Divergent narrow and broad tropisms HIV-1 R5 viruses

描述(申请人提供)：L型人类免疫缺陷病毒需要与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，所有的HIV-1都使用一种或两种。使用CCR5的(R5)病毒优先传播。使用CXCR4的(X4)病毒可以从高达50%的艾滋病患者身上分离出来。X4病毒在T细胞中具有更广泛的趋向性，并与CD4+T细胞更快耗尽和疾病进展有关。然而，在仅能分离出R5病毒的患者中，会发生CD4耗尽和艾滋病。在没有X4病毒的情况下，导致CD4细胞枯竭的机制尚不清楚。我们的假设是，HIV-1R5变异体在CD4+T细胞中具有更广泛的趋向性，在疾病发生较晚时出现，并通过直接杀伤和加剧细胞死亡的间接机制导致其枯竭。初步数据显示，HIV-1R5膜对T细胞和巨噬细胞具有明显的宽或窄取向。R5包膜的广泛取向是由于能够利用低水平的CD4和CCR5进行感染。具有狭义/R5取向的包膜需要高CD4感染，但抵抗中和抗体，这表明狭义/宽向性由中和效力决定。因此，中和敏感的广亲和R5病毒可能会在免疫力下降时进化。这种病毒也可能在急性期和免疫缺陷组织中优先传播和占优势。我们建议调查具有窄的或宽的R5取向的HIV-1是否与特定的疾病阶段相关。还将对精液中存在的HIV-1包膜的趋向性进行评估。将确定狭义/宽泛取向的包络决定因素。最后，我们将调查不同的R5取向是否会影响针对CCR5的新疗法。我们提出了四个目标。 目的1.分析从HIV-1阳性患者不同病期、精液和复制急性期扩增的HIV-1 R5囊膜的亲和性和受体需求。目的2.确定决定HIV-1R5对T细胞和巨噬细胞的宽、窄趋向性的R5包膜决定因素以及利用低水平受体进行感染的能力。 目的3.评价HIV-1R5的广义和狭义趋向性对中和抗体受体配体的敏感性以及与CD4和CCR5的包膜相互作用的影响。目的4.研究HIV-1R5病毒趋向性多样性对CCR5抑制剂敏感性和逃逸突变株进化的影响。

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.