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Toward an AIDS-Free Generation:
Can Antibodies Help? / HIV-neutralizing antibody
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Posted on January 19, 2016 by Dr. Francis Collins
This year, an estimated 50,000 Americans will learn they have been newly infected with the human immunodeficiency virus (HIV), which causes AIDS [1]. The good news is that if these people are diagnosed and receive antiretroviral therapy (ART) promptly, most will enjoy a near-normal lifespan.The bad news is that, barring any further research advances, they will have to take ART every day for the rest of their lives, a regimen that's inconvenient and may cause unpleasant side effects. Clearly, a new generation of safe, effective, and longer-lasting treatments to keep HIV in check is very much needed.
That's why I'm encouraged to see some early signs of progress emerging from a small, NIH-supported clinical trial of an HIV-neutralizing antibody. While the results need to be replicated in much larger studies, researchers discovered that a single infusion of the antibody reduced levels of HIV in the bloodstreams of several HIV-infected individuals by more than 10-fold [2]. Furthermore, the study found that this antibody-known as a broadly neutralizing antibody (bNAb) for its ability to defend against a wide range of HIV strains-is well tolerated and remained in the participants' bloodstreams for weeks.
While the human immune system is generally unable to fend off HIV-in part because the virus tends to mutate as it multiplies-a minority of infected individuals eventually do produce bNAbs with the ability to target the virus in its many forms. The antibody featured in the new study, called VRC01, is a manufactured version of a protein identical to one that researchers from NIH's National Institute of Allergy and Infectious Diseases (NIAID) isolated from the blood of an infected patient back in 2009 [3]. The NIAID team went on to show that VRC01 and a related antibody could stop more than 90 percent of known HIV strains from infecting human cells in the laboratory.
The secret to VRC01's power to fight off many HIV strains is its ability to target one of a few conserved areas on the viral surface [4]. This discovery has inspired efforts to devise a vaccine that could train the immune system to make antibodies with a similarly broad neutralizing ability. It also raised the possibility that direct infusions of bNAbs might benefit HIV-infected people unable to produce these antibodies themselves.
To test this idea, researchers at the NIAID's Vaccine Research Center led by Julie Ledgerwood and John Mascola evaluated VRC01 in 23 HIV-infected people, including 15 who were taking ART and eight who were not. Those treated with ART received two VRC01 infusions 28 days apart. Those with untreated HIV received a single infusion. The average participant was 35 years old, most were college educated, and about 80 percent were male.
In a study published in the journal Science Translational Medicine, researchers reported that the antibody treatment proved safe in all participants. While the antibody didn't appear to lower levels of HIV inside of blood cells, it did significantly reduce levels of free-floating virus in the bloodstreams of six of the eight ART-untreated individuals. The reductions, which ranged from 12-to-59 fold, persisted for an extended period of time. What's more, in two of these six, the antibody reduced free-floating HIV to undetectable levels for about three weeks-or as long as VRC01 remained at therapeutic concentrations.
As for the two ART-untreated individuals who didn't respond to the antibody, they were found to carry viral strains that were more resistant or less sensitive to VRC01. Also, the antibody didn't have any apparent added benefit for 15 participants who were already taking effective ART.
While promising, the findings suggest it will take more than VRC01 alone to treat chronic HIV infection. It's possible the antibody could have a more potent effect in people who are newly infected with the virus, and another early phase trial to test this notion is set to begin soon in sub-Saharan Africa [5]. There's also evidence that VRC01 infusions delivered prior to HIV exposure might prevent infection. Clinical studies of VRCO1 infusion in healthy adults at high risk of infection are expected to begin this year in the U.S. and sub-Saharan Africa [6], and an early phase safety study in exposed infants is currently recruiting patients in locations around the world [7].
There's a long road still ahead in the quest to develop more effective means to treat and prevent HIV. But, with continued advances such as these, the path toward our ultimate goal is finally coming into view: a world in which new HIV infections are rare and deaths due to AIDS are even rarer.
Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection
Science Translational Medicine 23 Dec 2015
Passive aggression for HIV
Antibodies that neutralize HIV could add to the therapeutic arsenal to prevent and treat disease. Lynch et al. have now tested one such antibody-VRC01-in HIV-infected individuals. Although little difference was observed in viral reservoir in individuals on antiretroviral therapy, plasma viremia was reduced in untreated subjects with a single infusion of VRC01, preferentially suppressing neutralization-sensitive strains. Passive immunization with neutralizing antibodies could therefore aid in viral suppression in HIV-infected individuals.
Passive immunization with HIV-1-neutralizing monoclonal antibodies (mAbs) is being considered for prevention and treatment of HIV-1 infection. As therapeutic agents, mAbs could be used to suppress active virus replication, maintain suppression induced by antiretroviral therapy (ART), and/or decrease the size of the persistent virus reservoir. We assessed the impact of VRC01, a potent human mAb targeting the HIV-1 CD4 binding site, on ART-treated and untreated HIV-1-infected subjects. Among six ART-treated individuals with undetectable plasma viremia, two infusions of VRC01 did not reduce the peripheral blood cell-associated virus reservoir measured 4 weeks after the second infusion. In contrast, six of eight ART-untreated, viremic subjects infused with a single dose of VRC01 experienced a 1.1 to 1.8 log10 reduction in plasma viremia. The two subjects with minimal responses to VRC01 were found to have predominantly VRC01-resistant virus before treatment. Notably, two subjects with plasma virus load <1000 copies/ml demonstrated virus suppression to undetectable levels for over 20 days until VRC01 levels declined. Among the remaining four subjects with baseline virus loads between 3000 and 30,000 copies, viremia was only partially suppressed by mAb infusion, and we observed strong selection pressure for the outgrowth of less neutralization-sensitive viruses. In summary, a single infusion of mAb VRC01 significantly decreased plasma viremia and preferentially suppressed neutralization-sensitive virus strains. These data demonstrate the virological effect of this neutralizing antibody and highlight the need for combination strategies to maintain virus suppression.
Although highly active antiretroviral therapy (ART) has been used successfully to manage HIV-1 infection for 20 years, additional prevention and cure strategies are needed to further reduce the global incidence of new infections (1). Potent HIV-1-neutralizing antibodies could play a role in both prevention of infection and augmentation of current treatment approaches, including limiting the seeding of the reservoir during acute infection, maintaining virus suppression induced by ART, and reducing the cell-associated virus reservoir during chronic infection (2-5). HIV-1 infection induces a robust polyclonal antibody response targeting numerous virus antigens, including the surface-exposed virus envelope glycoprotein (Env) that is composed of surface unit gp120 and membrane-anchored gp41 molecules. Although Env-specific antibodies usually neutralize the autologous infecting virus, rapid emergence of neutralization-resistant variants limits the ability of antibodies to control HIV-1 infection. During the course of chronic infection, the neutralizing antibody response broadens in response to the antigenic diversification of the circulating virus quasispecies (6-9). Consequently, the sera of some HIV-1-infected donors contain potent, broadly neutralizing antibodies (bNAbs), although their own virus has escaped antibody-mediated clearance (10-12).
