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Combination HIV Antibody Infusions Safely Maintain Viral Suppression in Select Individuals: "phase 1b clinical trial in which a combination of 3BNC117 and 10-1074, two potent monoclonal anti-HIV-1 broadly neutralizing antibodies that target independent sites on the HIV-1 envelope spike, was administered during analytical treatment interruption"
 
 
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"Study eligibility criteria included ongoing ART for at least 24 months with plasma HIV-1 RNA levels of <50 copies per ml for at least 18 months (one blip <500 copies per ml was allowed) and <20 copies per ml at screening, as well as CD4+ T cell counts >500 cells per μl (Extended Data Figs. 1b, 2a). Enrolled participants received three infusions of 30 mg kg-1 of 3BNC117 and 10-1074 each at three-week intervals beginning two days before treatment interruption (Fig. 1a). Individuals whose regimens contained non-nucleoside reverse transcriptase inhibitors were switched to an integrase inhibitor-based regimen four weeks before discontinuing ART (Extended Data Figs. 1b, 2a). Viral load and CD4+ T cell counts were monitored every 1-2 weeks (Supplementary Table 2). ART was reinitiated and antibody infusions were discontinued if viraemia of >200 copies per ml was confirmed. Time of viral rebound was defined as the first of two consecutive viral loads of >200 copies per ml. Fifteen individuals were enrolled, but four of them showed viral loads of >20 copies per ml two weeks before or at the time of the first bNAb infusion and they were excluded from efficacy analyses (Extended Data Fig. 1b and Supplementary Table 2)........Individuals harbouring viruses sensitive to 3BNC117 and 10-1074 maintained viral suppression during ATI for a median of almost four months after the final antibody administration. However, HIV-1 is a highly diverse virus with varying levels of sensitivity to specific bNAbs. As a result, maintenance therapy with just the combination of 3BNC117 and 10-1074 would only be possible for the approximately 50% of clade B-infected individuals that are sensitive to both antibodies. This problem may be overcome by addition of or substitution with other antibodies14,15,43, or long-acting small-molecule antiretroviral drugs......For the 11 individuals who had complete viral suppression (HIV-1 RNA <20 copies per ml) during the screening period and at day 0, combination antibody therapy was associated with maintenance of viral suppression for between 5 and more than 30 weeks (Fig. 1b, c and Supplementary Table 2). The median time to rebound was 21 weeks compared to 2.3 weeks for historical controls who participated in previous non-interventional ATI studies10 and 6-10 weeks for monotherapy with 3BNC1179 (Fig. 1c). Together, 9 of the 11 participants maintained viral suppression for at least 15 weeks, although two rebounded at weeks 5 and 7 (Fig. 1b, c)......Quantitative and qualitative viral outgrowth assays (Q2VOA) were used to retrospectively analyse the replication-competent latent viral reservoir in all individuals. Phylogenetic analysis showed that the trial participants were infected with epidemiologically distinct clade B viruses (Extended Data Fig. 3). Q2VOA analysis revealed that the pre-infusion latent reservoir in the two individuals who rebounded early, 9245 and 9251, harboured 10-1074- or 3BNC117-resistant viruses, respectively (Fig. 2 and Supplementary Table 4). Therefore, these two individuals were effectively subjected to antibody monotherapy, because there was pre-existing resistance in the reservoir of these individuals to one of the two bNAbs. Consistent with this idea, the delay in rebound in these two participants was within the anticipated range of antibody monotherapy9,11 (Fig. 1c). In addition, all four of the individuals excluded from the analysis due to incomplete viral suppression showed pre-existing resistance or viruses that were not fully neutralized by one or both of the antibodies and these individuals rebounded before week 12 (Extended Data Figs. 4, 5 and Supplementary Table 4)."
 
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HIV Did Not Develop Resistance to Experimental Treatment
 
September 26, 2018
 
https://www.niaid.nih.gov/news-events/combination-hiv-antibody-infusions-safely-maintain-viral-suppression-select-individuals?utm_campaign=+34605768&utm_content=&utm_medium=email&utm_source=govdelivery&utm_term=
 
A small group of people living with HIV sensitive to two potent anti-HIV broadly neutralizing antibodies (bNAbs) (link is external)-3BNC117 and 10-1074-tolerated multiple infusions of the antibodies and suppressed HIV for more than 15 weeks after stopping antiretroviral therapy (ART). The new findings, from a pilot clinical trial supported by the National Institutes of Health (NIH), the Bill & Melinda Gates Foundation and others, are reported today in Nature.
 
