2 New HIV Antibodies Studies Reported, combining 3 antibodies
Download the PDF here
Download the PDF here
from Jules: I remind you Aging & HIV - which receives less attention & programatic funding than cure from the federal govt and advocates but not patients - is at least as important as HIV cure research, if not more important at least to HIV-infected; considering that 80% of HIV-infected in the USA are over 45 years old, 50% are over 50, 20% are over 60-65. Declinig health, frailty and multiple comorbidities and polypharmacy are the hallmark of aging with HIV - not to mention increased suicidal ideation & great decline in quality of life -, as patients age over 65 increased frailty & accumulated affects of the "aging syndrome" start to have more serious affects. Healthcare costs for the aging population will double that of younger HIV-infected on ART & debilitation & death will increase quite a lot. Future challenges for clinical care of an ageing population infected with HIV: a "geriatric-HIV" modelling study - [Healthcare Costs].... Very Sobering Analysis go Aging in HIV+....60% frail - (09/15/16)........
Cost of Care in Older Aging patients with Increased Comorbidities......Non-HIV care provider....Aging, Worse Still to Come? http://www.natap.org/2016/HIV/120816_02.htm
In the field of HIV research, antibodies continue to be a targeted area.
Two new studies published today in Science Translational Medicine offer potential new treatment pathways that could make the condition a thing of the past - or at least slow its progression.
The results are promising, but to prove it works it must be tested in people with HIV.
Dr. Antonio Urbina, an associate professor of medicine at the Icahn School of Medicine at Mount Sinai Hospital in New York, was also optimistic about the results of the study.
"But in order to truly eradicate HIV, the potent CD8 T cell responses would also need to penetrate other reservoir sites outside of lymph tissue, for example, the central nervous system," he told Healthline.
One of today's studies explained how scientists have created a two-pronged antibody that aids the immune system in finding and eliminating HIV-infected cells that are hard to see.
In the other study, researchers found that three antibodies could neutralize and stall the virus.
HIV can hide in the CD4 helper cells that are located in the lymph nodes, which has made it more difficult to fight the disease.
In the past, vaccines and checkpoint inhibitors were able to boost CD8 T cells to kill the virus, but they weren't effective if they didn't have access to the area where HIV was replicating.
The CD8 T cells were able to get into the lymph node follicles but couldn't kill the virus.
However, researchers discovered killer CD8 T cells in that same area that could be used to hunt down the infected cells. They showed that the CD8 T cells could be triggered to kill CD4 cells when they were cultured with a dual-functioning antibody that was made to target the virus and dispatch CD8 T cells.
They say that these bispecific antibodies could be a treatment strategy.
In addition, they emphasize the use of bispecific antibodies may be considered as part of a "shock-and-kill" treatment strategy in those people taking suppressive antiretroviral therapy (ART) for extended periods of time.
In the other study, researchers found that three antibodies could neutralize and stall the virus.
For most people with HIV, the virus spreads rapidly throughout the body and goes undetected by the immune system.
In rare cases, though, some people develop broadly neutralizing antibodies (bNAbs) that keep the pathogen hidden for extended periods of time.
While doing research on treating humanized mice, researchers discovered three bNAbs in one person. Scientists believe the bNAbs can keep HIV infection from progressing to AIDS over a span of 30 years.
When they looked at that person's virus five times between 2006 and 2015, they found that the HIV was vulnerable to neutralization by at least one of the antibodies. In total, a single bNAb was associated with decreased virus, and all three together lowered it 10 times over.
As a result, the researchers believe that the three bNAbs could be used as a passive immunotherapy. Further clinical trials are needed to evaluate its efficacy.
Johnston noted that the combination of antibodies can prevent a treatment-resistant virus from emerging.
"It would be very interesting to know whether the antibodies ... can not only neutralize the virus, but also kill the cells that produce it," Johnston noted.
Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies
"Our data demonstrate an accumulation of fCD8 T cells in chronic HIV and that these cells can act as potent effectors in conjunction with bispecific antibodies as part of a strategy to eliminate HIV-infected cells in vivo."