In recent years, such bNAbs have been isolated from HIV-1-infected donors, and their potency, breadth, and structural mode of recognition have been characterized (6-8, 13, 14). After passive infusion, several of these bNAbs have demonstrated efficacy as both preventive and therapeutic agents in humanized mouse and simian-human immunodeficiency virus (SHIV) rhesus macaque animal models (3, 15-23). Each of the bNAbs identified to date targets one of several relatively conserved epitopes on the virus Env spike (7, 24-32). A subset of these antibodies, the VRC01-class, is composed of antibodies that target the conserved CD4 receptor-binding site (CD4bs) on gp120 and neutralize HIV-1 by partially mimicking the binding of CD4 to this site (33-39). The human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) VRC01 neutralizes about 90% of diverse virus strains with a geometric mean 50% inhibitory concentration (IC50) of 0.33 μg/ml and IC80 of 1.0 μg/ml (26). Thus, VRC01 is considered to be both potent and broadly reactive. Furthermore, VRC01 and its clonal variants have demonstrated complete protection against infection in several animal models (18-23), and passive VRC01 infusion conferred complete protection against high-dose vaginal and rectal SHIV challenge of macaque monkeys (22). As a therapeutic agent, VRC01 has demonstrated the ability to suppress virus replication during acute SHIV infection (5). In humans, the safety of passive infusion of HIV-1 mAbs into HIV-1-infected subjects has been established in previous studies of less potent, first-generation mAbs 2F5, 4E10, and 2G12. These studies demonstrated small decreases in plasma viremia or delayed virus rebound during treatment interruption from antiretrovirals (ARVs). Notably, the rebound virus contained escape mutations only from 2G12, suggesting that only this mAb exerted selection pressure on the virus (40-43). Recently, mAb 3BNC117, which is a VRC01 class antibody but not a clonal relative of VRC01, was assessed in a phase 1 clinical trial and was shown, after a single infusion, to lower plasma viremia in HIV-1-infected individuals not receiving ART (44). The VRC01 drug product was developed by the Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH) and has been found to be safe in healthy, uninfected adults (45). Here, we assessed the virologic impact of short-term administration of VRC01 on cell-associated virus load in HIV-1-infected subjects with plasma virus load suppressed on ART, and on plasma viremia in subjects not on ART in clinical trial VRC 601. Our results demonstrate the ability of the VRC01 neutralizing mAb to suppress plasma viremia and provide initial correlations of in vitro neutralization and in vivo virologic effects.
Infusion with VRC01 is safe, well tolerated, and long-lasting in subjects on and off ART
A total of 15 subjects on ART received one or two infusions of VRC01 by intravenous (IV) or subcutaneous (SC) administration (table S1 and Fig. 1). An additional eight viremic subjects not on ART received a single VRC01 IV infusion of 40 mg/kg (table S1 and Fig. 1). Demographics of study participants were 81.5% male with a mean age of 35.4 years, 59.3% were Black or African-American, and 77.8% had a college/university or advanced degree (table S2). Overall, the 36 infusions of VRC01 administered throughout the study were safe and well tolerated with no dose-limiting toxicities (table S3).
After VRC01 infusion, the maximum serum concentration of the antibody increased as the administered dose increased (Fig. 2, A to F). The terminal half-life of VRC01 in HIV-1-infected subjects was 12 days for IV and 11 days for SC infusions (table S4). This half-life was slightly lower than the half-life reported for IV infusion of VRC01 into healthy uninfected subjects (n = 18) of 15 days (45). Anti-VRC01 antibody responses were not detected at days 28, 84, and 112 (fig. S1). Furthermore, infused VRC01 was functional in the presence of autologous antibodies after infusion as evidenced by achieving the expected increase in serum HIV neutralization breadth and potency measured on a selected virus panel (fig. S2). Population model pharmacokinetic (PK) analysis using data from this study as well as previously published data generated from VRC01 infusion in HIV-uninfected adults (45) showed no correlation between subject IgG gamma marker allotype and VRC01 half-life, nor between subject baseline virus load and VRC01 half-life (fig. S3).
VRC01 does not reduce cell-associated virus load in individuals receiving effective ART
We evaluated the effect of two VRC01 infusions given 28 days apart on HIV-1 persistence in individuals treated with effective ART by measuring residual plasma virus load and cell-associated virus load. Analysis was restricted to the highest dose groups (group 4, 20 mg/kg and group 5A, 40 mg/kg), where treatment effect would be expected to be greatest. At baseline, plasma virus loads measured by single-copy assay (SCA) were near or below the limit of detection in all but one individual (Fig. 3A and table S5). The one individual with a higher baseline plasma virus load (donor #16; 3.43 copies/ml) showed no decrease 7 days after the second of two VRC01 infusions. Because no single assay has yet been shown to measure total replication-competent cell-associated HIV-1 with high sensitivity and specificity in individuals receiving ART, we used several assays to quantify CD4 T cell-associated virus at baseline and after VRC01 infusion. Levels of total (Fig. 3B and table S5) and integrated HIV DNA (Fig. 3C and table S5) in CD4 T cells were measured as were frequencies of CD4 T cells expressing multiply spliced tat/rev RNA [tat/rev inducible limiting dilution assay (TILDA); Fig. 3D and table S5] and replication-competent HIV (Fig. 3E and table S5) after stimulation in vitro. We observed no consistent decrease in any of these measures at 7 days after the second VRC01 infusion. Furthermore, measurement of total cell-associated HIV DNA (Fig. 3, F and G, and table S5), unspliced gag RNA (Fig. 3, H and I, and table S5), and multiply spliced rev RNA (Fig. 3, J and K, and table S5) in sorted central memory (CM) and effector memory (EM) CD4 T cell subsets from blood (fig. S4) showed no consistent decrease after one or two infusions of VRC01. Levels of gag RNA were on the order of one copy per HIV DNA copy, and levels of rev RNA were frequently below the limits of detection, consistent with a quiescent cellular reservoir minimally expressing the virus even before VRC01 infusion.
