Viral Determinants of HIV-1 Transmission in African Heterosexuals

HIV-1病毒变异和HIV-1传播。作为一种慢病毒，HIV-1具有巨大的 for variation变化.然而，尽管有这种明显的能力，具体的病毒特性对传播风险的影响还没有得到很好的理解。以前对HIV-1异性性传播的研究已经允许描述HIV-1传播的重要风险因素，例如传播伙伴的HIV-1血浆RNA[2]、GUD[3，4]和可治愈的STI（例如，梅毒、淋病、衣原体和滴虫）[5]和缺乏男性包皮环切术[6，8]。如果特定的病毒序列特征也能被清楚地记录下来，以改变HIV-1传播的风险，HIV-1疫苗的开发可以集中在针对这些病毒特征的宿主免疫反应上。此外，如果可变因素与感染HIV-1的伴侣产生更多可传播变异的可能性增加有关，则预防干预措施可侧重于针对这些可变因素，以降低产生可传播变异的风险。 3.2关于传播的HIV-1变异体特征的现有知识概要。早期研究 HIV-1变异与母婴传播[9]和性传播[10，11]的关系表明，HIV-1 B亚型血清转换者与其传播伙伴相比，HIV-1库的多样性较低，并且传播的变异体通常与传播伙伴血浆中低频率存在的病毒变异体密切相关。 然而，在一项对32名非洲异性恋女性和10名非洲异性恋男性进行的研究中，A和D亚型HIV-1 RNA检测后的中位数分别为59和65天，通过异源双链迁移率测定（HMA）评估的病毒多样性显示，20/32名女性中存在多种HIV-1变体，而10/10名男性中仅发现单一变体（p=0.001）。这些数据表明，感染的伴侣性别和/或病毒亚型改变了创始者变体的特征[12]。 病毒特征可能影响传播性的进一步证据随后来自于对多个血浆和PBMC衍生的HIV-1 C亚型env克隆的分析，这些克隆在HIV-1血清转化的3-4个月内从8对最初HIV-1血清不一致的赞比亚异性夫妇的伴侣中分离。HIV-1 env序列数据表明，在8个血清转换者中，每一个都有一个创始病毒的传播或暴发性生长（包括男性到女性和女性到男性的传播）。与原始感染传播部分中存在的变异体相比，传播变异体通常具有更可能对中和敏感的HIV-1包膜糖蛋白、较低的PNLGS频率和较短的可变区[13]。两者的重要性 在对23名感染HIV-1亚型A的肯尼亚妇女的血浆进行的一项研究中，证实了包膜糖蛋白中PNLGS的可变区更短和频率增加[14]。对13对HIV-1 D亚型传播血清不一致夫妇的研究也支持传播性与较短的env可变长度相关，但未发现与PNLGS相关[15]。这些病毒特征对B亚型变异传播的影响还没有明确的定义，但到目前为止还没有发现相同的区别[16，17]。 最近，两项研究对新感染HIV-1亚型B（n= 102;只有20%承认有同性恋接触）[18]和亚型C（n=69;都声称是异性恋）病毒的个体在感染后不同时间的大量血浆衍生变体进行了测序。在这两项研究中评估的171名个体中，109名（64%）在Fiebig阶段I-IV（估计为感染后<30天）期间进行评估。这些研究报告说，在77%的新感染者中，病毒种群在系统发育分析中是同质的，而在23%的新感染者中检测到多种变异。从对37名感染HIV-1亚型B的MSM的研究中获得了类似的结果，这些MSM在Fiebig I期和II期时被评估[20]。虽然这些频率 均质和异质性创始者感染的风险因素被解释为与感染者的亚型、传播途径和性别无关，这些研究的行为和临床数据有限，无法描述均质和异质性感染的风险因素[18，19]。此外，由于在这些研究中仅评估了血清转化伴侣，因此他们无法推断感染伴侣的病毒库的特征。由于许多传播被认为是在TP新感染时发生的[21]，这些潜在的急性期TP不太可能传播多个创始人变体。

HIV-1 viral variation and HIV-1 transmission. As a lentivirus, HIV-1 has a tremendous proven capacity for variation. However, despite this evident capacity, the effect of specific viral properties on risk of transmission is not well understood. Previous studies of HIV-1 heterosexual transmission have permitted characterization of important risk factors for HIV-1 transmission such as the transmitting partner's HIV-1 plasma RNA[2]^ GUD[3,4] and curable STI (e.g.,' syphilis, gonorrhea, chlamydia and trichomonas)[5] and lack of male circumcision[6,8]. If specific viral sequence characteristics can also be clearly documented to modify risk of HIV-1 transmission, HIV-1 vaccine development could focus on targeting host immune responses to these virus characteristics. Furthermore, if modifiable factors are associated with increased likelihood that an HIV-1 infected partner will generate more transmissible variants, prevention interventions can be focused to target those modifiable factors to reduce the risk of generating transmissible variants. 3.2 Synopsis of current knowledge about characteristics of transmitted HIV-1 variant(s). Early studies of HIV-1 variation in relation to mother-to-child[9] and sexual transmission [10,11] suggested that HIV-1 subtype B seroconverters have less diverse HIV-1 pools compared to their transmitting partners, and that transmitted variants are often closely related to virus variants present in low frequency in the transmitting partner's plasma. However, in a study of 32 heterosexual African women and 10 