Cellular Superspreaders: an Epidemiological Perspective on HIV Infection Inside the Body
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Opinion Cellular Superspreaders: An Epidemiological Perspective on HIV Infection inside the Body Kristina Talbert-Slagle1,2*, Katherine E. Atkins1, Koon-Kiu Yan3, Ekta Khurana3, Mark Gerstein3, Elizabeth H. Bradley1,2, David Berg2,4, Alison P. Galvani1, Jeffrey P. Townsend1 1 Yale School of Public Health, New Haven, Connecticut, United States of America, 2 Global Health Leadership Institute, Yale University, New Haven, Connecticut, United States of America, 3 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America, 4 Yale University School of Medicine, New Haven, Connecticut, United States of America Introduction CD4+ T cells may play a similarly critical population, there exists a distribution of role in the establishment and spread of individual reproductive numbers, of which Worldwide, more than 250 people HIV in the genital mucosa after sexual R0 is the mean [14]. In populations of become infected with HIV every hour exposure. homogeneous individuals, the distribution [1], yet an individual’s chance of becom- of individual reproductive numbers will be ing infected after a single sexual exposure, Basic and Individual clustered around the population average the predominant mode of HIV transmis- value of R , and thus, this average value Reproductive Number 0 sion, is often lower than one in 100 [2]. will more accurately predict the likelihood When sexually transmitted HIV-1 infec- To quantify the spread of infectious of transmission from each infected to each tion does occur, it is usually initiated by a disease, epidemiologists use the basic susceptible individual. If R0.1, then an single virus, called the founder strain, reproductive number, R , which describes outbreak is likely to become an epidemic, despite the presence of thousands of 0 the average number of secondary infec- and if R0,1, then an outbreak will not genetically diverse viral strains in the tions that arise from one infected individ- spread beyond a few initially infected transmitting partner [3]. Here we review ual in an otherwise totally susceptible individuals [15,16]. evidence from molecular biology and population [15]. The basic reproductive In heterogeneous populations, however, virology suggesting that heterogeneity number can be approximated as the the population average value of R0 is less among CD4+ T cells could yield wide product of the following: (1) the average predictive of transmission dynamics [14]. variation in the capability of individual number of susceptible individuals contact- For example, in populations with highly cells to become infected and transmit HIV ed by an infected individual during the right-skewed distributions of individual to other cells. Using an epidemiological infectious period (the ‘‘number of con- reproductive numbers, most individuals framework, we suggest that such hetero- tacts’’) and (2) the average probability that infect few, if any, others, but a few geneity among CD4+ T cells in the genital a susceptible individual will become in- individuals infect many others. In such mucosa could help explain the low infec- fected by a single infected individual populations, there is a high probability tion-to-exposure ratio and selection of the during its infectious period (the ‘‘shedding that a disease outbreak will not be founder strain after sexual exposure to potential’’). Thus, sustained in the population and will HIV. instead go extinct [14]. In some cases, During sexual transmission, founder however, those rare individuals in the tail R &Number of contacts viral strains preferentially infect CD4+ T 0 of the distribution with a much higher- cells using the CCR5 coreceptor [4,5]. At |Shedding potential: than-average individual reproductive the time of initial exposure to HIV, these number while they are infected, known CD4+ T cells exhibit baseline heterogene- as ‘‘superspreaders’’ [15], can have a ity due to stochasticity in cellular gene The number of secondary infections significant impact on whether an outbreak expression [6] and dynamic variation in caused by a specific individual throughout becomes an epidemic or goes extinct. immunological status (activated, resting, the time that the individual is infectious is Epidemiological outbreak investigations, etc.) [7]. In addition, because CD4+ T called the ‘‘individual reproductive num- which track the spread of disease by a cells are mobile, they are heterogeneously ber’’ [14]. For any disease within a given technique called contact tracing, have distributed in the genital mucosa, with varying degrees of clustering and contact Citation: Talbert-Slagle K, Atkins KE, Yan K-K, Khurana E, Gerstein M, et al. (2014) Cellular