Cellular Superspreaders: An Epidemiological Perspective on HIV Infection inside the Body

Worldwide, more than 250 people become infected with HIV every hour [1], yet an individual's chance of becoming infected after a single sexual exposure, the predominant mode of HIV transmission, is often lower than one in 100 [2]. When sexually transmitted HIV-1 infection does occur, it is usually initiated by a single virus, called the founder strain, despite the presence of thousands of genetically diverse viral strains in the transmitting partner [3]. Here we review evidence from molecular biology and virology suggesting that heterogeneity among CD4+ T cells could yield wide variation in the capability of individual cells to become infected and transmit HIV to other cells. Using an epidemiological framework, we suggest that such heterogeneity among CD4+ T cells in the genital mucosa could help explain the low infection-to-exposure ratio and selection of the founder strain after sexual exposure to HIV. During sexual transmission, founder viral strains preferentially infect CD4+ T cells using the CCR5 coreceptor [4], [5]. At the time of initial exposure to HIV, these CD4+ T cells exhibit baseline heterogeneity due to stochasticity in cellular gene expression [6] and dynamic variation in immunological status (activated, resting, etc.) [7]. In addition, because CD4+ T cells are mobile, they are heterogeneously distributed in the genital mucosa, with varying degrees of clustering and contact [8]–[11]. In other contexts, it is well-known that heterogeneity among isogeneic cells inside the body can affect many cellular behaviors and outcomes, including infection dynamics [12], [13]. Epidemiological analyses of disease outbreaks among people indicate that heterogeneity in the ability of individuals in a population to spread disease can have a significant impact on whether a local outbreak becomes an epidemic [14]. Heterogeneity among a population of CD4+ T cells may play a similarly critical role in the establishment and spread of HIV in the genital mucosa after sexual exposure.