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Journal of Virology, November 2001, p. 10200-10207, Vol. 75, No. 21
Department of Surgery, Duke University Medical Center,
Durham, North Carolina 27710,1 and
Partners AIDS Research Center and Infectious Disease
Division, Massachusetts General Hospital and Harvard Medical
School, Boston, Massachusetts 021142
Received 31 May 2001/Accepted 27 July 2001
Immediate treatment of acute human immunodeficiency virus type 1 (HIV-1) infection has been associated with subsequent control of
viremia in a subset of patients after therapy cessation, but the immune
responses contributing to control have not been fully defined. Here we
examined neutralizing antibodies as a correlate of viremia control
following treatment interruption in HIV-1-infected individuals in whom
highly active antiretriviral therapy (HAART) was initiated during early
seroconversion and who remained on therapy for 1 to 3 years.
Immediately following treatment interruption, neutralizing antibodies
were undetectable with T-cell-line adapted strains and the autologous
primary HIV-1 isolate in seven of nine subjects. Env- and Gag-specific
antibodies as measured by enzyme-linked immunosorbent assay were also
low or undetectable at this time. Despite this apparent poor maturation
of the virus-specific B-cell response during HAART, autologous
neutralizing antibodies emerged rapidly and correlated with a
spontaneous downregulation in rebound viremia following treatment
interruption in three subjects. Control of rebound viremia was seen in
other subjects in the absence of detectable neutralizing antibodies.
The results indicate that virus-specific B-cell priming occurs despite
the early institution of HAART, allowing rapid secondary
neutralizing-antibody production following treatment interruption in a
subset of individuals. Since early HAART limits viral diversification,
we hypothesize that potent neutralizing-antibody responses to
autologous virus are able to mature and that in some persons these
responses contribute to the control of plasma viremia after treatment cessation.
Results of passive-antibody
studies in nonhuman primate models of pathogenic simian
immunodeficiency virus (SIV) and simian-human immunodeficiency viruses
(SHIV) have shown that neutralizing antibodies can block infection
completely when present at the time of virus exposure or shortly
thereafter (9, 14, 23, 24, 37). The same may be true for
human immunodeficiency virus type 1 (HIV-1) infection in humans. It
remains less certain whether neutralizing antibodies exert a clinically
beneficial impact on the virus after infection has been established.
For example, neutralizing-antibody production is delayed in
HIV-1-infected individuals to an extent that it is not detected until
weeks or months after the initial downregulation in peak plasma viremia
that occurs during primary infection (2, 16, 27, 33, 34).
Existing information on the virologic and immunologic profile of
primary HIV-1 infection strongly indicate that virus-specific
CD8+ cytotoxic T lymphocytes (CTL) are the major mediators
of early viremia control (7, 10, 16, 31), but these CTL
ultimately fail to prevent immunologic suppression and AIDS in the
absence of antiretroviral therapy. Any means of augmenting the
neutralizing-antibody response to episodes of increased viremia,
whether in the acute or chronic phase of HIV-1 infection, might have a
clinical benefit when added to the antiviral CTL response.
Early effective treatment with highly active antiretroviral therapy
(HAART) influences the immune response to HIV-1 infection. This leads
to augmented T-helper-cell responses (21, 30, 36), presumably by limiting or preventing the immunologic dysfunction caused
by infection (3, 30, 38). HIV-1-specific helper T cells
are associated with viremia control in nontreated individuals (36), probably through augmentation of CTL responses.
Anecdotal reports and now prospective trials showing at least temporary virus containment following treatment interruption (19,
29) have led to a growing interest in immune-based interventions
as an adjunct to HAART.
Efforts to develop effective immune intervention strategies for HIV-1
would benefit from a more complete understanding of the functional
immune responses that correlate with viremia control following
treatment interruption. In this regard, little is know about the effect
of HAART on the virus-specific neutralizing-antibody response. The
observation that HAART can preserve and restore normal B-cell functions
(12, 28) suggests a possible benefit for the
virus-specific antibody response. Contrary to this notion, however,
current evidence suggests that the B-cell response wanes when HAART is
initiated during chronic infection and fails to mature when HAART is
begun early in infection (17, 20, 22, 28). In the few
cases where neutralizing antibodies were examined, widely disparate
effects of HAART have been observed (6, 13, 19, 29).
Interestingly, anecdotal cases of an improved neutralizing-antibody response in a small number of HIV-1-infected individuals who were intermittently nonadherent to HAART have been reported (6, 29).