Superspreaders: An [8–11]. In other contexts, it is well-known Epidemiological Perspective on HIV Infection inside the Body. PLoS Pathog 10(5): e1004092. doi:10.1371/ that heterogeneity among isogeneic cells journal.ppat.1004092 inside the body can affect many cellular Editor: Glenn F. Rall, The Fox Chase Cancer Center, United States of America behaviors and outcomes, including infec- Published May 8, 2014 tion dynamics [12,13]. Copyright: ß 2014 Talbert-Slagle et al. This is an open-access article distributed under the terms of the Epidemiological analyses of disease Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any outbreaks among people indicate that medium, provided the original author and source are credited. heterogeneity in the ability of individuals Funding: KTS was supported by a Ruth L. Kirschstein National Research Service Award (http://grants.nih.gov/ in a population to spread disease can have training/nrsa.htm). The funders had no role in study design, data collection and analysis, decision to publish, or a significant impact on whether a local preparation of the manuscript. outbreak becomes an epidemic [14]. Competing Interests: The authors have declared that no competing interests exist. Heterogeneity among a population of * E-mail: [email protected] PLOS Pathogens | www.plospathogens.org 1 May 2014 | Volume 10 | Issue 5 | e1004092 identified the existence of superspreaders among CD4+ T cells in the genital mucosa is not close enough to others to transmit in many well-known infectious disease of a single individual could generate a virus by direct contact [8]. Thus, hetero- outbreaks, including typhoid fever, mea- skewed distribution in the individual geneity in cell distribution and clustering sles, smallpox, Ebola, and severe acute cellular reproductive number, or ICRN, inside the body could generate wide respiratory syndrome (SARS) [14,17,18]. in the context of HIV infection. Here we variation in the efficiency of virus trans- These rare individuals often make a review evidence for heterogeneity among mission from cell to cell and in ICRN. significant, sometimes deciding, contribu- CD4+ T cells that could lead to wide Transmission of virus from an infected tion to the dynamics of disease spread variation in ICRN and possibly give rise to to a susceptible cell also depends on a cell’s (Table 1). cellular superspreaders. permissivity to productive infection. The During the 2003 SARS outbreak in level of surface expression of CD4 and Singapore, for example, the majority of Number of Contacts CCR5 (the predominant coreceptor uti- individuals who became infected spread lized during acute infection [32]) varies the virus either to no one else or to only CD4+ T cells exhibit considerable widely among CD4+ T cells [25,33], even one other [14]. Five infected individuals, heterogeneity in activation status (e.g., in a single individual [34], and affects however, were superspreaders, each in- resting or activated) and expression of cellular permissivity to HIV [35,36]. fecting at least 20 others (Figure 1) [19]. In surface molecules important for HIV Indeed, low expression of CD4 or CCR5 this example, R0, which is an average infection (including the HIV coreceptors can completely inhibit infection of CD4+ population value, did not adequately CCR5 and CXCR4) in human penile T cells by certain viral strains [37]. A describe the dynamics of SARS because [21], foreskin [22,23], cervical [24,25], recent multiparameter analysis of HIV it did not capture the heterogeneity among and rectal [26] tissue. In addition, various entry efficiency at the level of single cells individuals in their ability to spread disease studies that stain for CD4+ T cells in indicated large cell-to-cell variation in or the key contribution made by super- uninfected genital mucosal tissue, such as expression of CD4, CCR5, and the spreaders to establishment and spread of cervical tissue [27] and human foreskin coreceptor CXCR4, which subsequently the virus [14]. [22], indicate that T cells vary in their influenced permissivity of individual cells spatial distribution and the extent to which to HIV binding and entry [38]. In Individual Cellular they form clusters. Cell density and spatial addition, CD4+ T cells isolated from Reproductive Number arrangement have been identified as rectal and cervical tissue exhibit consider- important sources of heterogeneity among able heterogeneity in expression of the For a population of HIV-infected cells cells that can affect virus spread in vitro surface integrin a4b7, which can specifi- inside the body, the basic reproductive [8,28–30]. Indeed, imaging studies explor- cally bind the V2 loop of the HIV number, R0 (a population average), has ing the dynamics of virus spread in a envelope protein