"A safe, reliable, antibody-based treatment regimen would open new possibilities for people living with HIV," said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases, part of NIH. "This study represents an important, early step towards that goal and, importantly, helps establish that a combination of broadly neutralizing antibodies to HIV can safely suppress the virus in certain individuals without the apparent development of viral resistance."
 
Rockefeller University investigators and their colleagues recruited 15 volunteers whose HIV was suppressed with ART and was initially found to be sensitive to both 3BNC117 and 10-1074. Participants received infusions of both bNAbs, stopped taking ART two days later, and received additional infusions three and six weeks later.
 
In previous studies, researchers found that infusions of a single bNAb did not suppress HIV because resistant strains developed in some individuals. The new study tested the theory thata combination of multiple antibodies targeting distinct regions of HIV would both suppress the virus and prevent the development of resistance.
 
Among the 11 people who completed the study, nine maintained viral suppression without ART for an average of 15 weeks, until the amount of bNAbs in their bodies fell below protective levels. Two of the nine participants maintained virologic control through the end of the 30-week study follow-up period. The other two participants were found to harbor HIV resistant to at least one bNAb and experienced viral rebound before 12 weeks after stopping ART.
 
Overall, the findings suggest that like combination ART, combination bNAb infusions may be able to suppress HIV if the antibodies are maintained at therapeutic levels in people who do not harbor resistant virus. Further research is needed to identify bNAb combinations that can suppress HIV long-term in people whose HIV sensitivity to bNAbs is unknown. The Rockefeller University team currently is enrolling people living with HIV in a larger study to evaluate an optimized regimen of 3BNC117 and 10-1074. Learn more about the study reported in Nature by visiting ClinicalTrials.gov using study identifier NCT02825797 (link is external), and learn more about the currently enrolling study under identifier NCT03526848 (link is external).
 
Reference: P Mendoza et al. Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature DOI: 10.1038/s41586-018-0531-2 (2018).
 
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Combination therapy with anti-HIV-1 antibodies maintains viral suppression
 
Nature volume 561, pages479-484 (2018)
 
Abstract
 
Individuals infected with HIV-1 require lifelong antiretroviral therapy, because interruption of treatment leads to rapid rebound viraemia. Here we report on a phase 1b clinical trial in which a combination of 3BNC117 and 10-1074, two potent monoclonal anti-HIV-1 broadly neutralizing antibodies that target independent sites on the HIV-1 envelope spike, was administered during analytical treatment interruption. Participants received three infusions of 30 mg kg-1 of each antibody at 0, 3 and 6 weeks. Infusions of the two antibodies were generally well-tolerated. The nine enrolled individuals with antibody-sensitive latent viral reservoirs maintained suppression for between 15 and more than 30 weeks (median of 21 weeks), and none developed viruses that were resistant to both antibodies. We conclude that the combination of the anti-HIV-1 monoclonal antibodies 3BNC117 and 10-1074 can maintain long-term suppression in the absence of antiretroviral therapy in individuals with antibody-sensitive viral reservoirs.
 
Discussion
 
First-generation anti-HIV-1 bNAbs were generally ineffective in suppressing viraemia in animal models and humans leading to the conclusion that this approach should not be pursued17,18,28. The advent of new methods for anti-HIV-1 antibody cloning29 and subsequent discovery of a new, more potent generation of bNAbs revitalized this area of research30,31.
 
bNAb monotherapy with 3BNC117 or VRC01 is not enough to maintain control during ATI in HIV-1-infected humans9,11. Similar results were obtained in participant 9251 who effectively received 10-1074 monotherapy due to pre-existing resistance to 3BNC117. By contrast the combination of 3BNC117 and 10-1074 is sufficient to maintain viral suppression in sensitive individuals when the concentration of both antibodies remains above of 10 μg ml-1 in serum. Rebound occurred when 3BNC117 levels dropped below 10 μg ml-1 effectively leading to 10-1074 monotherapy, from which viruses in nearly all individuals rapidly escaped by mutations in the 10-1074 contact site. The observation that nine individuals infected with distinct viruses were unable to develop viruses who were resistant to both antibodies over a median period of 21 weeks suggests that viral replication was severely limited by this combination of antibodies.
 
