness loss in an RNA virus, and to unveil unusual genetic lesions (with phenotypic consequences) that hide in mutant spectra (detailed in the coming Section 6.5.2).…”