Lack of detectable HIV-1 molecular evolution during suppressive antiretroviral therapy.
Lack of detectable HIV-1 molecular evolution during suppressive antiretroviral therapy.
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DOI：
10.1371/journal.ppat.1004010
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发表时间：
2014-03
期刊：
影响因子：
6.7
通讯作者：
Maldarelli F
中科院分区：
文献类型：
--
作者：
Kearney MF;Spindler J;Shao W;Yu S;Anderson EM;O'Shea A;Rehm C;Poethke C;Kovacs N;Mellors JW;Coffin JM;Maldarelli F
通过抗逆转录病毒联合治疗（cART）更好地了解HIV-1群体遗传学的变化对于设计根除策略至关重要。因此，我们分析了患者在cART前、cART抑制期间和病毒反弹后血浆中HIV-1的遗传变异和分化。在cART之前（N = 14）、cART抑制期间（N = 14）和/或cART中断后病毒反弹后（N = 5），获得了HIV-1感染患者血浆HIV-1 RNA的单基因组序列。采用平均两两差异（APD）测量患者群体多样性。种群结构通过系统发育分析和panmixia试验进行评估。种群内多样性的测量显示，在接受cART治疗长达15年的患者中，总体遗传变异没有显著损失。然而，一项panmixia测试显示，2/10的患者在短期cART（<1年）后，7/10的患者在长期cART（1 - 15年）后，群体结构发生了显著变化。在cART期间，这些变化包括在cART转移到包含一个或多个遗传均匀亚群的群体之前的各种病毒变体集。尽管群体结构发生了这些显著变化，但长期cART后的反弹病毒与治疗前病毒几乎没有差异，这暗示cART前感染的长寿命细胞是反弹病毒的来源。基因上一致的病毒群体的出现以及在长时间的cART和cART中断后缺乏分化提供了强有力的证据，证明在cART启动之前感染的长寿命细胞中存在HIV-1，其中一些感染细胞可能具有增殖能力，并且正在进行的病毒复制周期并不明显。抗艾滋病毒化合物在预防艾滋病发病方面非常有效，但它们不能治愈感染者。尽管进行了抗病毒治疗，但大多数患者的血液中仍可检测到极低水平的病毒，如果停止治疗，病毒水平会飙升。了解为什么目前的治疗方法不能治愈艾滋病毒感染是至关重要的，这样才能开发出解决这些缺点的新疗法。通过表征患者在抗病毒治疗前和治疗期间的HIV基因序列，我们发现在接受治疗的患者血液中检测到的低水平病毒不是来自新感染的细胞，而是来自治疗开始时已经感染的细胞或细胞的子细胞。这一发现表明，经过长期抗病毒治疗后，血液中存在的艾滋病毒来源于治疗前感染的细胞，这些细胞可能随着时间的推移通过细胞分裂而扩大。如此长寿的受感染细胞很可能是开发治疗HIV感染策略的关键目标。
A better understanding of changes in HIV-1 population genetics with combination antiretroviral therapy (cART) is critical for designing eradication strategies. We therefore analyzed HIV-1 genetic variation and divergence in patients' plasma before cART, during suppression on cART, and after viral rebound. Single-genome sequences of plasma HIV-1 RNA were obtained from HIV-1 infected patients prior to cART (N = 14), during suppression on cART (N = 14) and/or after viral rebound following interruption of cART (N = 5). Intra-patient population diversity was measured by average pairwise difference (APD). Population structure was assessed by phylogenetic analyses and a test for panmixia. Measurements of intra-population diversity revealed no significant loss of overall genetic variation in patients treated for up to 15 years with cART. A test for panmixia, however, showed significant changes in population structure in 2/10 patients after short-term cART (<1 year) and in 7/10 patients after long-term cART (1–15 years). The changes consisted of diverse sets of viral variants prior to cART shifting to populations containing one or more genetically uniform subpopulations during cART. Despite these significant changes in population structure, rebound virus after long-term cART had little divergence from pretherapy virus, implicating long-lived cells infected before cART as the source for rebound virus. The appearance of genetically uniform virus populations and the lack of divergence after prolonged cART and cART interruption provide strong evidence that HIV-1 persists in long-lived cells infected before cART was initiated, that some of these infected cells may be capable of proliferation, and that on-going cycles of viral replication are not evident. Anti-HIV compounds are highly effective for preventing the onset of AIDS but they do not cure infected individuals. Very low levels of virus remain detectable in the blood of most patients despite antiviral treatment and levels surge if treatment is stopped. It is crucial to understand why current treatments are not equipped to cure HIV infection so that new therapies addressing these shortcomings can be developed. By characterizing genetic sequences of HIV in patients before and during antiviral treatment, we found that the low levels of virus detected in the blood of treated patients did not result from newly infected cells but originated from cells, or the daughters of cells, that were already infected when treatment was initiated. This finding demonstrates that HIV present in blood after prolonged antiviral treatment is derived from cells infected prior to treatment which likely expanded over time through cell division. Such long lived, infected cells are likely the critical target for developing strategies to cure HIV infection.
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影响因子：
56.9
作者：
COFFIN, JM
通讯作者：
COFFIN, JM
DOI：
10.1073/pnas.0804192105
发表时间：
2008-10-28
影响因子：
11.1
作者：
Joos, Beda;Fischer, Marek;Guenthard, Huldrych F.
通讯作者：
Guenthard, Huldrych F.
影响因子：
9.4
作者：
Palmer, S;Kearney, M;Coffin, JM
通讯作者：
Coffin, JM
影响因子：
1.5
作者：
Benito, JM;López, M;Soriano, V
通讯作者：
Soriano, V
影响因子：
6.4
作者：
Hatano, Hiroyu;Hayes, Timothy L.;Deeks, Steven G.
通讯作者：
Deeks, Steven G.