In human studies, monotherapy with 3BNC117 is associated with enhanced humoral immunity and accelerated clearance of HIV-1-infected cells5,32. In addition, when administered early to macaques infected with the chimeric simian/human immunodeficiency virus SHIVAD8, combined 3BNC117 and 10-1074 immunotherapy induced host CD8+ T cell responses that contributed to the control of viraemia in nearly 50% of the animals3. However, virus-specific CD8+ T cells that were responsible for control of viraemia in these macaques were not detected in the circulation, and their contribution to viral suppression was only documented after CD8+ T cell depletion3. In most macaques that maintained viral control, complete viral suppression was only established after rebound viraemia that followed antibody clearance3.
 
Two individuals in this study remained suppressed for over 30 weeks after ATI, 9254 and 9255. Neither participant had detectable levels of ART in the blood or carried the B*27 and B*57 HLA alleles that are most frequently associated with elite control33. The first, 9254, reports starting ART within 4-5 months after probable exposure to the virus with an initial viral load of 860,000 copies per ml. Despite relatively early therapy, and excellent virological control for 21 years on therapy, this individual had an IUPM of 0.68 by Q2VOA at the 12-week time point (Extended Data Fig. 10b). The second individual, 9255, showed several viral blips that were spontaneously controlled beginning 15 weeks after ATI when antibody levels were waning. This individual was infected for at least 7 months before starting ART with an initial viral load of 85,800 copies per ml and had an IUPM of 1.4 at the 12-week time point. A small fraction of individuals on ART10 show spontaneous prolonged virologic control after ART is discontinued, and this number appears to increase when ART treatment is initiated during the acute phase of infection34,35,36,37,38. Whether antibody-enhanced CD8+ T cell responses contribute to the prolonged control in the two out of nine individuals who received combination immunotherapy and whether this effect can be enhanced by latency reactivating agents or immune checkpoint inhibitors remains to be determined.
 
A substantial fraction of the circulating latent reservoir is composed of expanded clones of infected T cells24,26,39,40,41,42. These T cell clones appear to be dynamic in that the specific contribution of individual clones of circulating latently infected CD4+ T cells to the reservoir of individuals receiving ART fluctuates over time24,25. Individuals that maintain viral suppression by antibody therapy appear to show similar fluctuations in reservoir clones that do not appear to be associated with antibody sensitivity. Whether the apparent differences observed in the reservoir during immunotherapy lead to changes in the reservoir half-life cannot be determined from the available data and will require reservoir assessments in additional individuals at multiple time points over an extended observation period.
 
Individuals harbouring viruses sensitive to 3BNC117 and 10-1074 maintained viral suppression during ATI for a median of almost four months after the final antibody administration. However, HIV-1 is a highly diverse virus with varying levels of sensitivity to specific bNAbs. As a result, maintenance therapy with just the combination of 3BNC117 and 10-1074 would only be possible for the approximately 50% of clade B-infected individuals that are sensitive to both antibodies. This problem may be overcome by addition of or substitution with other antibodies14,15,43, or long-acting small-molecule antiretroviral drugs.
 
In macaques, the therapeutic efficacy of anti-HIV-1 antibodies is directly related to their half-life4,12,13, which can be extended by mutations that enhance Fc domain interactions with the neonatal Fc receptor4,13,44. These mutations also increase the half-life of antibodies in humans by 2-4-fold45. Our data suggest that a single administration of combinations of bNAbs with extended half-lives could maintain suppression for 6-12 months in individuals harbouring sensitive viruses.
 
Main
 
During infection, HIV-1 is reverse transcribed and integrated as a provirus into the host genome. Although the vast majority of infected cells die by apoptosis or pyroptosis1, a small percentage survive and harbour transcriptionally silent, integrated proviruses that comprise a reservoir that can be reactivated. Once established, the latent reservoir has an estimated half-life of 44 months, resulting in the lifelong requirement for antiretroviral therapy (ART)2. Passive administration of potent broadly neutralizing monoclonal anti-HIV-1 antibodies (bNAbs) represents a potential alternative to antiretroviral drugs because, in addition to neutralizing the virus, antibodies engage the host immune system and have long half-lives3,4,5.
 
