In Vivo HIV-1 Cell-to-Cell Transmission Promotes Multicopy Micro-compartmentalized Infection

Abstract

HIV-1 infection is enhanced by adhesive structures that form between infected and uninfected T cells called virological synapses (VSs). This mode of transmission results in the frequent co-transmission of multiple copies of HIV-1 across the VS, which can reduce sensitivity to antiretroviral drugs. Studying HIV-1 infection of humanized mice, we measured the frequency of co-transmission and the spatiotemporal organization of infected cells as indicators of cell-to-cell transmission in vivo. When inoculating mice with cells co-infected with two viral genotypes, we observed high levels of co-transmission to target cells. Additionally, micro-anatomical clustering of viral genotypes within lymphoid tissue indicates that viral spread is driven by local processes and not a diffuse viral cloud. Intravital splenic imaging reveals that anchored HIV-infected cells induce arrest of interacting, uninfected CD4(+) T cells to form Env-dependent cell-cell conjugates. These findings suggest that HIV-1 spread between immune cells can be anatomically localized into infectious clusters.

New Connections: Cell-to-Cell HIV-1 Transmission, Resistance to Broadly Neutralizing Antibodies, and an Envelope Sorting Motif

“…The authors of that study proposed that a cycle of pathogenesis is initiated by a virological synapse, in which the productively infected donor cell dies of apoptosis while the bystander acceptor cell dies through pyroptosis. There is strong evidence that cell-to-cell infection facilitates local spread of virus in lymph node microclusters through T cell motility and tethering interactions (17,29,30). All of these studies support the notion that cell-to-cell transfer of HIV-1 through virological synapses is an important component of viral spread and ensuing pathogenesis.…”

Visualization of HIV T Cell Virological Synapses and Virus-Containing Compartments by Three-Dimensional Correlative Light and Electron Microscopy

“…Recent studies indicate that cell-to-cell infection plays an important role in HIV-1 pathogenesis (1)(2)(3)(4)(5). Accumulating evidence supports the idea that HIV-1 cell-tocell spread contributes to both productive infection (6)(7)(8)(9) and CD4 ϩ T cell depletion (10).…”

HIV Cell-to-Cell Spread Results in Earlier Onset of Viral Gene Expression by Multiple Infections per Cell

“…Reasons for high turnover may include targeting of infected cells by cytotoxic T lymphocytes [69, 70], or a limited infection window due to bystander killing of target cells [71–74], all operating in environments such as lymph nodes where cell-to-cell infection is likely to occur [29, 31, 71, 73]. In exponential expansion at the R 0 observed during primary HIV infection (~8, [75]), decreasing the infection cycle time by one quarter can lead to a 2 order of magnitude increase in the number of infected cells over several weeks.…”

“…Such interactions can occur between donor and target cells by various mechanisms [1–12], all of which involve the directed delivery of virions very close to the target cell, minimizing the distance over which virions need to diffuse and the consequent loss of virions en route [1–9, 11–24]. Because of the resulting high efficiency of viral delivery, target cells in cell-to-cell spread are exposed to multiple virions per cell both in in vitro infections and in vivo [17, 18, 25–31]. Multiple infections per cell decrease the sensitivity of cell-to-cell spread to antiretroviral drugs [17, 25, 27, 32, 33] and neutralizing antibodies [18, 34–36], and can overcome low infectivity and cellular restriction factors [37], since they increase the chances that at least one of the transmitted virions will successfully infect the cell despite inhibitors or unfavorable infection conditions [27, 38].…”