Cell-to-cell infection by HIV contributes over half of virus infection
Comment on “Cell-to-cell infection by HIV contributes over half of virus infection”.
Dominik Wodarz (1), Natalia L Komarova (2), David N Levy (3)
(1) Department of Ecology and Evolutionary Biology, 321 Steinhaus Hall, University of California, Irvine, CA 92697
(2) Department of Mathematics, Rowland Hall, University of California, Irvine, CA 92697
(3) Department of Basic Science, New York University College of Dentistry, 921 Schwartz Building, 345 East 24th Street, New York, NY 10010-9403
HIV-1 can spread through cell populations by release of free virions from infected cells into the extracellular environment or via direct contact between infected and uninfected cells. This cell-cell interaction forms a receptor-mediated contact region called a virological synapse that facilitates direct transfer of viral particles [1]; usually many virions at a time are directed into target cells. Synaptic virus transmission has received a lot of attention recently, with several groups demonstrating that it is a highly efficient method of virus transmission that promotes productive infection with multiple viruses [2-4]. The facilitation of multiple infections is of particular interest to us [5], as there are several important consequences for the virus’ ability to spread and to evolve which we have investigated through a combination of experimentation and mathematical analysis [6, 7]. In addition, it has been observed that cell-cell transmission reduces HIV-1 susceptibility to anti-viral drugs [8] and is required for HIV-1 induction of pyroptosis in lymphoid CD4 T cells [9].
The extent to which synaptic transmission contributes to the rate at which the virus spreads through its target cell population and expands in number is an important question. The rate of virus spread has been shown to correlate strongly with the post-acute set-point virus load, as well with the speed of disease progression in SIV-infected macaques [10]. The relative contribution of free virus vs. synaptictransmission to the rate of virus growth was investigated by us in T cells [11] , with a combination of in vitro experiments and mathematical models. Using an existing experimental methodology [12] where gentle shaking of a culture inhibited virological synapse formation, we compared virus growth to standard culture conditions where both transmission pathways could operate. We built the first mathematical virus dynamics model that explicitly took into account both synaptic and free virus transmission (see also [13] ), and applied this model in order to calculate the relative contribution of synaptic transmission to virus spread. We concluded that synaptic transmission contributed approximately half to the rate of virus growth [11]. This result suggested that both pathways of virus spread must be inhibited to therapeutically block virus replication, a result with implications for our understanding of antibody activity as well as small molecule inhibitors of virus binding and entry.
The paper by Iwami et al. [14] repeats much of of our past study, both experimentally and mathematically, and they reach nearly identical conclusions. It is reassuring that our methods and findings are readily reproducible and thus likely to be valid. However, the work by Iwami et al. [14] does not represent a novel approach or provide fundamentally new insights.
To highlight the similarities between the two studies more specifically, Iwami et al. [14] also disrupted synaptic transmission experimentally by gently shaking the cultures, and compared the resulting virus growth kinetics to those observed under static culture conditions. The same T cell line was used as in our study. As in our paper, they applied a mathematical model to these experimental data in order to estimate the relative contribution of synaptic and free virus transmission to virus growth. The mathematical model they used is very similar to ours, with the following minor differences: (i) While our model assumed exponential growth of the target cells in culture, Iwami et al assumed logistic growth. Because cells did not run out of space in our cultures, this difference is irrelevant. (ii) We assumed that the rate of infection saturated with higher target cell density, while Iwami et al assumed that the rate of infection was directly proportional to the population size of target cells. Our formulation has been shown to fit data more accurately [15]. (iii) The model by Iwami et al. [14] includes the population of free viruses as a separate variable, while our model assumes that the free virus population is in a quasi-steady state. This is common practice in HIV modeling because the turnover of the free virus population is much faster than that of the infected cells [16]. Iwami et al. [14] make the incorrect statement that our model takes the two transmission pathways into account only implicitly (we do, in fact directly consider the two transmission pathways [11, 13]). The experiments by Iwami et al. are also carried out over longer time courses, but this does not change any qualitative results.
Looking forward, an important uncertainty in our [11] as well as Iwami et al.’s [14] estimation is whether the results might be dependent on the experimental technique used to separate the two transmission pathways. Additional experimental methodologies have become available after our own paper was published, which might be used to separate the two transmission pathways and expand our understanding beyond that provided by our initial study and that by Iwami et al. Recently, antibodies have been developed that specifically target free virus and do not affect virus transmitted through virological synapses [17]. Additionally, HIV-1 mutants have been generated that transmit almost exclusively via cell- cell contact [18]. It will be an important contribution to our understanding of HIV-1 replication to repeat the estimate using these newly developed methodologies, and to compare the results to the ones obtained by us [11] and essentially reproduced by Iwami et al [14].
References
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