Recombination-mediated escape from primary CD8+ T cells in acute HIV-1 infection.
TL;DR: This study shows that recombination between multiple T/F viruses provide greater options for acute escape from CD8+ T cell responses than seen in cases of single T-F virus infection.
Abstract: A major immune evasion mechanism of HIV-1 is the accumulation of non-synonymous mutations in and around T cell epitopes, resulting in loss of T cell recognition and virus escape. Here we analyze primary CD8+ T cell responses and virus escape in a HLA B*81 expressing subject who was infected with two T/F viruses from a single donor. In addition to classic escape through non-synonymous mutation/s, we also observed rapid selection of multiple recombinant viruses that conferred escape from T cells specific for two epitopes in Nef. Our study shows that recombination between multiple T/F viruses provide greater options for acute escape from CD8+ T cell responses than seen in cases of single T/F virus infection. This process may contribute to the rapid disease progression in patients infected by multiple T/F viruses.
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TL;DR: An approach that involves HIV-1 latency reversal and viral clearance is reviewed, showing that instantaneous reversal of latency across all cells harboring integrated proviruses may be challenging and suggests that effective LRA strategies will likely need to be delivered serially over time.
Abstract: BACKGROUND A central challenge to emerging efforts to cure HIV infection is the persistence of quiescent but replication-competent proviral genomes in resting CD4 + T lymphocytes and, to an unknown extent, in other cell populations. Targeted approaches are sought to reverse latency, induce viral antigen expression within formerly latently infected cells, and use immune clearance mechanisms to eradicate persistent infection. Small-molecule HIV latency-reversing agents (LRAs) capable of modulating pathways that control HIV-1 latency are the first tools to be studied in this effort. However, despite the successful reversal of latency, the only clinical interventions to date producing a significant decrease in the viral reservoir involved bone marrow transplantation. Moreover, whether the HIV-1 RNA expression induced by LRAs leads to durable viral protein presentation on the surface of infected cells sufficient to allow immune mediated clearance is unknown. Because multiple mechanisms are involved in maintaining the transcriptional silence of HIV-1, a combination of LRAs may be necessary to effectively perturb persistent HIV-1 infection. Defining the cells that harbor persistent HIV-1 is technically challenging, burdening the development of antilatency therapy. Last, immune interventions designed to clear persistently infected cells have yet to be combined with LRAs in a successful, coordinated therapeutic strategy. ADVANCES Histone deacetylase (HDAC) inhibitors have been the most widely investigated LRAs, inducing cell-associated HIV-1 RNA in four clinical studies. The complex nature of the mechanisms that restrict HIV-1 expression of the population of latent integrated proviruses suggests the hypothesis that combinations of agents could more effectively disrupt latency. Numerous in vitro studies support this hypothesis, but thus far, only one animal model study used several LRAs; although results appeared promising, the effect of this combination was not directly assessed. A study of latently infected cells obtained from HIV-1 + donors on antiretroviral therapy revealed that instantaneous reversal of latency across all cells harboring integrated proviruses may be challenging and suggests that effective LRA strategies will likely need to be delivered serially over time. This study also illustrates the limitations of assessing the persistence of latent infection via HIV-1 RNA expression because a majority of such RNA transcripts are defective and therefore irrelevant. New approaches,such as novel techniques that can quantitate the frequency of rare cells in a large population that are capable of expressing viral antigen, may surmount this challenge. Other recent efforts have examined the obstacles to clearance of persistent, latent infection. For example, the latent reservoir harbors viral mutant subspecies that have previously escaped the extant antiviral immune response. Tissue sanctuaries that may be poorly accessed by the cytotoxic T lymphocyte (CTL) response have been described, as has the potential for some LRAs to interfere with CTL activity. Whether the extent of antigen presentation induced by the current generation of LRAs is sufficient to allow targeting and clearance of infected cells remains unknown. OUTLOOK Although the challenges of latent HIV-1 infection are daunting, the stability of the latent pool over years of antiviral therapy gives hope that an effective perturbation of the homeostasis that maintains the latent pool may allow substantial depletion, and eventually eradication, of persistent infection. The steady advances in animal models of HIV-1 latency, tools for the assessment of persistent infection, LRAs to disrupt latency, and emerging immunotherapeutics to clear persistently infected cells suggest that the first effective combination studies may be close at hand. Such studies will likely represent progress toward the goal of HIV-1 cure while also revealing new challenges to be overcome.
203 citations
TL;DR: In this article, the authors combine methods from evolutionary dynamics and statistical physics to simulate in vivo HIV sequence evolution, predicting the relative rate of escape and the location of escape mutations in response to T-cell-mediated immune pressure in a cohort of 17 persons with acute HIV infection.
Abstract: Human immunodeficiency virus (HIV) evolves within infected persons to escape being destroyed by the host immune system, thereby preventing effective immune control of infection. Here, we combine methods from evolutionary dynamics and statistical physics to simulate in vivo HIV sequence evolution, predicting the relative rate of escape and the location of escape mutations in response to T-cell-mediated immune pressure in a cohort of 17 persons with acute HIV infection. Predicted and clinically observed times to escape immune responses agree well, and we show that the mutational pathways to escape depend on the viral sequence background due to epistatic interactions. The ability to predict escape pathways and the duration over which control is maintained by specific immune responses open the door to rational design of immunotherapeutic strategies that might enable long-term control of HIV infection. Our approach enables intra-host evolution of a human pathogen to be predicted in a probabilistic framework.
