Ma Zhong-Min, Dutra Joseph, Fritts Linda, Miller Christopher J
Center for Comparative Medicine and California National Primate Research Center, University of California, Davis, Davis, California, USA.
Center for Comparative Medicine and California National Primate Research Center, University of California, Davis, Davis, California, USA
J Virol. 2016 Mar 28;90(8):4093-4104. doi: 10.1128/JVI.02947-15. Print 2016 Apr.
The human immunodeficiency virus (HIV) is primarily transmitted by heterosexual contact, and approximately equal numbers of men and women worldwide are infected with the virus. Understanding the biology of HIV acquisition and dissemination in men exposed to the virus by insertive penile intercourse is likely to help with the rational design of vaccines that can limit or prevent HIV transmission. To characterize the target cells and dissemination pathways involved in establishing systemic simian immunodeficiency virus (SIV) infection, we necropsied male rhesus macaques at 1, 3, 7, and 14 days after penile SIV inoculation and quantified the levels of unspliced SIV RNA and spliced SIV RNA in tissue lysates and the number of SIV RNA-positive cells in tissue sections. We found that penile (glans, foreskin, coronal sulcus) T cells and, to a lesser extent, macrophages and dendritic cells are primary targets of infection and that SIV rapidly reaches the regional lymph nodes. At 7 days after inoculation, SIV had disseminated to the blood, systemic lymph nodes, and mucosal lymphoid tissues. Further, at 7 days postinoculation (p.i.), spliced SIV RNA levels were the highest in the genital lymph nodes, indicating that this is the site where the infection is initially amplified. By 14 days p.i., spliced SIV RNA levels were high in all tissues, but they were the highest in the gastrointestinal tract, indicating that the primary site of virus replication had shifted from the genital lymph nodes to the gut. The stepwise pattern of virus replication and dissemination described here suggests that vaccine-elicited immune responses in the genital lymph nodes could help prevent infection after penile SIV challenge.
To be the most effective, vaccines should produce antiviral immune responses in the anatomic sites of virus replication. Thus, understanding the path taken by HIV from the mucosal surfaces, which are the site of virus exposure, to the deeper tissues where the virus replicates will provide insight into where AIDS vaccines should produce immunity to be the most effective. In this study, we determined that, by day 7 after penile inoculation, SIV has moved first to the inguinal lymph nodes and replicates to high levels. Although the virus is widely disseminated to other tissues by day 7, replication is largely limited to the inguinal lymph nodes. The step-by-step movement of SIV from penile mucosal surfaces to the draining lymph nodes may allow an HIV vaccine that produces immunity in these lymph nodes to block HIV from establishing an infection in an exposed person.
人类免疫缺陷病毒（HIV）主要通过异性接触传播，全球感染该病毒的男性和女性数量大致相等。了解通过插入式阴茎性交接触病毒的男性中HIV感染和传播的生物学机制，可能有助于合理设计能够限制或预防HIV传播的疫苗。为了表征建立系统性猴免疫缺陷病毒（SIV）感染所涉及的靶细胞和传播途径，我们在阴茎接种SIV后1、3、7和14天对雄性恒河猴进行了尸检，并对组织裂解物中未剪接的SIV RNA和剪接的SIV RNA水平以及组织切片中SIV RNA阳性细胞的数量进行了定量。我们发现阴茎（龟头、包皮、冠状沟）T细胞，以及程度较轻的巨噬细胞和树突状细胞是主要感染靶细胞，并且SIV迅速到达局部淋巴结。接种后7天，SIV已扩散到血液、全身淋巴结和黏膜淋巴组织。此外，接种后7天（p.i.），剪接的SIV RNA水平在生殖器淋巴结中最高，表明这是感染最初扩增的部位。到接种后14天，剪接的SIV RNA水平在所有组织中都很高，但在胃肠道中最高，表明病毒复制的主要部位已从生殖器淋巴结转移到肠道。这里描述的病毒复制和传播的逐步模式表明，生殖器淋巴结中疫苗引发的免疫反应可能有助于预防阴茎SIV攻击后的感染。
为了达到最有效的效果，疫苗应在病毒复制的解剖部位产生抗病毒免疫反应。因此，了解HIV从作为病毒暴露部位的黏膜表面到病毒复制的更深组织所采取的途径，将有助于深入了解艾滋病疫苗应在何处产生免疫力才能最有效。在这项研究中，我们确定，阴茎接种后7天，SIV首先转移到腹股沟淋巴结并大量复制。虽然到第7天病毒已广泛扩散到其他组织，但复制主要限于腹股沟淋巴结。SIV从阴茎黏膜表面逐步转移到引流淋巴结，这可能使在这些淋巴结中产生免疫力的HIV疫苗能够阻止HIV在暴露个体中建立感染。
