Adaptation of HIV-1 depends on the host-cell environment

Abstract

Many viruses have the ability to rapidly develop resistance against antiviral drugs and escape from the host immune system. To which extent the host environment affects this adaptive potential of viruses is largely unknown. Here we show that for HIV-1, the host-cell environment is key to the adaptive potential of the virus. We performed a large-scale selection experiment with two HIV-1 strains in two different T-cell lines (MT4 and C8166). Over 110 days of culture, both virus strains adapted rapidly to the MT4 T-cell line. In contrast, when cultured on the C8166 T-cell line, the same strains did not show any increase in fitness. By sequence analyses and infections with viruses expressing either yellow or cyan fluorescent protein, we were able to show that the absence of adaptation was linked to a lower recombination rate in the C8166 T-cell line. Our findings suggest that if we can manipulate the host-cellular factors that mediate viral evolution, we may be able to significantly retard viral adaptability.

Figure 1. Change in relative fitness of viruses cultured on two distinct T-cell lines.

A) The 6 wildtype replicates that are cultured on MT4 T-cells show a linear increase in fitness. The inset shows a single representative example of replicate wt-1. B) The 6 mutant MT4 cultured replicates show an initial fitness increase that seems to reach a maximum at around a relative fitness of 1.04±0.02. All trajectories are best described by an exponential regression model with an upper limit (F-test, p<0.05). The inset shows a single representative example of replicate mt-1 (see Table 2 for relative fitness values at day 110). C and D) relative fitness of 6 wt and 6 mt C8166 cultured viruses, respectively. Relative fitness did not significantly deviate from the starting virus over the course of the experiment (ANOVA, p>>0.05; see Table 3 for relative fitness values at day 110). Fitness is relative to reference strain v13 (also see materials and methods section.

Figure 2. Genetic variation in the Long Terminal Repeat (LTR) and envelope region (Env) of MT4 and C8166 cultured viruses.

For each culture, ten clones of both the LTR and Env region were sequenced and this was repeated for five points in time. Thus, each data point corresponds to the amount of genetic variation within a single serial passage line at a certain point in time. Genetic variation (Kimura 2 parameter) is plotted separately for the two cell-lines. A) No correlation in genetic variation in MT4 evolved viruses was observed (n = 44, r² = 0.011, p = 0.49). B) There is a strong linear correlation in genetic variation between the LTR and Env in C8166 cultured viruses (n = 39, r² = 0.745, p<0.0001). Even if the two outliers are taken out, the strong correlation remains (n = 37, r² = 0.475, p<0.0001).