Impact of HIV-1 fitness on disease progression

描述（由申请人提供）：在这个竞争性更新的A1修订申请中，我们将重点关注HIV-1复制适应度的影响，因为它与传播效率和随后的疾病进展有关。根据我们为期十年的乌干达/津巴布韦（Ug/Zim）自然HIV-1病史队列研究，涉及270名妇女（100万数据/样本点），C型感染妇女的CD4细胞下降明显慢于A型和D型感染妇女。在目标1中，我们将继续分析该队列中的HIV-1适应度，并将根据病毒载量和CD4细胞计数确定HIV-1建立急性/早期感染的致病适应度是否预测随后的疾病进展。来自约200名患者血液的传播/创始人（TF） HIV-1将用于多个竞赛，现在可以使用新的454方法和复杂的算法快速分析。我们现在表明，缓慢的疾病进展与不太适合的HIV-1分离株（通常是C亚型）的感染有关，而D亚型TF HIV-1分离株具有最高的复制适合度，并导致最快的疾病进展。C亚型可能在艾滋病毒大流行中扩大，因为传播机会增加（疾病进展时间延长），但亚型之间的相对传播效率是R0方程的另一半。在目标2中，我们将使用不同的人类粘膜组织（阴茎、宫颈和直肠）进行感染/竞赛，其中含有来自急性/早期感染的5-10种病毒的混合物，以确定在离体模型中的传播适应性。根据初步数据，C型TF HIV-1在阴茎和宫颈组织中的传播适应度高于A型和D型TF HIV-1。我们也有初步数据表明，HET TF HIV-1可能与来自男男性行为者（MSM）、静脉吸毒者（IVDU）或血友病患者（HEMO）的乙型TF HIV-1亚型具有不同的表型特性。在目的2中，我们将确定HET亚型B TF HIV-1在宫颈和阴茎组织模型中的传播适应度是否略高于MSM TF HIV-1或IVDU/HEMO TF HIV-1。我们认为，阴茎、宫颈和阴道粘膜将在HIV-1从HET和MSM传播中选择不同的表型特性（目的3），因为它们比直肠组织或血液中发现的屏障更显著。在特定的ai 3中，我们将控制致病和传播适应度的机制。我们认为，pbmc、T细胞和巨噬细胞的“致病性”适应度与宿主细胞进入的效率直接相关，因为更适合的原代HIV-1分离株具有更快的进入动力学，更有能力感染低CD4/低CCR5（亲和蛋白）的细胞，并且通常对进入不太敏感

DESCRIPTION (provided by applicant): In this revised A1 application for competitive renewal, we will focus on the impact of HIV-1 replicative fitness as it relates to transmission efficiency and subsequent disease progression. Based on our ten year Uganda/Zimbabwe (Ug/Zim) natural HIV-1 history cohort study involving 270 women (>10,000 data/sample points), CD4 cell declines in subtype C infected women were significantly slower than in subtype A and subtype D infected women. In aim 1, we will continue our analyses of HIV-1 fitness in this cohort and will determine if the pathogenic fitness of the HIV-1 establishing acute/early infection predicts subsequent disease progression based on viral loads and CD4 cell counts. The transmitted/founder (TF) HIV-1 from the blood of ~200 patients will be used in multiple competitions that can now be rapidly analyzed with a new 454 approach and sophisticated algorithms. We now show that slow disease progression is associated with infection by a less fit HIV-1 isolate, generally subtype C whereas subtype D TF HIV-1 isolates have the highest replicative fitness and causes the fastest disease progression. Subtype C may have expanded in HIV pandemic based increased opportunity for transmission (longer disease progression) but relative transmission efficiency between subtypes is the other half of the R0 equation. In aim 2, we will perform infections/competitions using various human mucosal tissue (penile, cervical, and rectal) with a mixture of 5-10 viruses derived from acute/early infection to determine transmission fitness in an ex vivo model. Based on preliminary data, the subtype C TF HIV-1 had higher transmission fitness than subtype A and D TF HIV-1 in the penile and cervical tissue. We also have preliminary data suggesting that HET TF HIV-1 may have different phenotypic properties than subtype B TF HIV-1 derived from men-who-have-sex- with-men (MSM), IV drug users (IVDU), or hemophiliacs (HEMO). In aim 2, we will determine if HET subtype B TF HIV-1 have slightly higher transmission fitness in cervical and penile tissue models than MSM TF HIV-1 or than IVDU/HEMO TF HIV-1. We propose that the penile, cervical, and vaginal mucosa will select for distinct phenotypic properties (aim 3) in the TF HIV-1 from HET and MSM transmission due to a more significant barrier than found in rectal tissue or blood. In specific ai 3, we will the mechanisms controlling pathogenic and transmission fitness. We propose that this "pathogenic" fitness in PBMCs, T cells, and macrophages is directly related to the efficiency of host cell entry considering that more fit primary HIV-1 isolates have faster entry kinetics, greate ability to infect cells of low CD4/low CCR5 (Affinofile), and are typically less sensitive to entry inhibitors (aim 3). Based on preliminary data, transmission fitness may be more dependent on higher CD4 affinity, reduced levels of N linked glycosylation on the virus envelope, and reduced lectin binding affinity. We propose that the majority of HIV-1 transmitted from donor to recipient is trapped in the mucosal tissue (e.g. cervix) due to lectin binding and other barriers that effectively "keep pathogens out".