Recently, a group of HIV-1-infected individuals in whom HAART was
initiated early in infection and who later underwent one or more
supervised treatment interruptions exhibited a spontaneous reduction in
their rebound viremia (35). This viremia control was
associated with maintenance of virus-specific T-helper-cell responses
and an increase in virus-specific CD8+ T-cell responses.
Moreover, analysis of autologous virus in these individuals indicated
that early treatment impaired viral diversification, suggesting that at
least some of the improved control in these individuals might be due to
a more homogeneous virus population with less opportunity for immune
escape (1). Here we establish that in addition to cellular
immunity, neutralizing antibodies are associated with viremia control
in a subset of individuals treated in the earliest stages of acute
infection and in whom therapy is discontinued. Since early therapy
prevents viral diversification (1), we hypothesize that
treatment allowed the maturation of a strain-specific response that was
able to control the homogeneous virus population that emerged when
therapy was stopped.
Subjects.
Nine individuals who were identified with
symptomatic acute HIV-1 infection and in whom HAART was initiated at
the time of their diagnosis (35) were selected for study.
These subjects belonged to a larger cohort and were selected because
they showed evidence of viremia control following one or more
structured treatment interruptions. Antiretroviral regimens consisted
of two nucleoside reverse transcriptase inhibitors combined with a
protease inhibitor (Table 1). HAART was
discontinued for the first time after 1 to 3 years of treatment and
reinitiated if plasma viral loads exceeded either 5,000 RNA copies/ml
for three consecutive weeks or 50,000 RNA copies/ml at one time point.
All individuals suppressed plasma viremia to a level below the limit of
detection (<50 RNA copies/ml) for a minimum of 8 months prior to
treatment interruption and showed no evidence of mutations conferring
drug resistance (35). Moreover, all subjects had
HIV-1-specific T-helper-cell function that exceeded a stimulation index
of 10 and net counts per minute of
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.21.10200-10207.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Neutralizing Antibodies Associated with Viremia
Control in a Subset of Individuals after Treatment of Acute Human
Immunodeficiency Virus Type 1 Infection
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
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Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
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Introduction
Materials and Methods
Results
Discussion
References
800 prior to treatment
interruption (35).
TABLE 1.
Description of subjects
Virus isolation and phenotyping.
HIV-1 was isolated from
each subject by peripheral blood mononuclear cell (PBMC) coculture as
described previously (25). Virus-containing culture fluids
collected at the time of peak p24 Gag antigen production were made cell
free by 0.45-µm-pore-size filtration and stored at 
80°C in 1-ml
aliquots. All assays were performed with virus either in the original
isolation fluids or after a single passage in PBMC. Biologic phenotypes
were assigned in accordance with established nomenclature
(4) and were based on the differential infection of MT-2,
U87-CD4-CCR5, and U87-CD4-CXCR4 cells (15) as measured by
p24 Gag protein synthesis. Virus was isolated prior to the first
treatment-interruption from subjects AC-10, AC-06, AC-16, AC-14 and
AC-02. A second isolate from subject AC-10 was obtained during a brief
episode of rebound plasma viremia following treatment interruption (1.5 months). Virus from the remaining subjects was isolated 1.5 months into
the second treatment phase (AC-13), 1 week after the third treatment
interruption (AC-05), 3 weeks after the second treatment interruption
(AC-04), and 4.7 months into the fourth treatment phase (AC-01). All
viruses exhibited an R5 biologic phenotype with the exception of the
virus from subject AC-04, which exhibited an X4 phenotype.
Neutralizing-antibody assays. Antibody-mediated neutralization of the subjects' HIV-1 isolates was assessed in phytohemagglutinin (PHA)-stimulated PBMC by using a reduction in p24 production as described previously with minor modifications (25). Briefly, cell-free virions (500 50% tissue culture infectious doses) were incubated with various dilutions of plasma for 1 h at 37°C in triplicate prior to the addition of 1-day-old PHA-stimulated PBMC. The cells were washed 4 h later and incubated in fresh interleukin-2-containing growth medium. The concentration of HIV-1 p24 Gag antigen in culture supernatants was measured in an antigen capture enzyme-linked immunosorbent assay (ELISA) (DuPont/NEN) at a time when p24 production in the absence of test plasma was in an early linear phase of increase (usually 3 to 4 days), which is when optimal sensitivity is achieved (39). Neutralization was considered positive when p24 production was reduced by at least 80% relative to the corresponding dilution of a negative control plasma sample from a healtly, noninfected individual. Neutralization of HIV-1IIIB and HIV-1MN was measured in MT-2 cells as described previously (26). Neutralization titers in the MT-2 assay were defined as the plasma dilution at which 50% of cells were protected from virus-induced killing as measured by neutral red uptake. A 50% protection from cell killing corresponds to an approximate 90% reduction in p24 Gag antigen synthesis in the MT-2 assay (8).