Plasma virus load significantly decreases in individuals with circulating VRC01-sensitive virus
Eight study participants not currently receiving ART and with detectable baseline virus loads ranging from 237 to 27,894 copies/ml (Fig. 4A and table S1) received a single high dose of VRC01 (40 mg/kg IV). To analyze the role of the preexisting autologous circulating virus, we amplified 19 to 42 virus env genes from the plasma of each subject by single-genome amplification (SGA) on a time point within 7 days before infusion for each subject. Virus env sequences indicated that all eight subjects were infected with genetically distinct subtype B viruses; furthermore, one subject (#23) was infected with two genetically distinct subtype B strains (fig. S5). After infusion with VRC01, plasma virus load declined 12- to 59-fold in six of the eight subjects, and all subjects returned to baseline virus load (within 0.5 log10 of baseline) within 56 days after VRC01 infusion (Fig. 4B and table S6). Notably, subjects 22 and 27 who entered the study with the lowest average baseline plasma virus loads (745 and 237 copies/ml, respectively) maintained undetectable virus loads (<20 copies/ml) for more than 20 days after infusion. Compared to baseline, the average virus load of all eight viremic subjects together was significantly decreased between days 3 and 21 after infusion, with the nadir at day 9 (Fig. 4C). These eight individuals were also examined for reduction in levels of total and integrated HIV DNA within peripheral blood CD4 T cells after a single VRC01 infusion (group 5B, 40 mg/kg). Compared to a single preinfusion measurement for each participant, these levels were not consistently decreased at days 7, 35, or 56 after infusion (fig. S6).
Virus load returns to baseline as VRC01 concentration decreases and as VRC01 selects for less- sensitive viruses
To test for neutralization sensitivity of baseline virus, representative gp160 env sequences from each subject were cloned and expressed as pseudoviruses. As we investigated virus characteristics over time in these eight viremic subjects, we observed three main patterns of antibody and virus kinetics. In pattern 1, seen in subjects 21 and 26, the predominant circulating preinfusion virus was relatively resistant to VRC01. The geometric mean IC80 of the 10 autologous preinfusion Envs we tested for subject 21 was 30.3 μg/ml, and the geometric mean IC80 was 17.1 μg/ml for the 15 preinfusion Envs isolated from subject 26 (Fig. 5A). Consequently, these two subjects only had a twofold decrease in virus load (table S6). In pattern 2, seen in subjects 22 and 27, the low baseline plasma virus load (745 and 237 copies/ml, respectively) was reduced to undetectable levels after infusion and began to return to baseline on days 56 and 42, respectively, as VRC01 sera concentration waned (Fig. 5B and table S6). In pattern 3, seen in subjects 20, 23, 24, and 25, the representative preinfusion Envs tested for neutralization (7 to 11 clones per subject) were all sensitive to VRC01 with geometric mean IC80s ranging from 0.361 to 1.93 μg/ml (Fig. 5A). In these subjects, plasma virus loads declined 14- to 59-fold but were not fully suppressed, and virus loads began increasing to baseline 10 days after infusion (Fig. 5B and table S6).