heterosexual African men evaluated a median of 59 and 65 days, respectively, after subtype A and D HIV-1 RNA detection, viral diversity assessed by heteroduplex mobility assay (HMA) revealed multiple HIV-1 variants present in 20/32 women while only a single variant was found in each of 10/10 men (p=0.001). These data suggest that the infected partner gender and/or virus subtype modify characteristics of the founder variant[12]. Further evidence that viral characteristics may influence transmissibility came subsequently from analysis of multiple plasma- and PBMC-derived HlV-1 subtype C env clones isolated within 3-4 months of HIV-1 seroconversion from both partners of 8 initially HIV-1 serodiscordant Zambian heterosexual couples. HIV-1 env sequence data suggested transmission or fulminate outgrowth of one founder virus in each of the 8 seroconverters (including male-to-female and female-to-male transmissions). Transmitted variants often had HIV-1 envelope glycoproteins more likely to be neutralization-sensitive, lower frequency of PNLGS and shorter variable regions compared to variants present in the original infected transmitting partne[13]. The importance of both the shorter variable regions and increased frequency of PNLGS in the envelope glycoprotein was corroborated in a study of plasma derived from 23 Kenyan women infected with HIV-1 subtype A[14]. A study of 13 HIV-1 subtype D transmitting serodiscordant couples also supports the association of transmissibility with shorter env variable lengths, but did not find an association with PNLGS[15]. The impact of these viral characteristics on transmission of subtype B variants has not been clearly defined, but to date the same distinctions have not beeen found[16,17]. Recently, two studies sequenced a large number of plasma-derived variants from individuals newly infected with HIV-1 subtype B (n= 102; only 20% admitted homosexual contacts)[18] and subtype C (n=69; all claimed to be heterosexuals)" viruses at various times after infection. Among the 171 individuals evaluated in these two studies, 109 (64%) were assessed during Fiebig stage l-IV (estimated to be <30 days post-infection). These studies reported that in 77% of newly infected individuals, virus populations were homogeneous in phylogenetic analysis, while in 23% multiple variants were detected. Similar results were obtained from a study of 37 MSM infected with HlV-1 subtype B who were assessed while in Fiebig stages I and ll [20]. While these frequencies of homogeneous and heterogeneous founder infection were interpreted as being independent of subtype, transmission route and gender of the infected person, these studies had limited behavioral and clinical data on which to characterize risk factors for homogenous and heterogeneous infection[18,19]. Furthermore, since only the seroconverting partners were assessed in these studies, they were unable to infer the characteristics of the infected partners' viral pool. As many transmissions are thought to occur when the TP is newly infected[21], these potentially acute-stage TP are unlikely to be capable of transmitting multiple founder variants.