ELISA. HIV-1 Env- and Gag-specific binding antibodies were assessed in Immuno Plates (MaxiSorb F96) (Nunc, Roskilde, Denmark) coated with either baculovirus-derived HIV-1MNgp120 or HIV-1IIIBp24 (Quality Biologicals, Inc., Gaithersburg, Md.) at 0.5 µg/ml as described previously (11).
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RESULTS |
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Materials and Methods
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Neutralizing antibodies prior to treatment interruption in treated acute infection. Neutralizing antibodies were first examined with T-cell-line-adapted (TCLA) strains and the autologous primary HIV-1 isolate. Initial results with TCLA strains gave a strong indication that the concentration of antiretroviral drugs in plasma samples was sufficient to inhibit HIV-1 in vitro, an activity that could be mistaken for the presence of neutralizing antibodies. Specifically, plasma samples from subjects who were on therapy inhibited HIV-1IIIB and HIV-1MN at high dilutions (1:100 to 1:2,000) despite having low-level or absent MNgp120-specific antibodies as detected by ELISA (data not shown). Furthermore, their plasma had little or no antiviral activity within 14 days following treatment interruption but the activity returned and was sustained soon after HAART was reinitiated (data not shown), indicating the presence in plasma of drug that was affecting the measurement of neutralizing antibodies.
To distinguish between the activity of antiretroviral drugs and neutralizing antibodies, all subsequent assays were performed on plasma samples obtained during treatment interruption, and it is only these data that are presented here. The earliest plasma sample following the first treatment interruption (2 to 35 days) in six of eight subjects had no detectable neutralizing antibodies even though these individuals had been infected for at least 1 to 3 years (Fig. 1 and 2). This was true for neutralizing antibodies measured with either the autologous virus isolate or highly neutralization-sensitive TCLA strains of HIV-1. Moreover, these samples had little or no detectable gp120-specific and p24-specific binding antibodies (Fig. 3). These results suggest that HAART uniformly suppressed the virus-specific antibody response in those subjects. One additional subject in the treatment group had a low neutralizing-antibody titer to HIV-1 MN (AC-13), while another subject had detectable neutralizing antibodies to all three TCLA strains and his autologous virus (AC-01). Serum samples were unavailable for the ninth individual (AC-02) following the first interruption of therapy. The overall poor antibody responses in most subjects was in marked contrast to their T-helper-cell and CTL responses, which were clearly detectable in all (35). Negative neutralization results in many subjects confirmed the clearance of antiretroviral drugs by the time the first samples were obtained post-therapy (minimum of 2 days [AC-16]).
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Neutralizing antibodies in persons in whom viremia was controlled following initial treatment cessation. Most previous studies of untreated acute HIV infection failed to detect neutralizing antibodies at the time when peak viremia was brought under control (2, 16, 18, 27, 33, 34). The presence of detectable CTL has been used as evidence that cellular immunity is largely contributing to viral containment in most cases (7, 10, 16, 31). We first examined an individual (AC-10) who achieved viral control after a single treatment interruption. This person was selected for initial analysis because only a modest and slowly developing CTL response directed against a single epitope was detected (35). Titers of autologous neutralizing antibodies in this individual were undetectable immediately following treatment cessation but soon rose to a titer of greater than 1:300 as peak viremia began to decline (Fig. 1). Interestingly, the presence of these autologous neutralizing antibodies was not predicted by MNgp120-specific ELISA reactivities, which were negative at the peak of the neutralizing-antibody response and rose only slightly therafter (Fig. 3). The strong autologous neutralizing activities of plasma samples from subject AC-10 shown in Fig. 1 were measured with virus isolated at the time of rebound viremia. These plasma samples had similar neutralization potencies when assayed with the virus variant isolated at the time of diagnosis (1.5 years earlier [data not shown]), suggesting that little or no changes occurred in the neutralization determinants of this subject's virus while he was on HAART. Of note, no neutralizing antibodies were detected with TCLA strains until approximately 6 weeks after the first detection of autologous neutralizing antibodies (Fig. 1). The coincident increase of autologous neutralizing antibodies at the time the viral load was decreasing is consistent with the hypothesis that these antibodies contributed to virus suppression in this individual. Moreover, the development of a strong secondary neutralizing-antibody response and the kinetics of this response indicate that it was primed during the initial infection.