Science Translational Medicine Jan 18 2017
Constantinos Petrovas,1 * Sara Ferrando-Martinez,1 * Michael Y. Gerner,2‡ Joseph P. Casazza,1 Amarendra Pegu,3 Claire Deleage,4 Arik Cooper,3 Jason Hataye,1 Sarah Andrews,5 David Ambrozak,1 Perla M. Del Río Estrada,6 Eli Boritz,7 Robert Paris,8 Eirini Moysi,1 Kristin L. Boswell,1 Ezequiel Ruiz-Mateos,9 Ilias Vagios,10 Manuel Leal,9 Yuria Ablanedo-Terrazas,6 Amaranta Rivero,6 Luz Alicia Gonzalez-Hernandez,6 Adrian B. McDermott,5 Susan Moir,11 Gustavo Reyes-Terán,6 Fernando Docobo,9 Giuseppe Pantaleo,12 Daniel C. Douek,7 Michael R. Betts,13 Jacob D. Estes,4 Ronald N. Germain,2 John R. Mascola,3 Richard A. Koup1
Follicular CD8 T cells might ferret out HIV
HIV-infected CD4 T cells may lurk in lymphoid follicles that are normally devoid of CD8 T cells, making these areas a safe haven for the viral reservoir. Petrovas et al. examined human lymph nodes and tonsils and somewhat surprisingly found that CD8 T cells did infiltrate follicles in HIV-infected individuals. When compared with cells from healthy individuals, these CD8 T cells were less likely to produce cytokines but were still able to kill target cells, especially when cultured with a bispecific antibody to redirect killing toward HIV-infected cells. The use of bispecific antibodies in patients to provoke follicular CD8 T cells may be a path toward a potential HIV cure.
Cytolytic CD8 T cells play a crucial role in the control and elimination of virus-infected cells and are a major focus of HIV cure efforts. However, it has been shown that HIV-specific CD8 T cells are infrequently found within germinal centers (GCs), a predominant site of active and latent HIV infection. We demonstrate that HIV infection induces marked changes in the phenotype, frequency, and localization of CD8 T cells within the lymph node (LN). Significantly increased frequencies of CD8 T cells in the B cell follicles and GCs were found in LNs from treated and untreated HIV-infected individuals. This profile was associated with persistent local immune activation but did not appear to be directly related to local viral replication. Follicular CD8 (fCD8) T cells, despite compromised cytokine polyfunctionality, showed good cytolytic potential characterized by high ex vivo expression of granzyme B and perforin. We used an anti-HIV/anti-CD3 bispecific antibody in a redirected killing assay and found that fCD8 T cells had better killing activity than did non-fCD8 T cells. Our results indicate that CD8 T cells with potent cytolytic activity are recruited to GCs during HIV infection and, if appropriately redirected to kill HIV-infected cells, could be an effective component of an HIV cure strategy.
The ability to eliminate HIV-infected cells in vivo is a major obstacle in the fight to cure HIV infection. Therapeutic vaccination and/or the use of checkpoint inhibitors to improve cytotoxic T lymphocyte (CTL) activity, and thereby augment clearance of HIV-producing cells, have been proposed as interventions that could accomplish better viral clearance in vivo as part of a shock-and-kill strategy (46, 47). For such strategies to be effective, CTLs would need access to the major sites of active HIV replication. Several lines of evidence suggest that the B cell follicle and particularly the GCs serve as major sites for active HIV replication and reactivation of the latent virus reservoir (1-5). Here, we demonstrate that chronic HIV infection is associated with trafficking of highly potent cytolytic CD8 T cells into B cell follicles and GCs. However, despite the presence of potent cytolytic CD8 T cells in follicles, these cells fail to adequately control or eliminate the virus.
