Antithetic effect of interferon-α on cell-free and cell-to-cell HIV-1 infection.

In HIV-1-infected individuals, transmitted/founder (TF) virus contributes to establish new infection and expands during the acute phase of infection, while chronic control (CC) virus emerges during the chronic phase of infection. TF viruses are more resistant to interferon-alpha (IFN-α)-mediated antiviral effects than CC virus, however, its virological relevance in infected individuals remains unclear. Here we perform an experimental-mathematical investigation and reveal that IFN-α strongly inhibits cell-to-cell infection by CC virus but only weakly affects that by TF virus. Surprisingly, IFN-α enhances cell-free infection of HIV-1, particularly that of CC virus, in a virus-cell density-dependent manner. We further demonstrate that LY6E, an IFN-stimulated gene, can contribute to the density-dependent enhancement of cell-free HIV-1 infection. Altogether, our findings suggest that the major difference between TF and CC viruses can be explained by their resistance to IFN-α-mediated inhibition of cell-to-cell infection and their sensitivity to IFN-α-mediated enhancement of cell-free infection. HIV-1 experiences a strong bottleneck during transmission, and only the virus(es) with higher resistance to the host’s innate immunity, interferon (IFN), can be successfully transmitted. Because the IFN resistance tends to be disappeared during infection in infected individuals, this phenotype would be crucial for human-to-human transmission. By combining mathematical modeling with well-designed time-series viral infection experiments, we investigated the difference on the IFN resistance of two types of HIV-1, which were respectively isolated at the acute and chronic phases of infection, and classified it into two virus transmission modes, cell-free and cell-to-cell infections. We found that IFN suppresses HIV-1 cell-to-cell infection, but surprisingly, promotes cell-free infection. Moreover, the virus isolated during chronic infection is more sensitive to the IFN-mediated promoting effect than that isolated during acute infection. Our results suggest that HIV-1 selects different strategies to adapt to different host environments. We further provide an insight how viruses evolve to counteract or hijack the host immunity.

在HIV - 1感染者中，传播/奠基（TF）病毒有助于建立新的感染，并在感染急性期扩增，而慢性控制（CC）病毒在感染慢性期出现。TF病毒比CC病毒对干扰素 -α（IFN -α）介导的抗病毒作用更具抗性，然而，其在感染者中的病毒学相关性仍不清楚。在此我们进行了一项实验 - 数学研究，发现IFN -α强烈抑制CC病毒的细胞间感染，但对TF病毒的细胞间感染影响较弱。令人惊讶的是，IFN -α以病毒 - 细胞密度依赖的方式增强HIV - 1的无细胞感染，尤其是CC病毒的无细胞感染。我们进一步证明，一种干扰素刺激基因LY6E可导致无细胞HIV - 1感染的密度依赖性增强。总之，我们的研究结果表明，TF病毒和CC病毒之间的主要差异可通过它们对IFN -α介导的细胞间感染抑制的抗性以及对IFN -α介导的无细胞感染增强的敏感性来解释。 HIV - 1在传播过程中经历一个强烈的瓶颈，只有对宿主先天免疫（干扰素，IFN）具有较高抗性的病毒才能成功传播。因为在感染者体内感染过程中干扰素抗性往往会消失，所以这种表型对人传人至关重要。通过将数学建模与精心设计的时间序列病毒感染实验相结合，我们研究了在感染急性期和慢性期分别分离的两种HIV - 1对干扰素抗性的差异，并将其分为两种病毒传播模式，即无细胞感染和细胞间感染。我们发现干扰素抑制HIV - 1的细胞间感染，但令人惊讶的是，它促进无细胞感染。此外，慢性感染期分离的病毒比急性期分离的病毒对干扰素介导的促进作用更敏感。我们的结果表明，HIV - 1选择不同的策略来适应不同的宿主环境。我们进一步深入了解了病毒如何进化以对抗或劫持宿主免疫。