Because plasma from subject AC-10 had potent autologous virus-specific neutralizing activity, we tested whether the sample could cross-neutralize heterologous primary HIV-1 isolates. The plasma failed to neutralize HIV-1 isolates from subjects AC-06, AC-16, AC-05, and AC-04 when tested at a 1:4 dilution and, in an extended analysis, neutralized 5 of an additional 50 heterologous primary isolates when tested at a 1:20 dilution (data not shown). These results indicate that the neutralizing antibodies had minimal cross-reactivity. Autologous neutralizing antibodies were examined in a second subject (AC-16) in whom viremia was controlled following the first cessation of HAART, but the pattern was quite different in this person. This individual developed strong and broadly directed CTL responses with treatment interruption, and the increase in CTL responses was coincident with the drop in viremia (35). In contrast, neutralizing antibodies to TCLA viruses as well as autologous virus were undetectable at all time points tested (Fig. 2), as were Env-specific binding antibodies (Fig. 3). Low but gradually increasing levels of Gag-specific binding antibodies were observed (Fig. 3) as additional evidence that virus was replicating at low levels. An early peak in viremia was associated with an increase in the breadth and magnitude of CTL responses (35), but despite continued low-level viral replication, there were no detectable neutralizing antibodies. Thus, these data indicate that prolonged control of viremia can occur in the absence of detectable neutralizing antibodies, suggesting that cellular immune responses alone can control viremia under certain circumstances.Neutralizing-antibody detection following multiple treatment interruptions. Seven of the nine persons in this study did not show control of their viremia with the first treatment interruption and therefore underwent additional courses of therapy and interruptions. Because therapy was reinitiated in these subjects, it is not known if the virus would have been controlled after a longer period of treatment cessation. Nonetheless, four of these individuals (AC-06, AC-13, AC-14, and AC-02) went on to show control of viremia after the second treatment interruption. In three of these persons for whom assays were completed during the first treatment interruption, no neutralizing antibodies were detected in two (AC-06, and AC-14) and only low titers of neutralizing antibodies to HIV-1MN and the autologous virus were detected in one (AC-13) prior to the reinitiation of treatment (Fig. 1 and 2). In contrast, with the second interruption, two subjects developed autologous neutralizing-antibody responses (AC-06 and AC-13) that coincided with the drop in viremia and persisted as viremia continued to be controlled. These responses peaked at titers of 1:8 and 1:25, respectively, and thus were less robust than those seen in subject AC-10. However, in both persons they increased as the viral load decreased. The rebound in viremia and the appearance of detectable neutralizing antibodies were accompanied by an increase in ELISA reactivity to HIV-1 Env and Gag in all four subjects, and the magnitude of Env-specific reactivity was greatest in AC-06 and AC-13 (Fig. 3).
Two additional subjects (AC-05 and AC-04) exhibited a transient downregulation in their rebound viremia during a second period of treatment interruption despite the absence of autologous neutralizing antibodies. Both subjects exhibited an increase in the level of Gag-specific antibodies coincident with rebound viremia (Fig. 3). An increase in the level of Env-specific antibodies was most notable in subject AC-05, who developed high-titer neutralizing antibodies to HIV-1MN. The lack of autologous neutralizing antibodies suggests that CTL (35) or other immune responses played a major antiviral role in these two subjects. A final subject (AC-01) underwent three treatment interruptions, the last two being accompanied by a lower level of rebound viremia suggestive of increasing immune control. This individual possessed autologous neutralizing antibodies during each treatment interruption (Fig. 2) and his serum had strong ELISA reactivity to HIV-1 Env and Gag, which appeared to boost during therapy (Fig. 3). It is notable that the neutralizing antibodies were always detected with a late virus isolate (4.7 months into the fourth treatment phase, which is after the last plasma sample examined here). The ability of early plasma samples to neutralize a later virus isolate suggests that the neutralization determinants remained unchanged during the course of study. Alternatively, this individual might possess neutralizing antibodies to a highly conserved neutralization determinant.| |
DISCUSSION |
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Materials and Methods
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Discussion
References
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The results presented here indicate that immediate treatment of acute HIV-1 infection not only results in low levels of HIV-1-specific binding antibodies detected by ELISA but also retards the development of detectable neutralizing-antibody responses. Typically, much stronger seroconversion is seen within 1 year of infection in the absence of HAART, including the presence of detectable neutralizing antibodies (27, 33, 34). We conclude that early HAART has a suppressive effect on the normal antibody response to HIV-1, presumably by limiting the concentration of viral antigens needed to drive virus-specific B-cell maturation.