In human clinical trials, viraemic individuals who received 3BNC117 or VRC01, two related bNAbs that target the CD4 binding site on the HIV-1 envelope spike, or 10-1074, a bNAb that targets the base of the V3 loop and surrounding glycans, showed significant reductions in viremia6,7,8. Moreover, in HIV-1-infected individuals undergoing analytical treatment interruption (ATI) of antiretroviral therapy, four infusions of 3BNC117 maintained virus suppression for a median of 10 weeks compared to 2.3 weeks in historical controls9,10. By contrast, six infusions of VRC01 maintained suppression for 5.6 weeks11. The difference in activity between VRC01 and 3BNC117 in preclinical experiments12,13 and clinical trials6,7,9,11 is consistent with the lower relative neutralization potency of VRC01.
 
Across all bNAb clinical trials to date, and similar to monotherapy with antiretroviral drugs, treatment with any single bNAb was associated with the emergence of antibody-resistant viral variants6,7,8,9,11. Like antiretroviral drugs, combinations of bNAbs are more effective than individual antibodies in HIV-1 infected humanized mice and simian/human immunodeficiency virus (SHIV)-infected macaques14,15,16. By contrast, antibody combinations showed little if any efficacy in suppressing viraemia during ATI in humans17,18. However, these earlier studies were performed using bNAbs that were less potent than 3BNC117 and 10-1074. Here we investigate whether the bNAb combination of 3BNC117 and 10-1074 can maintain viral suppression during ATI in HIV-1-infected humans.
 
Combination bNAb infusion is well-tolerated
 
To evaluate the effects of the combination of 3BNC117 and 10-1074 on maintaining HIV-1 suppression during ATI, we conducted a phase 1b clinical trial (Fig. 1a). HIV-1-infected individuals on ART were pre-screened for 3BNC117 and 10-1074 sensitivity of bulk outgrowth culture-derived viruses in an in vitro neutralization assay using TZM-bl cells19. Consistent with previous results, 64% and 71% of the outgrowth viruses were sensitive to 3BNC117 and 10-1074, respectively, and 48% were sensitive to both8,9,20 (half-maximum inhibitory concentration (IC50) ≤ 2 μg ml-1; Extended Data Fig. 1a and Supplementary Table 1).
 
Study eligibility criteria included ongoing ART for at least 24 months with plasma HIV-1 RNA levels of <50 copies per ml for at least 18 months (one blip <500 copies per ml was allowed) and <20 copies per ml at screening, as well as CD4+ T cell counts >500 cells per μl (Extended Data Figs. 1b, 2a). Enrolled participants received three infusions of 30 mg kg-1 of 3BNC117 and 10-1074 each at three-week intervals beginning two days before treatment interruption (Fig. 1a). Individuals whose regimens contained non-nucleoside reverse transcriptase inhibitors were switched to an integrase inhibitor-based regimen four weeks before discontinuing ART (Extended Data Figs. 1b, 2a). Viral load and CD4+ T cell counts were monitored every 1-2 weeks (Supplementary Table 2). ART was reinitiated and antibody infusions were discontinued if viraemia of >200 copies per ml was confirmed. Time of viral rebound was defined as the first of two consecutive viral loads of >200 copies per ml. Fifteen individuals were enrolled, but four of them showed viral loads of >20 copies per ml two weeks before or at the time of the first bNAb infusion and they were excluded from efficacy analyses (Extended Data Fig. 1b and Supplementary Table 2).
 
Antibody infusions were generally safe and well-tolerated with no reported serious adverse events or antibody-related adverse events, except for mild fatigue in two participants (Supplementary Table 3). The mean CD4+ T cell count was 685 and 559 cells per μl at the time of first antibody infusion and at rebound, respectively (Extended Data Fig. 2b and Supplementary Table 2). Reinitiation of ART after viral rebound resulted in resuppression of viraemia (Supplementary Table 2). We conclude that combination therapy with 3BNC117 and 10-1074 is generally safe and well-tolerated.
 
The serum half-life of each antibody was measured independently by TZM-bl assay and anti-idiotype enzyme-linked immunosorbent assay (ELISA, Extended Data Fig. 2c, d and Supplementary Table 2). 3BNC117 had a half-life of 12.5 and 17.6 days as measured using TZM-bl and ELISA, respectively (Extended Data Fig. 2c, d). The half-life of 10-1074 was 19.1 and 23.2 days as measured by TZM-bl and ELISA, respectively; significantly longer than 3BNC117 in both assays (P = 0.0002 and P = 0.02, Extended Data Fig. 2e, f). These measurements are similar to those observed when each antibody was administered alone in ART-treated HIV-1-infected individuals6,8,9. We conclude that the pharmacokinetic profiles of 3BNC117 and 10-1074 are not altered when they are used in combination.
 