Our studies provide a comprehensive analysis of the phenotype, function, localization, and gene signature of CD8 T cell populations in LNs and particularly those in the B cell follicle and GC. We applied several methods to investigate the localization of CD8 T cell populations in LN areas, including flow cytometry and quantitative confocal microscopy. Our quantitative analysis of the imaging data demonstrated a significant increase of fCD8 T cells in LNs from HIV+ individuals, consistent with our flow cytometry data. It was the combined application of multispectral confocal imaging and multiparametric flow cytometry analysis (histo-cytometry) that allowed us to definitively and quantitatively assess T cell populations within anatomically distinct regions of the LN.
The factors that regulate LN CD8 T cell dynamics during HIV infection are not known. GCs are a site of active virus replication (7, 8), and as such, local viral expression could play a role in recruiting CD8 T cells into GCs. Because CD8 T cells do not traffic in response to cognate antigen, but rather to specific chemoattractants, it is likely that virus replication could initiate a cascade, including production of such chemoattractants, that leads to recruitment of bulk fCD8 T cells. However, the low viral expression assessed by p24 staining in the GCs especially in cART-treated donors could, at least in part, explain the relative paucity of HIV-specific CD8 T cells found in these areas.
Our data indicate that local inflammation and immune activation may serve in an antigen-nonspecific manner as the more relevant forces driving the accumulation of CD8 T cells in B cell follicles. This conclusion is supported by (i) the lack of evidence that local HIV antigens act as attractants for CD8 T cells in the GC; (ii) the presence of increased inflammatory cells and CXCL-13, the major ligand for CXCR5, in HIV+ LNs, particularly in the follicular/perifollicular areas; (iii) the significant correlation between CD8 T cells and collagen 1 deposition, a surrogate of inflammation and disease progression (48); (iv) the up-regulation of pathways associated with cell activation in the fCD8 compared to non-fCD8 T cells; and (v) the absence of preferential localization of HIV-specific CD8 T cells in follicular areas, in line with previous reports (1, 3).
Contrary to CD4 T cells (36, 48), a positive correlation between LN CD8 T cells and collagen deposition was found, suggesting that CD4 T cells, but not CD8 T cells, have a distinct dependence on fibroblastic reticular cell-produced homeostatic cytokines [which are progressively lost with increased fibrosis (36)] and that alteration of the normal LN architecture affects CD4 and CD8 T cell populations differently. cART results in reduced immune activation although not to levels observed in HIV-uninfected individuals (49, 50). Our data show that although cART effectively shuts off local viral replication, local inflammatory environment and CXCL-13 levels persist compared to HIV- LNs, as does the accumulation of fCD8 T cells, lending further credence to the conclusion that inflammation, and not virus-specific signals, is primarily responsible for fCD8 T cell accumulation during HIV infection. Further longitudinal studies using LNs from individuals on cART are needed to dissect the cellular mechanisms regulating CD8 T cell trafficking in LN areas.
We found a relatively higher frequency of HIV-specific CD8 T cells expressing a nonfollicular rather than a follicular phenotype, but CD8 T cells were not completely excluded from the GC, as previously suggested (1, 3). Notably, a higher frequency of HIV-specific CD8 T cells in the extrafollicular area could, at least in part, contribute to the lower expression of HIV RNA and DNA in sorted non-TFH versus TFH CD4 cells, in line with previously described data in SIV-infected monkeys (10). Utilization of the SIV model could provide critical information regarding the cellular and molecular mechanisms governing the trafficking of CD8 T cells within the LN areas. Analysis of fCD8 T cells during different stages of infection (acute, early chronic, and late chronic) could provide additional information with respect to the relative impact of the viral replication and immune activation on fCD8 T cell maturation and dynamics.
fCD8 T cells were characterized by impaired cytokine and chemokine polyfunctionality, a profile associated with increased expression of several co-inhibitory surface receptors. Multiple negative regulators of T cell function, such PD-1 and TIGIT, were found on fCD8 T cells even in virally suppressed individuals. In vitro blocking of PD-1/PD-L1 axis increased the capacity of tissue-derived CD8 T cells for cytokine production, indicating that manipulation of checkpoint inhibitors could improve some functions of fCD8 T cells. Furthermore, the complex network of co-inhibitory receptors expressed on fCD8 T cells, even after long-term treatment, indicates that manipulation of multiple co-inhibitory signals may be needed for optimal recovery of their function.