Despite weak antibody responses while on HAART, autologous
neutralizing-antibody production commenced rapidly and correlated with
a downregulation in rebound viremia following treatment interruption in
three individuals. The fact that autologous neutralizing antibodies are
rarely detected as peak viremia is downregulated during primary infection in patients who do not receive HAART (2, 16, 18, 27,
33, 34) suggests that a secondary neutralizing-antibody response
was operating in these three subjects. A secondary antibody response
was most probably primed early in infection, before viremia was brought
under control by HAART. The preservation and possible augmentation of
this priming while on HAART, combined with a lack of viral evolution,
might explain the rapid secondary neutralizing-antibody response to
rebound viremia (Fig. 4). The ability of
those antibodies to neutralize the autologous virus isolate makes it
possible that they contributed to immune control of viremia.
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The potency of the secondary neutralizing-antibody response varied considerably among the three subjects mentioned above, as did the magnitude and longevity of viremia control. The net immunologic effect on the virus most probably reflects combined activities of virus-specific CTL, neutralizing antibodies, and other inducible antiviral mechanisms, such as cytokine and chemokine production. While we cannot be certain of the relative contributions of CTL and neutralizing antibodies to the control of viremia in these subjects, it is worth noting that a potent autologous neutralizing-antibody response was seen in subject AC-10, who had limited virus-specific CTL and maintained low virus loads for at least 230 days following treatment interruption. Subjects AC-06 and AC-13, who had less potent autologous neutralizing antibodies but strong CTL, also maintained low virus loads for an extended period.
Rebound viremia failed to generate a secondary autologous neutralizing-antibody response in other subjects. In these cases, the control of viremia may be attributed to a vigorous virus-specific CD8+ CTL response (35). Antibodies that neutralize TCLA strains of virus were sometimes detected in these latter individuals, but it is doubtful that such antibodies were effective (32). It is not clear why autologous neutralizing antibodies were detected in some individuals but not others. We saw no evidence that neutralizing-antibody induction was related to the magnitude of rebound viremia. Other possible explanations include (i) the extent of B-cell priming before and during HAART; (ii) the degree of immune function preservation, restoration, and augmentation while on HAART; (iii) the relative immunogenicity of the major neutralization determinant(s) on the emerging virus variant; and (iv) host genetic factors. HIV-1 Gag-specific T-helper-cell responses in all study participants were either maintained or augmented while they were on HAART (35), and although not investigated here, it is possible that similar Env-specific T-helper-cell responses played a role in neutralizing-antibody induction. Is has been suggested, however, that Gag-specific but not Env-specific antibody responses are T-cell dependent (5). Clearly, additional work is needed to clarify the role of T-cell help in eliciting HIV-1-specific neutralizing antibodies.
Our observations suggest that appropriate virus-specific B-cell priming can lead to rapid and effective secondary neutralizing-antibody production in response to episodes of viremia in HIV-1-infected individuals. This may be especially true in cases where immune cell functions are preserved, virus specific T-cell responses are generated, and viral genetic diversification has been limited. Efforts to boost the neutralizing-antibody response by therapeutic exposure to appropriate HIV-1 Env immunogens in patients on HAART seem warranted, especially in cases where HAART is intiated early in infection. These results also support the notion that virus-specific B-cell priming, combined with CD8+ CTL induction, may be beneficial for HIV-1 vaccines that aim to suppress viremia in the absence of complete protection to prevent disease and reduce the rate of virus transmission.
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ACKNOWLEDGMENTS |
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We gratefully acknowledge the HIV-1-infected individuals who participated in this study.
This work was funded by National Institutes of Health grants AI40237 (D.C.M.) and AI01541 (E.S.R.), with further support from the Doris Duke Charitable Foundation (B.D.W. and E.S.R.)
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Surgery, Box 2926, Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-5278. Fax: (919) 684-4288. E-mail: monte{at}duke.edu.
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Discussion
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Journal of Virology, November 2001, p. 10200-10207, Vol. 75, No. 21
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.21.10200-10207.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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