The combination of bNAbs maintains viral suppression
 
For the 11 individuals who had complete viral suppression (HIV-1 RNA <20 copies per ml) during the screening period and at day 0, combination antibody therapy was associated with maintenance of viral suppression for between 5 and more than 30 weeks (Fig. 1b, c and Supplementary Table 2). The median time to rebound was 21 weeks compared to 2.3 weeks for historical controls who participated in previous non-interventional ATI studies10 and 6-10 weeks for monotherapy with 3BNC1179 (Fig. 1c). Together, 9 of the 11 participants maintained viral suppression for at least 15 weeks, although two rebounded at weeks 5 and 7 (Fig. 1b, c).
 
Quantitative and qualitative viral outgrowth assays (Q2VOA) were used to retrospectively analyse the replication-competent latent viral reservoir in all individuals. Phylogenetic analysis showed that the trial participants were infected with epidemiologically distinct clade B viruses (Extended Data Fig. 3). Q2VOA analysis revealed that the pre-infusion latent reservoir in the two individuals who rebounded early, 9245 and 9251, harboured 10-1074- or 3BNC117-resistant viruses, respectively (Fig. 2 and Supplementary Table 4). Therefore, these two individuals were effectively subjected to antibody monotherapy, because there was pre-existing resistance in the reservoir of these individuals to one of the two bNAbs. Consistent with this idea, the delay in rebound in these two participants was within the anticipated range of antibody monotherapy9,11 (Fig. 1c). In addition, all four of the individuals excluded from the analysis due to incomplete viral suppression showed pre-existing resistance or viruses that were not fully neutralized by one or both of the antibodies and these individuals rebounded before week 12 (Extended Data Figs. 4, 5 and Supplementary Table 4).
 
To examine the viruses that arose in the early rebounding individuals, we performed single genome analysis (SGA) of plasma viruses obtained at the time of rebound. In addition to the pre-existing sequences associated with resistance in the 10-1074 target site (N332T and S334N, Fig. 2a), rebound viruses in 9245 also carried an extended V5 loop and potential N-linked glycosylation sites that could interfere with 3BNC117 binding (Extended Data Fig. 6). Conversely, genetic features associated with resistance to 3BNC117 were found in the pre-infusion reservoir of 9251 and were accompanied by mutations in the 10-1074 target site in the rebounding viruses (S334N, Fig. 2a and Extended Data Fig. 6). For both individuals, resistance of rebound viruses to both antibodies was confirmed by the TZM-bl neutralization assay (Fig. 2b, c and Supplementary Table 4). Thus, bulk outgrowth cultures used for screening failed to detect pre-existing resistance in the reservoir of 2 of the 11 studied individuals. This result is not surprising given that bulk cultures are dominated by a limited number of rapidly growing viral species that may not be representative of the diversity of the latent reservoir.
 
The median time to rebound in the seven individuals that had no detectable resistant viruses in the pre-infusion latent reservoir, and rebounded during the study period, was also 21 weeks and different from the 6-10 weeks found for monotherapy with 3BNC1179 (Fig. 1c). In these participants, viral suppression was maintained for 15-26 weeks after ART discontinuation (Supplementary Table 2). The two remaining participants (9254 and 9255) completed study follow-up at 30 weeks without experiencing rebound (Supplementary Table 2). Notably, viral rebound never occurred when the concentration of both administered antibodies was above 10 μg ml-1. The average serum concentration of 3BNC117 (determined by TZM-bl assay) at the time of rebound in sensitive individuals that rebounded during study follow-up was 1.9 μg ml-1 (Fig. 1b and Supplementary Table 2). By contrast, the average serum concentration of 10-1074 at rebound was 14.8 μg ml-1 (Fig. 1b and Supplementary Table 2). The difference in the antibody concentrations at the time of rebound is consistent with the longer half-life of 10-1074, which resulted in a period of 10-1074 monotherapy (Fig. 1b, Extended Data Fig. 2c-f and Supplementary Table 2). Finally, these nine individuals showed little or no pre-existing neutralizing antibodies against a diagnostic panel of viruses before bNAb infusion (Supplementary Table 5).
 