In contrast to their impaired cytokine polyfunctionality, fCD8 T cells express potent cytolytic activity characterized by high ex vivo levels of cytolytic molecules in chronic and long-term treated HIV infection. Our imaging analysis further confirmed the accumulation of GrzB+ fCD8 T cells within the GCs in HIV-infected LNs. However, few of these cells are HIV-specific. To re-direct their killing activity, we used bispecific antibodies and demonstrated that fCD8 T cells have a potent ability to kill HIV-infected targets. Our data suggest that delivery of GrzB and/or Prf is the dominant killing mechanism in this system. We verified the cytolytic activity of fCD8 by using (i) in vitro HIV-infected cells (CEM cell line or sorted tonsil-derived primary TFH CD4 T cells) and (ii) sorted primary TFH cells from HIV+ LNs in our bispecific antibody killing assay. Although tonsils and LNs represent lymphoid organs of different anatomical position and cellularity, fCD8 T cells from both tissue types showed a similar pattern of bispecific antibody-directed killing activity further supporting their inherent cytolytic ability. Our data consistently demonstrated potent killing of HIV-infected cells by fCD8 T cells in the presence of bispecific antibodies.
The presence of follicular cytolytic CD8 T cells in mouse models of chronic infection and HIV was recently reported (12, 13). The expression of CXCR5 was necessary for their trafficking into follicles (12), although their development was critically regulated by the Bcl-6/Blimp1 axis (12, 13). In line with these data (13), we found a higher cytotoxic capacity of fCD8 compared to non-fCD8 T cells despite the expression of co-inhibitory receptors such as PD-1 and 2B4 (12, 13). In addition, when we blocked the PD-1/PD-L1 axis in vitro, we saw an increased capacity of fCD8 T cells to produce cytokines. This is consistent with the significantly higher therapeutic potential of fCD8 T cells that was observed when the PD-1/PD-L1 interaction was blocked in vivo (13).
One major limitation of our study is the absence of longitudinal LN samples that could provide definitive data regarding the role of tissue viral replication and local immune activation in the observed dynamics of fCD8 T cells. An accurate estimation of the disease duration for the tissues tested was also not possible. Therefore, analysis of fCD8 T cells during different stages of infection (acute, early chronic, and late chronic) and disease (progressors versus elite controllers) is needed. Furthermore, in the context of the current study, we were not able to investigate whether the dynamics we observed apply to LNs from different anatomical sites. Future studies using the SIV NHP model could provide critical information regarding these issues.
In line with previous reports (27, 30), our findings justify the further evaluation of bispecific antibodies for the elimination of HIV-infected cells. We should emphasize that this strategy overcomes the relatively low frequency of HIV-specific CD8 T cells in the follicle, the epitope specificity of CTLs within the B cell follicle, or even the potential presence of CTL escape variants within the latent reservoir of HIV (51). Our data indicate that fCD8 T cells persist, and continue to have strong cytolytic capacity, even after long-term suppressive cART. Hence, the use of bispecific antibodies could be considered as part of a shock-and-kill strategy in individuals on long-term suppressive ART. Further development of such a strategy could involve the testing of bispecific antibodies with differential anti-CD3 affinity as well as the inclusion of other specificities targeting surface receptors that are uniquely expressed on fCD8 T cells. The expression pattern of co-inhibitory receptors (PD-1 and TIGIT) on fCD8 T cells indicates that manipulation of checkpoint inhibitors could improve the polyfunctionality of fCD8 T cells in the context of such a strategy. Our data demonstrate an accumulation of fCD8 T cells in chronic HIV and that these cells can act as potent effectors in conjunction with bispecific antibodies as part of a strategy to eliminate HIV-infected cells in vivo.