117 citations
Journal Article•
TL;DR: Methods from evolutionary dynamics and statistical physics are combined to simulate in vivo HIV sequence evolution, predicting the relative rate of escape and the location of escape mutations in response to T-cell-mediated immune pressure in a cohort of 17 persons with acute HIV infection.
87 citations
TL;DR: Viruses emerging during ATI in individuals treated with 3BNC117 are not the dominant species found in the circulating latent reservoir, but frequently appear to represent recombinants of latent viruses.
Abstract: A clinical trial was performed to evaluate 3BNC117, a potent anti-HIV-1 antibody, in infected individuals during suppressive antiretroviral therapy and subsequent analytical treatment interruption (ATI). The circulating reservoir was evaluated by quantitative and qualitative viral outgrowth assay (Q2VOA) at entry and after 6 mo. There were no significant quantitative changes in the size of the reservoir before ATI, and the composition of circulating reservoir clones varied in a manner that did not correlate with 3BNC117 sensitivity. 3BNC117 binding site amino acid variants found in rebound viruses preexisted in the latent reservoir. However, only 3 of 217 rebound viruses were identical to 868 latent viruses isolated by Q2VOA and near full-length sequencing. Instead, 63% of the rebound viruses appeared to be recombinants, even in individuals with 3BNC117-resistant reservoir viruses. In conclusion, viruses emerging during ATI in individuals treated with 3BNC117 are not the dominant species found in the circulating latent reservoir, but frequently appear to represent recombinants of latent viruses.
83 citations
TL;DR: A computational tool is developed to track recombination in patients, identify recombination hot spots, and show contribution of recombination to antibody escape, which provides insight into molecular mechanisms by which viral recombination contributes to HIV-1 persistence and immunopathogenesis.
Abstract: Recombination in HIV-1 is well documented, but its importance in the low-diversity setting of within-host diversification is less understood. Here we develop a novel computational tool (RAPR (Recombination Analysis PRogram)) to enable a detailed view of in vivo viral recombination during early infection, and we apply it to near-full-length HIV-1 genome sequences from longitudinal samples. Recombinant genomes rapidly replace transmitted/founder (T/F) lineages, with a median half-time of 27 days, increasing the genetic complexity of the viral population. We identify recombination hot and cold spots that differ from those observed in inter-subtype recombinants. Furthermore, RAPR analysis of longitudinal samples from an individual with well-characterized neutralizing antibody responses shows that recombination helps carry forward resistance-conferring mutations in the diversifying quasispecies. These findings provide insight into molecular mechanisms by which viral recombination contributes to HIV-1 persistence and immunopathogenesis and have implications for studies of HIV transmission and evolution in vivo.
77 citations
References
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TL;DR: This final installment of the paper considers the case where the signals or the messages or both are continuously variable, in contrast with the discrete nature assumed until now.
Abstract: In this final installment of the paper we consider the case where the signals or the messages or both are continuously variable, in contrast with the discrete nature assumed until now. To a considerable extent the continuous case can be obtained through a limiting process from the discrete case by dividing the continuum of messages and signals into a large but finite number of small regions and calculating the various parameters involved on a discrete basis. As the size of the regions is decreased these parameters in general approach as limits the proper values for the continuous case. There are, however, a few new effects that appear and also a general change of emphasis in the direction of specialization of the general results to particular cases.
65,425 citations
TL;DR: The sensitivity of the commonly used progressive multiple sequence alignment method has been greatly improved and modifications are incorporated into a new program, CLUSTAL W, which is freely available.
Abstract: The sensitivity of the commonly used progressive multiple sequence alignment method has been greatly improved for the alignment of divergent protein sequences. Firstly, individual weights are assigned to each sequence in a partial alignment in order to down-weight near-duplicate sequences and up-weight the most divergent ones. Secondly, amino acid substitution matrices are varied at different alignment stages according to the divergence of the sequences to be aligned. Thirdly, residue-specific gap penalties and locally reduced gap penalties in hydrophilic regions encourage new gaps in potential loop regions rather than regular secondary structure. Fourthly, positions in early alignments where gaps have been opened receive locally reduced gap penalties to encourage the opening up of new gaps at these positions. These modifications are incorporated into a new program, CLUSTAL W which is freely available.
63,427 citations
"Recombination-mediated escape from ..." refers methods in this paper
...The sequences were aligned using CLUSTAL W [43] and the manual adjustment for optimal alignment was performed using Seaview....
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TL;DR: It is suggested that cellular immunity is involved in the initial control of virus replication in primary HIV-1 infection and a role for CTL in protective immunity to HIV- 1 in vivo is indicated.