Rebound and latent viruses
 
To examine the relationship between rebound viruses and the circulating latent reservoir, we compared env sequences obtained from plasma rebound viruses by SGA with sequences obtained by Q2VOA from both pre-infusion and week 12 samples. In addition, we measured the sensitivity of rebound outgrowth viruses and/or pseudoviruses to 3BNC117 and 10-1074 using the TZM-bl neutralization assay (Fig. 2b, c, 3, Extended Data Fig. 7 and Supplementary Table 4). A total of 154 viral env sequences obtained by plasma SGA were analysed and compared to 408 sequences obtained from the latent reservoir by Q2VOA. Although rebound and reservoir viruses clustered together for each individual (Extended Data Fig. 3), we found no identical sequences between the two compartments in any of the individuals studied (Figs. 3, 4a and Extended Data Fig. 7). The difference could be accounted for by distinct requirements for HIV-1 reactivation in vitro and in vivo, compartmentalization of reservoir viruses, HIV-1 mutation during the course of the trial and/or by viral recombination in some individuals20,21 (Extended Data Fig. 8). Whether or not bNAb therapy influences selection for recombination events remains to be determined.
 
Similar to 3BNC117 monotherapy, the vast majority of rebounding viruses clustered within low-diversity lineages consistent with expansion of 1-2 recrudescent viruses9 (Fig. 3, Extended Data Figs. 7, 9). By contrast, rebound viruses are consistently polyclonal during ATI in the absence of antibody therapy22,23. Thus, the antibodies restrict the outgrowth of latent viruses in vivo.
 
The emerging viruses in 6 of the 7 individuals who rebounded when the mean 3BNC117 and 10-1074 serum concentrations were 1.9 and 14.8 μg ml-1, respectively, carried resistance-associated mutations in the 10-1074 target site (Figs. 1b, 2a). Consistent with the sequence data, these rebound viruses were generally resistant to 10-1074, as shown by the TZM-bl neutralization assay, but remained sensitive to 3BNC117 (Fig. 2b, c and Supplementary Table 4). The level of sensitivity to 3BNC117 in these emerging viruses was similar to that found in the reservoir viruses in each of the individuals (Fig. 2b and Supplementary Table 4). One individual, 9244, showed rebound viruses that remained sensitive to both antibodies in TZM-bl neutralization assays. Rebound occurred when 3BNC117 and 10-1074 concentrations in serum of this individual were undetectable and 11.6 μg ml-1, respectively (Fig. 1b and Supplementary Table 2). The sensitivity of the plasma rebound viruses was similar to that of latent pre-infusion and week 12 viruses obtained in viral outgrowth cultures (Fig. 2b, c and Supplementary Table 4). Therefore, this individual did not develop resistance to either of the antibodies despite prolonged exposure to both. In conclusion, none of the nine individuals with pre-infusion reservoirs containing viruses that were sensitive to both antibodies developed double resistance during the observation period.
 
The latent reservoir
 
To determine whether there were changes in the circulating reservoir during the observation period, we compared the results of Q2VOA assays performed at entry and 12 weeks after the start of ATI for 8 of the 9 individuals that remained suppressed for at least 12 weeks (Fig. 4 and Extended Data Fig. 10). Similar to previous reports, 63% of all viruses obtained by Q2VOA belonged to expanded clones20,24,25,26 (Extended Data Fig. 10a, b). Comparison of the env sequences of the viruses that emerged in outgrowth cultures revealed that 60% of the sequences could be found at both time points. However, there were numerous examples of clones that appeared or disappeared between the time points and some of the changes were significant (Extended Data Fig. 10a). To determine the number of infectious units per million (IUPM, http://silicianolab.johnshopkins.edu/), 6.0 × 107-6.2 × 108 CD4+ T cells were assayed by Q2VOA for each time point for each individual (Fig. 4b). The difference between the two time points was never greater than 6.5-fold for any individual, and the IUPM values at the two time points were not statistically different (P = 0.078). Moreover, time to rebound was not directly correlated with IUPM (Extended Data Fig. 10c). Additional time points would be required to calculate the half-life of the reservoir in individuals who received immunotherapy27.

 
 
 
 
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