Coexistence of potent HIV-1 broadly neutralizing antibodies and antibody-sensitive viruses in a viremic controller
Science Translational Medicine Jan 18 2017
Natalia T. Freund,1 Haoqing Wang,2 * Louise Scharf,2 * Lilian Nogueira,1 Joshua A. Horwitz,1 Yotam Bar-On,1 Jovana Golijanin,1 Stuart A. Sievers,2‡ Devin Sok,3 Hui Cai,4 Julio C. Cesar Lorenzi,1 Ariel Halper-Stromberg,1 Ildiko Toth,5 Alicja Piechocka-Trocha,5 Harry B. Gristick,2 Marit J. van Gils,6 Rogier W. Sanders,6 Lai-Xi Wang,4 Michael S. Seaman,7 Dennis R. Burton,3,5 Anna Gazumyan,1 Bruce D. Walker,5,8 Anthony P. West Jr.,2 Pamela J. Bjorkman,2 Michel C. Nussenzweig1,8
"When combined, BG1, BG18, and NC37 durably suppressed viremia in HIV-1YU2-infected humanized mice. Although there are reports of autologous serum neutralization of circulating viruses (70), the role of monoclonal antibodies in HIV-1 control remains uncertain (51, 71-74). Our data indicate that monoclonal bNAbs and very low levels of neutralization-sensitive viruses coexist in EB354, suggesting that antibodies contribute to elite control in this individual.
HIV-1 escapes from monotherapy with bNAbs in humanized mice and humans infused with bNAbs (Fig. 4A) (35, 38, 75-78). In contrast, combination antibody therapy in humanized mice durably suppresses viremia (38, 79). In addition, infected humans treated with antibodies show enhanced humoral immunity (80) and accelerated clearance of infected cells (81), indicating that there may be immunological benefits to this form of therapy. Whether combination antibody therapy will also suppress viremia in humans remains to be determined by clinical studies. However, durable suppression of viremia in EB354 and in humanized mice treated with BG1, BG18, and NC37 suggests that combinations of bNAbs may in fact be able to contain HIV-1 infection in humans."
Antibodies can hold HIV-1 at an impasse
Neutralizing antibodies put selective pressure on pathogens to mutate and escape from immune detection, which is one of the reasons why HIV-1 infection is difficult to contain. In this issue, Freund et al. studied samples spanning almost a decade from an individual who naturally controls HIV-1 infection without progressing to AIDS. They discovered three potent antibodies coexisting with viral strains that were sensitive to antibody neutralization, indicating that these antibodies may be contributing to viral control. These antibodies were also able to prevent HIV-1 viremia in humanized mice, demonstrating that the antibodies may be beneficial as passive immunotherapy for infected individuals.
Some HIV-1-infected patients develop broad and potent HIV-1 neutralizing antibodies (bNAbs) that when passively transferred to mice or macaques can treat or prevent infection. However, bNAbs typically fail to neutralize coexisting autologous viruses due to antibody-mediated selection against sensitive viral strains. We describe an HIV-1 controller expressing HLA-B57*01 and HLA-B27*05 who maintained low viral loads for 30 years after infection and developed broad and potent serologic activity against HIV-1. Neutralization was attributed to three different bNAbs targeting nonoverlapping sites on the HIV-1 envelope trimer (Env). One of the three, BG18, an antibody directed against the glycan-V3 portion of Env, is the most potent member of this class reported to date and, as revealed by crystallography and electron microscopy, recognizes HIV-1 Env in a manner that is distinct from other bNAbs in this class. Single-genome sequencing of HIV-1 from serum samples obtained over a period of 9 years showed a diverse group of circulating viruses, 88.5% (31 of 35) of which remained sensitive to at least one of the temporally coincident autologous bNAbs and the individual's serum. Thus, bNAb-sensitive strains of HIV-1 coexist with potent neutralizing antibodies that target the virus and may contribute to control in this individual. When administered as a mix, the three bNAbs controlled viremia in HIV-1YU2-infected humanized mice. Our finding suggests that combinations of bNAbs may contribute to control of HIV-1 infection.
