Herbeck Joshua, Ghorai Suvankar, Chen Lennie, Rinaldo Charles R, Margolick Joseph B, Detels Roger, Jacobson Lisa, Wolinsky Steven, Mullins James I
Department of Global Health, University of Washington, Seattle, Washington, United States of America.
Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
PLoS One. 2015 Mar 6;10(3):e0119218. doi: 10.1371/journal.pone.0119218. eCollection 2015.
Some individuals remain HIV-1 antibody and PCR negative after repeated exposures to the virus, and are referred to as HIV-exposed seronegatives (HESN). However, the causes of resistance to HIV-1 infection in cases other than those with a homozygous CCR5Δ32 deletion are unclear. We hypothesized that human p21WAF1/CIP1 (a cyclin-dependent kinase inhibitor) could play a role in resistance to HIV-1 infection in HESN, as p21 expression has been associated with suppression of HIV-1 in elite controllers and reported to block HIV-1 integration in cell culture. We measured p21 RNA expression in PBMC from 40 HESN and 40 low exposure HIV-1 seroconverters (LESC) prior to their infection using a real-time PCR assay. Comparing the 20 HESN with the highest exposure risk (median = 111 partners/2.5 years prior to the 20 LESC with the lowest exposure risk (median = 1 partner/2.5 years prior), p21 expression trended higher in HESN in only one of two experiments (P = 0.11 vs. P = 0.80). Additionally, comparison of p21 expression in the top 40 HESN (median = 73 partners/year) and lowest 40 LESC (median = 2 partners/year) showed no difference between the groups (P = 0.84). There was a weak linear trend between risk of infection after exposure and increasing p21 gene expression (R2 = 0.02, P = 0.12), but again only in one experiment. Hence, if p21 expression contributes to the resistance to viral infection in HESN, it likely plays a minor role evident only in those with extremely high levels of exposure to HIV-1.
一些个体在反复接触病毒后仍保持HIV-1抗体和PCR检测阴性，被称为HIV暴露血清阴性者（HESN）。然而，除了纯合子CCR5Δ32缺失者外，其他情况下对HIV-1感染产生抗性的原因尚不清楚。我们推测人类p21WAF1/CIP1（一种细胞周期蛋白依赖性激酶抑制剂）可能在HESN对HIV-1感染的抗性中发挥作用，因为p21的表达与精英控制者中HIV-1的抑制有关，并且据报道在细胞培养中可阻断HIV-1整合。我们使用实时PCR检测法，在40名HESN和40名低暴露HIV-1血清转化者（LESC）感染前测量其外周血单核细胞（PBMC）中的p21 RNA表达。将20名暴露风险最高的HESN（中位数 = 111个性伴/2.5年）与20名暴露风险最低的LESC（中位数 = 1个性伴/2.5年）进行比较，在两个实验中只有一个实验显示HESN中的p21表达有升高趋势（P = 0.11对比P = 0.80）。此外，比较前40名HESN（中位数 = 73个性伴/年）和最低40名LESC（中位数 = 2个性伴/年）中的p21表达，两组之间没有差异（P = 0.84）。暴露后感染风险与p21基因表达增加之间存在微弱的线性趋势（R2 = 0.02，P = 0.12），但同样仅在一个实验中出现。因此，如果p21表达有助于HESN对病毒感染的抗性，它可能仅在那些HIV-1暴露水平极高的个体中发挥微小作用。
