Tropism and transmissibility of HIV-1 envelopes in semen

描述(由申请人提供)：人类免疫缺陷病毒1型需要与CD4和辅助受体相互作用才能感染。趋化因子受体CCR5和CXCR4是主要的辅助受体，所有HIV-1分离株都使用其中之一或两者都使用。使用CCR5的(R5)病毒几乎占了所有传播的份额。提供的初步数据表明，R5病毒在细胞嗜性方面存在很大差异，这取决于它们利用低水平的CD4和/或CCR5进行感染的能力。因此，R5取向可以描述为窄/R5和宽/R5。宽/R5膜可感染表达低水平CD4和/或CCR5的巨噬细胞和T细胞，而窄/R5膜仅感染表达高水平CD4的细胞。初步数据还表明，窄的/R5包膜对中和抗体更具抵抗力。值得注意的是，在免疫缺陷的脑组织中发现了具有宽/R5取向的包膜。我们的假设是，中和敏感的BRED/R5病毒在疾病后期进化，当免疫力下降时或在免疫缺陷组织中。在出现中和抗体之前，这种病毒可能会优先传播并在急性感染中占优势。 精液中HIV-1的来源和表型尚不清楚。目前尚不清楚是否存在具有广泛嗜性的R5菌株。精液中的病毒库可能有几个不同的来源，包括免疫组织和免疫缺陷组织，如睾丸。对于一些人来说，精液中的HIV-1序列与血液中的HIV-1序列具有不同的血统。精液中HIV-1序列的变异在多大程度上会转化为不同的生物学功能，如嗜性，从而影响HIV-1的传播能力，目前尚不清楚。此外，对捐赠者/接受者传播对的几项研究表明，在只传播一小部分病毒基因型的情况下，传播具有高度选择性。这项建议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组织培养中的特征。重要的是，传播病毒的包膜会容易受到中和抗体的攻击吗？提出了以下三个目标： 目的1.从不同疾病阶段的精液和血液中扩增HIV-1 R5膜蛋白，分析其细胞亲和性和受体需求。 目的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CD4和CCR5的相互作用。 目的3.评估精液包膜对宫颈外植体培养的感染能力。

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.