HIV transmission. Selection bias at the heterosexual HIV-1 transmission bottleneck.
HIV transmission. Selection bias at the heterosexual HIV-1 transmission bottleneck.
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DOI：
10.1126/science.1254031
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发表时间：
2014-07-11
期刊：
影响因子：
--
通讯作者：
Hunter E
中科院分区：
文献类型：
--
作者：
Carlson JM;Schaefer M;Monaco DC;Batorsky R;Claiborne DT;Prince J;Deymier MJ;Ende ZS;Klatt NR;DeZiel CE;Lin TH;Peng J;Seese AM;Shapiro R;Frater J;Ndung'u T;Tang J;Goepfert P;Gilmour J;Price MA;Kilembe W;Heckerman D;Goulder PJ;Allen TM;Allen S;Hunter E
异性性传播HIV-1是一个效率低下的过程，据报告，每一次无保护的性接触的传播率<1%。当发生传播时，系统性感染通常由单个遗传变异建立，该遗传变异来自供体中传播的遗传上不同的病毒群。创始者病毒是否代表一个偶然事件或系统性的青睐尚不清楚。我们的工作已经验证了一个中心假设，即创始病毒选择偏向于某些遗传特征。如果HIV-1的传播涉及对具有某些有利特征的病毒的选择，那么当在许多传播伙伴的许多病毒位点上观察时，这些优势应该会出现统计偏差。因此，我们确定了137赞比亚异性传播对，为他们提供血浆样本的捐助者和接受者的合作伙伴在传播后不久，并比较了从每个合作伙伴获得的病毒序列，以确定预测是否在捐助者的任何特定位置观察到的大多数氨基酸被传输的功能。我们将注意力集中在两个特征上：与病毒适应性相关的病毒遗传特征，以及影响传播的临床因素。统计模型表明，前者将有利于传输，而后者将抵消这种相对优势。我们观察到一个非常显着的选择偏差，有利于与健身增加相关的氨基酸的传输。这些特征包括研究队列中氨基酸的频率、氨基酸相对于蛋白质稳定性的相对优势以及与免疫逃逸和补偿相关的特征。这种选择偏差在传播风险高的夫妇中减少。特别是，与健康男性相比，在患有生殖器炎症的女性和男性中观察到的选择偏差显着减少，这表明女性生殖道中的环境比男性更宽松。与这一观察结果相一致，传播给女性的病毒的特征是预测适应性低于男性。在传播过程中有利的氨基酸的存在预测了供体中的哪种病毒传播给了他们的伴侣，而慢性感染的病毒群体的特征是这些氨基酸占优势的个体更有可能传播给他们的伴侣。这些数据突出了在随机过程的背景下，在传播过程中有利于适应性病毒的明显选择偏差。这种偏见的存在，并受到某些风险因素的缓和，表明传播的特点往往是许多流产的传播事件，其中一些靶细胞是非生产性感染。此外，为了有效传播，一些有利于传播伙伴生存的变化经常被丢弃，导致HIV-1在人群中的总体进化较慢。奇怪的是，通过增加在传播瓶颈处的选择偏差，易感性的降低可能会增加建立感染的突破性病毒的预期适应性，因此可能会使新感染伴侣的预后恶化。相反，削弱病毒的预防或治疗方法可以通过一种与循环病毒数量无关的机制降低总体传播率，因此即使在突破性感染时也可以提供长期益处。
Heterosexual HIV-1 transmission is an inefficient process with rates reported at <1% per unprotected sexual exposure. When transmission occurs, systemic infection is typically established by a single genetic variant, taken from the swarm of genetically distinct viruses circulating in the donor. Whether that founder virus represents a chance event or was systematically favored is unclear. Our work has tested a central hypothesis that founder virus selection is biased toward certain genetic characteristics. If HIV-1 transmission involves selection for viruses with certain favorable characteristics, then such advantages should emerge as statistical biases when viewed across many viral loci in many transmitting partners. We therefore identified 137 Zambian heterosexual transmission pairs, for whom plasma samples were available for both the donor and recipient partner soon after transmission, and compared the viral sequences obtained from each partner to identify features that predicted whether the majority amino acid observed at any particular position in the donor was transmitted. We focused attention on two features: viral genetic characteristics that correlate with viral fitness, and clinical factors that influence transmission. Statistical modeling indicates that the former will be favored for transmission, while the latter will nullify this relative advantage. We observed a highly significant selection bias that favors the transmission of amino acids associated with increased fitness. These features included the frequency of the amino acid in the study cohort, the relative advantage of the amino acid with respect to the stability of the protein, and features related to immune escape and compensation. This selection bias was reduced in couples with high risk of transmission. In particular, significantly less selection bias was observed in women and in men with genital inflammation, compared to healthy men, suggesting a more permissive environment in the female than male genital tract. Consistent with this observation, viruses transmitted to women were characterized by lower predicted fitness than those in men. The presence of amino acids favored during transmission predicted which individual virus within a donor was transmitted to their partner, while chronically infected individuals with viral populations characterized by a predominance of these amino acids were more likely to transmit to their partners. These data highlight the clear selection biases that benefit fitter viruses during transmission in the context of a stochastic process. That such biases exist, and are tempered by certain risk factors, suggests that transmission is frequently characterized by many abortive transmission events in which some target cells are nonproductively infected. Moreover, for efficient transmission, some changes that favored survival in the transmitting partner are frequently discarded, resulting in overall slower evolution of HIV-1 in the population. Paradoxically, by increasing the selection bias at the transmission bottleneck, reduction of susceptibility may increase the expected fitness of breakthrough viruses that establish infection and may therefore worsen the prognosis for the newly infected partner. Conversely, preventative or therapeutic approaches that weaken the virus may reduce overall transmission rates via a mechanism that is independent from the quantity of circulating virus, and may therefore provide long-term benefits even upon breakthrough infection.
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影响因子：
6.7
作者：
Chopera DR;Woodman Z;Mlisana K;Mlotshwa M;Martin DP;Seoighe C;Treurnicht F;de Rosa DA;Hide W;Karim SA;Gray CM;Williamson C;CAPRISA 002 Study Team
通讯作者：
CAPRISA 002 Study Team
影响因子：
5.4
作者：
Allen, TM;Altfeld, M;Walker, BD
通讯作者：
Walker, BD
影响因子：
5.4
作者：
Brockman, Mark A.;Brumme, Zabrina L.;Allen, Todd M.
通讯作者：
Allen, Todd M.
DOI：
10.1084/jem.20072457
发表时间：
2008-05-12
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Goepfert PA;Lumm W;Farmer P;Matthews P;Prendergast A;Carlson JM;Derdeyn CA;Tang J;Kaslow RA;Bansal A;Yusim K;Heckerman D;Mulenga J;Allen S;Goulder PJ;Hunter E
通讯作者：
Hunter E
DOI：
10.1073/pnas.0911796106
发表时间：
2009-12-08
影响因子：
11.1
作者：
Cicala, Claudia;Martinelli, Elena;Arthos, James
通讯作者：
Arthos, James