A fraction of HIV-1-infected individuals develop broadly neutralizing antibodies (bNAbs) that show potent neutralizing activity against a range of different HIV-1 isolates (1-4). bNAbs typically develop over a period of 1 to 3 years during which time there is coevolution of circulating viral strains and antibodies (5-9). Virus and antibody coevolution starts when the infecting virus elicits early antibody responses that exhibit some levels of autologous neutralization (6, 9-11). These early antibodies put pressure on the virus and spur HIV-1 evolution. Viral strains that are sensitive to the antibodies are subjected to negative selection, resulting in the emergence of antibody-resistant HIV-1 variants that are subsequently targeted by coevolving antibody variants (5-7, 9, 12).
The bNAbs that emerge have high levels of somatic mutations, suggesting that B cells that produce bNAbs develop by iterative rounds of antibody gene mutation and selection in germinal centers (2, 5, 6, 13-17). The end result of serial antibody and HIV-1 mutation is bNAbs that neutralize large numbers of heterologous viral variants but normally fail to neutralize autologous circulating viral strains (2, 6-9). Therefore, it is believed that bNAbs that develop during chronic infection are unable to control HIV-1 in the individual who develops them.
To reexamine the question of whether autologous bNAbs can coexist with bNAb-sensitive viruses and contribute to HIV-1 control, we studied an HLA (human leukocyte antigen)-B57*01 HIV-1 controller (18, 19) who developed elite levels of HIV-1 neutralizing activity and maintained low levels of HIV-1 viremia for several years. Here, we describe the neutralizing antibodies that developed in this donor, the coexisting plasma viruses, and show that when combined, these bNAbs can suppress HIV-1 replication and maintain low-level viremia in vivo in HIV-1-infected humanized mice.
Here, we describe a singular HIV-1-infected elite controller, EB354, who was followed prospectively for 9 years. During that time, EB354 donated samples for analysis at five different time points, enabling the isolation of three new bNAbs that account for serologic neutralizing activity and circulating viruses. We find that in this individual, viruses sensitive to the antibodies coexisted with the bNAbs for long periods of time.
BG18, the most potent of the three antibodies isolated from donor EB354, is directed against the Asn332gp120-centered glycan patch at the base of the V3 loop. This is a heavily glycosylated region that is a frequent target for anti-HIV-1 bNAbs, which includes carbohydrates at positions Asn332gp120, Asn301gp120, Asn386gp120, Asn392gp120, Asn137gp120, and Asn156gp120 (1, 4, 27, 31, 41, 42). A number of monoclonal bNAbs that bind to both protein and carbohydrate components at this site have been isolated, including PGT121-124, PGT128-135 (28), 10-1074 and variants (27), and the recently isolated PCDN antibodies (9). BG18 and its clonal variants resemble 10-1074 in that they rely exclusively on Asn332gp120 (27, 31), but BG18 is more potent than published anti-V3 bNAbs and is the first to be isolated from a clade B donor.
The BG18-Env EM structure, although not of sufficient resolution to identify detailed interactions, nevertheless demonstrates that BG18 approaches Env from a different angle, which is shifted by up to 40° toward the gp120 promoter relative to the approach angles of 10-1074 and PGT122 (a closely related variant of PGT121). In addition, the BG18 Fab differs from previously characterized members of this class by a distinctive orientation and a shorter length of its CDRH3. The lack of insertions or deletions in the BG18 CDRH3 suggests that BG18-like antibodies may be easier to elicit by vaccination.