To better understand the mechanism of virus load increase in the presence of VRC01, we amplified plasma virus sequences from 1-month postinfusion (day 28 or 35), and a subset of these amplicons was cloned. Neutralization sensitivity to VRC01 was compared between pre- and postinfusion Env clones for the six subjects whose viremia was >20 copies/ml at this time. We observed significant decreases in sensitivity to VRC01 for all subjects except 26, whose virus was already relatively resistant (Fig. 6A). Phylogenetic trees of longitudinal full-length gp160 env genes from days 2, 7, 28, and 35 after infusion revealed no overall changes in virus diversity, and that for all subjects, except subject 23, sequences remained intermingled over time (figs. S7 to S12). In subject 23, we observed preferential growth of a minor, genetically distinct population that was present at baseline, expanded at day 7, and represented the major population by day 28 (fig. S11).
To determine whether postinfusion reduction in VRC01 sensitivity resulted from development of a small number of resistance mutations or selection against residues that confer VRC01 sensitivity, we generated additional sequences from the preinfusion and 1-month postinfusion time points using a modified FCA assay to specifically amplify the CD4bs (HXB2 positions 141 to 477) (46). Resulting sequences were aligned with SGA sequences to identify positions within V1 to V5 at which amino acid sequences differed between preinfusion and 1-month postinfusion virus strains. We then used a neutralization-based epitope prediction (NEP) algorithm (http://exon.niaid.nih.gov/nep/) (47, 48) to predict mutational differences that could be associated with VRC01 selection. Subjects 23 and 26 were not included in this analysis because subject 23 was likely infected with two genetically distinct viruses, and one virus was predominantly circulating before infusion, whereas the other was dominant after infusion, precluding meaningful analysis. Subject 26 exhibited no effect on virus load after VRC01 infusion and subsequently had no detectable changes in sequence or neutralization phenotype (Fig. 6A and fig. S12). In subjects for whom virus selection was detected, the top-ranked residue for all subjects was found within or near VRC01 contact sites (table S7) and, interestingly, all residues being selected for postinfusion were found in preinfusion sequences (Fig. 6B). In subjects 20 and 21, overall selection occurred in or near the ß20/ß21 portion of the VRC01 epitope as well as within loop D and loop V5 (table S7). In particular, at positions 280 and 429, selection appeared to be for residues that were relatively rare in the preinfusion virus. In subjects 24 and 25, by contrast, the predominant selection occurred within loop V5 at position 462, and selection expanded the dominant preinfusion population, which was perhaps more resistant to VRC01 than minor populations. Finally, the length of loop V5 was analyzed before and after infusion. The three subjects for whom multiple residue changes in V5 were predicted to result from VRC01 selection indeed had significant differences in V5 loop length before and after infusion (Fig. 6C and table S7), and these length changes were significantly correlated to VRC01 IC80 within the subset of cloned Envs (fig. S13). In subjects 24 and 25, selection was for longer V5 loops, whereas in subject 20, selection was for shorter V5 loops.
Env clones from pre- and postinfusion were tested for neutralization sensitivity against an expanded panel of mAbs, and overall, postinfusion viruses were more resistant to VRC01-class antibodies with no corresponding change in sensitivity to membrane proximal region-targeting antibody 10E8 (table S8 and fig. S14). These data suggest that selection for certain residues within the VRC01 epitope may be sufficient to decrease the VRC01 sensitivity of circulating virus, thereby allowing increased circulating plasma virus load.
The rationale to evaluate the bNAb VRC01 as a therapeutic agent in humans was based on an emerging body of animal model data suggesting the ability of HIV-1 bNAbs to prevent virus infection and to suppress viremia during chronic infection (3, 15, 16, 22, 49-55). Here, we assessed the impact of VRC01 administration (two infusions given 28 days apart) on the size of the persistent HIV-1 reservoir and the ability of a single VRC01 infusion to suppress plasma viremia.
As candidate therapeutic agents, antibodies differ substantially from current antiretroviral drugs. In addition to their ability to bind free virus and inhibit new rounds of infection (that is, virus neutralization), antibodies can potentially target infected cells expressing virus antigens and mediate cell killing by Fc receptor-mediated effector mechanisms. To assess the potential impact of VRC01 infusion on the cell-associated virus reservoir, we studied HIV-1-infected subjects whose plasma viremia was suppressed by ART. We observed no difference in several measures of the frequency of infected cells in the peripheral blood compartment after two infusions of VRC01. Our PK studies indicated that two infusions at these dose levels of 20 and 40 mg/kg would produce peak plasma VRC01 levels of about 1000 μg/ml and a concentration of more than 10 μg/ml would be maintained over the 56-day time frame. Thus, the lack of observed effect seems unlikely to be due to insufficient antibody levels.