Abstract: Virologic and immunologic studies were performed on five patients presenting with primary human immunodeficiency virus type 1 (HIV-1) infection. CD8+ cytotoxic T lymphocyte (CTL) precursors specific for cells expressing antigens of HIV-1 Gag, Pol, and Env were detected at or within 3 weeks of presentation in four of the five patients and were detected in all five patients by 3 to 6 months after presentation. The one patient with an absent initial CTL response had prolonged symptoms, persistent viremia, and low CD4+ T-cell count. Neutralizing antibody activity was absent at the time of presentation in all five patients. These findings suggest that cellular immunity is involved in the initial control of virus replication in primary HIV-1 infection and indicate a role for CTL in protective immunity to HIV-1 in vivo.
2,614 citations
"Recombination-mediated escape from ..." refers background in this paper
...Background HIV-1 specific CD8+ T cells are first detected prior to peak viremia and expand concomitantly with decline of acute plasma virus load (pVL) [1,2]....
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TL;DR: HIV-1-specific CTL activity is a major component of the host immune response associated with the control of virus replication following primary HIV-1 infection and have important implications for the design of antiviral vaccines.
Abstract: Human immunodeficiency virus type 1 (HIV-1) Env-, Gag-, Pol-, Nef-, and Tat-specific cytotoxic T-lymphocyte (CTL) activities were quantitated temporally in five patients with symptomatic primary HIV-1 infection. A dominant CD8(+)-mediated, major histocompatibility complex class I-restricted CTL response to the HIV-1 envelope glycoprotein, gp160, was noted in four of the five patients studied. The level of HIV-1-specific CTL activity in the five patients paralleled the efficiency of control of primary viremia. Patients who mounted strong gp160-specific CTL responses showed rapid reduction of acute plasma viremia and antigenemia, while in contrast, primary viremia and antigenemia were poorly controlled in patients in whom virus-specific CTL activity was low or undetectable. These results suggest that HIV-1-specific CTL activity is a major component of the host immune response associated with the control of virus replication following primary HIV-1 infection and have important implications for the design of antiviral vaccines.
1,924 citations
"Recombination-mediated escape from ..." refers background in this paper
...Background HIV-1 specific CD8+ T cells are first detected prior to peak viremia and expand concomitantly with decline of acute plasma virus load (pVL) [1,2]....
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Los Alamos National Laboratory1, University of Massachusetts Amherst2, University of North Carolina at Chapel Hill3, Duke University4, University of Maryland, College Park5, University of California, San Francisco6, University of Rochester7, University of Cape Town8, Santa Fe Institute9, University of Alabama at Birmingham10
TL;DR: A mathematical model of random viral evolution and phylogenetic tree construction is developed and used to analyze 3,449 complete env sequences derived by single genome amplification from 102 subjects with acute HIV-1 (clade B) infection, suggesting a finite window of potential vulnerability of HIV- 1 to vaccine-elicited immune responses, although phenotypic properties of transmitted Envs pose a formidable defense.
Abstract: The precise identification of the HIV-1 envelope glycoprotein (Env) responsible for productive clinical infection could be instrumental in elucidating the molecular basis of HIV-1 transmission and in designing effective vaccines. Here, we developed a mathematical model of random viral evolution and, together with phylogenetic tree construction, used it to analyze 3,449 complete env sequences derived by single genome amplification from 102 subjects with acute HIV-1 (clade B) infection. Viral env genes evolving from individual transmitted or founder viruses generally exhibited a Poisson distribution of mutations and star-like phylogeny, which coalesced to an inferred consensus sequence at or near the estimated time of virus transmission. Overall, 78 of 102 subjects had evidence of productive clinical infection by a single virus, and 24 others had evidence of productive clinical infection by a minimum of two to five viruses. Phenotypic analysis of transmitted or early founder Envs revealed a consistent pattern of CCR5 dependence, masking of coreceptor binding regions, and equivalent or modestly enhanced resistance to the fusion inhibitor T1249 and broadly neutralizing antibodies compared with Envs from chronically infected subjects. Low multiplicity infection and limited viral evolution preceding peak viremia suggest a finite window of potential vulnerability of HIV-1 to vaccine-elicited immune responses, although phenotypic properties of transmitted Envs pose a formidable defense.
1,880 citations
"Recombination-mediated escape from ..." refers background or methods in this paper
...Fifty, 3′-half genome sequences were analyzed at screening (Fiebig I-II) giving > 90% confidence to detect virus variants at the 5% level [12]....
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...These observations provide empirical evidence of a mechanism beyond stochastic events to explain the emergence of recombination reported in acute infection [12,14,15,17]....
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...This in depth case study of a patient infected with two T/F HIV-1 viruses has demonstrated that the appearance of recombinants known to occur during acute infection [12,14,15,17] can be driven by the selective action of CD8+ T cell responses....
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...Infection with multiple T/F viruses is linked to factors that are known to increase overall transmission rates, such as higher risk sex acts and other concurrent sexually transmitted infections [12,15-19]....
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...HIV-1 is highly recombinogenic [26] and HIV-1 recombination has been observed in patients infected with multiple viruses within weeks-months of infection [12,14,15,17]....
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