I-103 HIV-1 cell-to-cell infection during acute infection and resistance to neutralizing antibodies

Interactions between infected T cells and uninfected T cells called virological synapses (VS) enhance HIV-1 infection. When studied in vitro, 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. Our studies of HIV-1 infection in humanized mice, have measured the frequency of co-transmission and the spatiotemporal organization of infected cells as indicators of cell-to-cell transmission in vivo. We inoculated mice with cells co-infected with 2 viral genotypes distinguished by 2 different fluorescent proteins, and observed high levels of co-transmission to target cells. The mixed genotype of the input cells was preserved in the first round of infection in vivo, suggesting that cell-to-cell transmission occurs in vivo. 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 can induce arrest of interacting, uninfected CD4(+) T cells to form Env-dependent cell-cell conjugates. Viral neutralization studies indicate that antibodies are less potent in their inhibitory capacity against cell-to-cell infection, when compared with the same virus presented in a cell-free form. Antibodies are both less potent and also can display significant decreases in the maximum inhibitory potential. We present models whereby HIV-1 spread between immune cells can be anatomically localized into infectious clusters and is represents an important mechanism of evasion from antibody responses.