The other two neutralizing specificities, in addition to BG18, are represented by BG1 and NC37. BG1 binds to the V1V2 region of Env, another frequent target of bNAbs arising during natural infection (20), and is the first antibody in this class to be isolated from a clade B-infected donor. Its potency is similar to members of the VRC26 antibody family (43) but is less potent than PG9/16 and PGDM1400 bNAbs. Like other V1V2 bNAbs isolated to date, BG1 has a long, tyrosine-rich CDRH3. The third neutralizing specificity is represented by NC37. NC37 and its clonal variants display sequence characteristics of both VH1-2- and VH1-46-derived bNAbs; however, structural analyses suggest that NC37 recognizes Env in a VH1-46-type manner (21). As a consequence, NC37 uses its light chain to the contact loop D residue Asn280gp120, whereas VH1-2-derived antibodies such as NIH45-46 use their heavy chains to contact Asn280gp120 (40, 44, 45). Superposing the NC37 Fab-gp120 complex onto an SOSIP.664 trimer structure suggests that the long NC37 CDRH3 makes contacts with the adjacent protomer within the Env trimer, thus NC37 recognizes a quaternary trimer epitope, the core of which overlaps with the CD4bs.
Most individuals rapidly develop strain-specific antibodies shortly after infection (6, 10, 15, 46-48). This response is associated with selection for resistant viral variants that, in some cases, elicit bNAbs (5, 12, 31, 49-51). However, the individuals studied in detail differ from EB354 in that the development of bNAbs is associated with rapid selection of autologous plasma viruses, which are resistant to coexisting bNAbs (6-9, 52, 53). Donor EB354 is significant because sensitive and resistant viral strains coexist with bNAbs, and the resistant strains fail to produce high levels of viremia because the viral strains are either in some way partially effective or kept in check by CD8+ T cells. Thus, the bNAb-sensitive plasma viruses were unable to escape immune pressure in this individual, resulting in bNAb:virus equilibrium, where the virus persists but is incapable of producing high levels of viremia.
EB354 is unusual in being both an elite controller and elite neutralizer. HIV-1 elite controllers are infected individuals who maintain low viral loads for many years (54-56). These individuals are less likely to transmit the virus (57), and they maintain long-term AIDS-free survival (58). HLA alleles B57*01 and/or B27*05 are found in 85% of HIV-1 elite controllers (19, 59), and these alleles are associated with enhanced CD8 T cell cytotoxic activity (18). Compared to viremic progressors (that is, patients with high viral loads), elite controllers are less likely to develop bNAbs (60-66). Irrespective of robust CD8+ T cell responses that may have partially controlled infection, there was sufficient HIV-1 replication in EB354 to support bNAb development and affinity maturation.
Like several other individuals who develop serologic breadth and potency, the bNAbs that account for serologic neutralizing activity in donor EB354 recognize several nonoverlapping epitopes (5, 20, 21, 67-69). In some well-documented cases, the emergence of one bNAb lineage facilitates the development of a second one by selecting for escape variants that expose areas on Env that support further development of additional bNAbs (52). Although samples are not available to test this idea, BG1 was the earliest bNAb lineage to emerge in EB354 and may also have been a helper lineage for NC37 and/or BG18.
When combined, BG1, BG18, and NC37 durably suppressed viremia in HIV-1YU2-infected humanized mice. Although there are reports of autologous serum neutralization of circulating viruses (70), the role of monoclonal antibodies in HIV-1 control remains uncertain (51, 71-74). Our data indicate that monoclonal bNAbs and very low levels of neutralization-sensitive viruses coexist in EB354, suggesting that antibodies contribute to elite control in this individual.
HIV-1 escapes from monotherapy with bNAbs in humanized mice and humans infused with bNAbs (Fig. 4A) (35, 38, 75-78). In contrast, combination antibody therapy in humanized mice durably suppresses viremia (38, 79). In addition, infected humans treated with antibodies show enhanced humoral immunity (80) and accelerated clearance of infected cells (81), indicating that there may be immunological benefits to this form of therapy. Whether combination antibody therapy will also suppress viremia in humans remains to be determined by clinical studies. However, durable suppression of viremia in EB354 and in humanized mice treated with BG1, BG18, and NC37 suggests that combinations of bNAbs may in fact be able to contain HIV-1 infection in humans.