Rather, it is possible that prolonged treatment with bNAbs such as VRC01, perhaps several months, and antibodies with augmented Fc-mediated effector functions, such as those that enhance antibody-dependent cellular cytotoxicity, may be required to affect the cell-associated HIV-1 reservoir during ART. Alternatively, the bulk of the cell-associated reservoir may be in a truly latent state and may not express viral antigens that could be recognized by antibodies. In this regard, sustained levels of antibody in conjunction with latency reversal agents that stimulate virus expression on the cell surface may be required to potentiate the ability of mAbs to kill infected cells under ART (56, 57). We found that levels of cell-associated HIV DNA were stable after VRC01 infusion even in the eight untreated, viremic study participants. Although this may, in part, reflect the imperfect association between levels of cell-associated HIV DNA and levels of virus replication in untreated individuals, it is also possible that VRC01 was more effective at clearing virions from plasma than at interrupting virus transmission between cells in the tissues where most replication occurs. Further studies will be required to determine whether different bNAbs or engineered bNAbs will more effectively target the virus in compartments outside peripheral blood.
In these untreated viremic individuals, we observed a clear effect on plasma viremia in six of eight subjects after a single VRC01 infusion at 40 mg/kg. Subjects were not screened for virus sensitivity to VRC01 before entry into the study. We noted the likely relevance of in vitro measurement of virus neutralization resistance (IC80 values >15 μg/ml). Thus, the two subjects with predominantly resistant virus did not respond to VRC01 infusion, whereas all four subjects with neutralization-sensitive virus displayed a >1 log10 reduction in plasma viremia. These data aid in our understanding of in vitro neutralization data and in vivo efficacy that should be useful in future therapeutic clinical studies. Notably, the two subjects with plasma virus load <1000 copies/ml at baseline achieved undetectable levels of virus for about 20 days following VRC01 infusion, with a slow return to baseline between days 42 and 56 after infusion. Because the circulating viruses in these two subjects were not more neutralization-sensitive that those found in the other four subjects, these data suggest that this more marked response was due to the lower levels of circulating virus. Furthermore, our data suggest that this return to baseline occurred because of decreased antibody concentration as opposed to selection of resistant strains, although this possibility is currently being explored by sequencing from later time points.
We also investigated phenotypic and genetic changes in the virus after VRC01 infusion among the four donors in whom plasma viremia was only partially suppressed. Here, we found evidence for preferential selection and outgrowth of viruses that were less sensitive to VRC01, a finding that is not surprising given that ARVs have long been used in combination to prevent virus escape. Residues associated with VRC01 selection (significantly changed between the pre- and postinfusion populations) were identified and could all be found in the preinfusion population at varying levels. Thus, the return of baseline viremia between days 16 and 35 in these subjects appears to be primarily related to an outgrowth of preexisting virus less sensitive to VRC01. Our data on the impact of mAb infusion on viremic subjects are similar to the recent phase 1 study in humans that reported that VRC01-class antibody 3BNC117 reduced plasma virus load by 0.8 to 2.5 log10 after infusion into chronically HIV-1-infected subjects (44).
A caveat to our study is the small number of subjects, which allowed in-depth analyses but cannot fully address the roles that antibody concentration, virus selection, and preinfusion virus load play in the return of virus load to baseline. The impact of these factors will be investigated in future studies and, together with the data presented here, will inform future combination strategies that will likely be needed for maintenance of virus suppression. In summary, the data from this phase 1 study indicate that a single antibody infusion can achieve full virus suppression in chronic HIV-1-infected subjects with low levels of plasma viremia. In the absence of full suppression, virus replication allows outgrowth of virus less sensitive to antibody neutralization-a finding that is consistent with our understanding of partial virus suppression observed with antiretroviral drug therapy. These data provide proof of concept for the virologic effect of the VRC01 mAb and highlight the potential relevance of in vitro measurements of neutralization resistance. These data inform the future use of HIV-1 mAbs for both prevention and treatment of HIV-1 infection.
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