Divergent narrow and broad tropisms HIV-1 R5 viruses

描述（由申请人提供）：人类免疫缺陷病毒l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都使用其中一种或两种。使用ccr5的（R5）病毒优先传播。使用cxcr4的（X4）病毒可以从多达50%的艾滋病患者中分离出来。X4病毒在t细胞中具有更广泛的趋向性，并且与CD4 + t细胞的更快消耗和疾病进展有关。然而，CD4细胞耗竭和艾滋病发生在只有R5病毒可以分离的患者身上。在缺乏X4病毒的情况下导致CD4细胞耗竭的机制尚不清楚。我们的假设是，在CD4 + t细胞中具有更广泛倾向的HIV-1 R5变异在疾病晚期出现，并通过直接杀死和加剧细胞死亡的间接机制导致其耗竭。初步数据显示，HIV-1 R5包膜对t细胞和巨噬细胞具有明显的宽或窄的趋向性。R5包膜的广泛趋向性是由于它能够利用低水平的CD4和CCR5进行感染。具有窄/R5趋向性的包膜需要高CD4才能感染，但抵抗中和抗体，表明窄/宽趋向性是由中和效力决定的。因此，当免疫力下降时，中和敏感的、广泛热带的R5病毒可能进化。这类病毒也可能优先传播并在急性期和免疫特权组织中占主导地位。我们建议调查具有狭窄或广泛R5倾向的HIV-1是否与特定的疾病阶段相关。精液中HIV-1包膜的趋向性也将被评估。将确定窄/宽向性的包络决定因素。最后，我们将研究不同的R5趋向性是否会影响针对CCR5的新疗法。我们提出了四个目标。

DESCRIPTION (provided by applicant): Human immunodeficiency virus type l requires interactions with CD4 and coreceptors for infection. The chemokine receptors, CCR5 and CXCR4 are major coreceptors and all HIV-ls use one or both. CCR5-using (R5) viruses are preferentially transmitted. CXCR4-using (X4) viruses can be isolated from up to 50% of AIDS patients. X4 viruses have a broader tropism among T-cells and are associated with a faster depletion of CD4 + T-cells and disease progression. Nevertheless, CD4 depletion and AIDS occur in patients from which only R5 viruses can be isolated. The mechanisms that confer CD4 cell depletion in the absence of X4 viruses are unclear. Our hypothesis is that HIV-1 R5 variants with a broader tropism among CD4 + T-cells emerge late in disease and cause their depletion by direct killing and exacerbating indirect mechanisms of cell death. Preliminary data shows that HIV-1 R5 envelopes confer distinct broad or narrow tropisms for T-cells and macrophages. The broad tropism of R5 envelopes is conferred by capacity to use low levels of CD4 and CCR5 for infection. Envelopes with a narrow/R5 tropism required high CD4 for infection but resisted neutralizing antibodies suggesting that narrow/broad tropism is determined by neutralization potency. Thus neutralization sensitive, broadly tropic R5 viruses may evolve when immunity is declining. Such viruses may also preferentially transmit and predominate in the acute phase and immunoprivileged tissues. We propose to investigate whether HIV-1 with narrow or broad R5 tropisms are associated with particular disease stages. The tropism of HIV-1 envelopes present in semen will also be evaluated. Envelope determinants of narrow/broad tropism will be identified. Finally, we will investigate if different R5 tropisms will impact new therapies that target CCR5. We propose four aims. Aim 1. Analysis of tropism and receptor requirements of HIV-1 R5 envelopes amplified from different disease stages oj HIV-1 + individuals, from semen and the acute phase of replication. Aim 2. Identification of the R5 envelope determinants that confer HIV-1 R5 broad, narrow tropisms for T-cells ana macrophages and capacity to exploit low levels of receptors for infection. Aim 3. Evaluation of the impact of HIV-1 R5 broad and narrow tropism on sensitivity to neutralizing antibodies receptor ligands and envelope interactions with CD4 and CCR5. Aim 4. Investigation of how HIV-1 R5 virus tropism diversity impacts on sensitivity to CCR5 inhibitors and the evolution of escape mutants.