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分离株都使用其中一种或两种。使用ccr5 （R5）的病毒几乎占了所有的传播。初步数据显示，R5病毒的细胞趋向性差异很大，这取决于它们利用低水平CD4和/或CCR5进行感染的能力。因此，R5向性可以描述为窄/R5和宽/R5。宽/R5包膜可感染表达低水平CD4和/或CCR5的巨噬细胞和t细胞，而窄/R5包膜仅感染CD4水平高的细胞。初步数据还表明，窄/R5包膜对中和抗体的抵抗力更强。值得注意的是，在免疫特权脑组织中发现了具有广泛/R5向性的包膜。我们的假设是，中和敏感的广谱/R5病毒在疾病晚期免疫力下降或免疫特权组织中进化。在产生中和抗体之前，这些病毒可能优先传播并在急性感染中占主导地位。

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.