Tropism and transmissibility of HIV-1 envelopes in semen

描述（由申请方提供）：人类免疫缺陷病毒1型需要与CD 4和辅助受体相互作用才能感染。趋化因子受体CCR 5和CXCR 4是主要的辅助受体，所有HIV-1分离株都使用一种或两种。使用CCR 5（R5）的病毒几乎占所有的传播。初步数据显示，R5病毒在细胞嗜性方面有很大差异，这取决于它们利用低水平的CD 4和/或CCR 5进行感染的能力。因此，R5向性可以描述为窄/R5和宽/R5。宽/R5包膜赋予表达低水平的CD 4和/或CCR 5的巨噬细胞和T细胞的感染，而窄/R5包膜仅感染具有高水平的CD 4的细胞。初步数据还表明，窄/R5包膜对中和抗体更具抗性。值得注意的是，在免疫豁免的脑组织中鉴定出具有广泛/R5向性的包膜。我们的假设是，中和敏感的，广泛的/R5病毒在疾病后期，当免疫力下降或在免疫豁免组织中进化。在中和抗体产生之前，这些病毒可能优先传播并在急性感染中占主导地位。 精液中HIV-1的来源和表型还不清楚。是否存在赋予广泛嗜性的R5菌株尚不清楚。几种不同的来源可能有助于精液中的病毒库，包括免疫组织和免疫豁免组织，例如睾丸。对于某些个体，精液中的HIV-1序列与血液中的序列显示出不同的谱系。精液中HIV-1序列变异转化为不同生物学功能的程度，例如影响HIV-1传播能力的嗜性，尚不清楚。此外，对供体/受体传播对的几项研究表明，传播是高度选择性的，只有一小部分病毒基因型被传播。该提案旨在调查精液中存在的HIV-1包膜的生物学特性，并确定有助于传播到宫颈外植体培养物中的特征。重要的是，赋予传播的包膜是否容易受到中和抗体的攻击？提出了以下三个目标： 目标1。从不同疾病阶段的精液和血液样本中扩增的HIV-1 R5包膜的细胞嗜性和受体需求分析 目标2.评价精液和血液来源的HIV-1包膜的生物学特性，包括对中和抗体、受体配体的敏感性以及包膜与CD 4和CCR 5的相互作用。 目标3：评估精液包膜对宫颈外植体培养物感染的能力。

DESCRIPTION (provided by applicant): Human immunodeficiency virus type 1 requires interactions with CD4 and coreceptors for infection. The chemokine receptors, CCR5 and CXCR4 are major coreceptors and all HIV-1 isolates use one or both. CCR5-using (R5) viruses account for almost all transmissions. Preliminary data presented shows that R5 viruses vary considerably in cell tropism depending on their capacity to exploit low levels of CD4 and/or CCR5 for infection. Thus, R5 tropisms can be described as narrow/R5 and broad/R5. Broad/R5 envelopes conferred infection of macrophages and T-cells that expressed low levels of CD4 and/or CCR5, while narrow/R5 envelopes only infected cells with high CD4 levels. Preliminary data also suggests that narrow/R5 envelopes are more resistant to neutralizing antibodies. Of note, envelopes with broad/R5 tropism were identified in immunoprivileged brain tissue. Our hypothesis is that neutralization sensitive, broad/R5 viruses evolve late in disease when immunity declines or in immunoprivileged tissues. Such viruses may preferentially transmit and predominate in acute infection before neutralizing antibodies arise. The origins and phenotypes of HIV-1 in semen are poorly defined. Whether R5 strains that confer broad tropism are present is not known. Several distinct sources may contribute to the pool of virus in semen, including both immune and immunoprivileged tissues e.g. the testes. For some individuals, HIV-1 sequences in semen show distinct lineages from those in blood. The extent HIV-1 sequence variation in semen translates into different biological functions e.g. tropism, that affect capacity of HIV-1 to transmit is unknown. Moreover, several studies of donor/recipient transmission pairs demonstrate that transmission is highly selective where only a small subset of viral genotypes are transmitted. This proposal aims to investigate the biological properties of HIV-1 envelopes present in semen and define the characteristics that facilitate transmission into cervical explant cultures. Importantly, will envelopes that confer transmission be vulnerable to neutralizing antibodies? The following three aims are proposed: Aim 1. Analysis of cell tropism and receptor requirements of HIV-1 R5 envelopes amplified from semen and blood sampled at different disease stages. Aim 2. Evaluation of the biological properties of semen and blood derived HIV-1 envelopes including sensitivity to neutralizing antibodies, receptor ligands and envelope interactions with CD4 and CCR5. Aim 3. Assessment of semen envelopes for their capacity to confer infection of cervical explant cultures.